Glycan compositions and methods of use

Abstract

Compositions, such as pharmaceutical compositions, nutritional compositions, medical foods, and food ingredients, and methods of use thereof for modulating exogenous substances, enzyme activity, and drug activity are provided.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Patent Application No. 62 / 361,998, filed July 13, 2016, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Maintaining or restoring human health faces many challenges due to the lack of effective treatment options. Novel therapies and treatment regimens are continually needed. Summary of the Invention [Means for solving the problem]

[0003] For example, processing of an exogenous substance, such as a drug, drug metabolite, drug additive, food, food additive, allergen, toxin, or poison, can be carried out in a subject by mammalian and / or microbial machinery. In some cases, processing of an exogenous substance can be mediated by the subject's microbial components, such as, for example, microorganisms in the subject's gut. For example, adjusting the processing, such as microbial-mediated processing, of an exogenous substance can alter the effect of the exogenous substance or its processed form on the subject.

[0004] The methods, compositions, kits, etc. described herein are based, at least in part, on the discovery that glycan compositions can alter how microorganisms (e.g., gut microorganisms) mediate the processing of exogenous substrates in a subject, e.g., a human subject. In one embodiment, the glycan composition regulates microbial-mediated processing by increasing or decreasing the number or abundance of microorganisms, e.g., bacterial taxa. In one embodiment, the glycan composition regulates microbial-mediated processing by increasing or decreasing the activity or level of a microbial component or product, e.g., an enzyme or metabolic product produced by a microorganism. In one embodiment, the glycan composition increases or decreases the transcription of an enzyme or other microbial protein (e.g., one or more protein components of a pathway, such as a metabolic pathway) that alters the activity of the microorganism.

[0005] In one aspect, the present invention provides a method of increasing drug activity in a subject, comprising: a) administering a glycan composition in an amount and for a period of time effective to increase drug activity in a subject; b) administering the glycan composition in an amount and for a time sufficient to increase the activity of the drug in the subject, wherein the subject contains a level of the drug at the time of administration of the glycan composition that provides a therapeutic effect in the presence of the administered glycan composition; c) administering a drug, wherein at the time of administration of the drug, the subject has already been administered a glycan composition in an amount and for a sufficient time to increase the activity of the drug in the subject; d) administering the drug in an amount and for a time sufficient to increase the activity of the drug in the subject, the subject being determined to be in need of the glycan composition, e.g., to increase the activity of the drug; or e) administering a drug and a glycan composition to a subject in an amount and for a time sufficient to increase the activity of the drug in the subject, wherein the administration of the drug and the glycan composition overlaps. Including, i) the glycan preparation comprises a glycan polymer comprising a glycan unit of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; ii) the average degree of branching (DB) of the glycan polymers in the glycan preparation is 0, 0.01-0.6, 0.05-0.5, 0.1-0.4, or 0.15-0.4; iii) at least 50% (at least 60%, 65%, 70%, 75%, 80%, or 85%, or less than 50%) of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, at least 3 and less than 10 glycan units, at least 5 and less than 25 glycan units, or at least 10 and less than 35 glycan units; iv) the average DP (average DP) of the glycan preparation is about 5-8, about 8-13, about 13-25, about 5-15, about 5-20, or about 5-15; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is 0, or about 0.8:1 to about 5:1, about 1:1 to about 5:1, about 1:1 to about 3:1, about 3:2 to about 2:1, or about 3:2 to about 3:1; vi) the glycan preparation contains 15 mol% to 75 mol% (20 mol% to 60 mol%, 25 mol% to 50 mol%, or 30 mol% to 45 mol%) of 1,6 glycosidic bonds; vii) the glycan preparation contains at least one, two, or three 1,2 glycosidic bonds, 1,3 glycosidic bonds, and 1,4 glycosidic bonds in an amount of 1 mol% to 40 mol% (1 mol% to 30 mol%, 5 mol% to 25 mol%, 10 mol% to 20 mol%), respectively; viii) the glycan preparation has a final solubility limit in water of at least about 50 (at least about 60, 70, at least about 75, or less than 50) Brix at 23°C; ix) the glycan preparation has a dietary fiber content of at least 50% (at least 60%, 70%, 80%, or at least 90%, or less than 50%); or x) any combination of two, three, four, five, six, seven, eight, or nine of i), ii), iii), iv), v), vi), vii), viii), viii), and ix); and Drugs are i) Cardiac glycosides; ii) sulfonamides; iii) a nucleoside analog; or iv) aminosalicylates Contains, or Drugs are -Nonsteroidal anti-inflammatory (NSAID) drugs; - chemotherapeutic drugs, or generally drugs that have an antiproliferative effect on target cells (e.g. cancer cells); -Antibiotics or antimicrobials; -Antifungal agents; -Antiparasitic agents, e.g., antinematodic drugs; -hormone; - sedatives; -cardiac medications; -hypertension medication; -Colony-stimulating factors; -Dopamine; -Opioid receptor agonists; -Statins; -Central nervous system stimulants; -sensitizers / radiotherapeutic agents; - Narcotic painkillers; -hypnotic drugs; -antacids; - Painkillers; -Uricase inhibitors; -Antipsychotics; -Laxatives; or Neurotrophic factors, e.g., anticonvulsants The method is characterized.

[0006] In another aspect, the invention provides a method of increasing the activity of a substance, e.g., a phytoestrogen or polyphenol, in an ingested substance, e.g., a food, dietary supplement, or medical food, in a subject, e.g., a human subject, comprising: a) administering a glycan composition in an amount and for a sufficient time to increase the activity of an ingested substance, such as a phytoestrogen or polyphenol, in a subject; b) administering the glycan composition in an amount and for a time sufficient to increase the activity of the ingested substance, e.g., a phytoestrogen or polyphenol, in the subject, wherein upon administration of the glycan composition, the subject contains a level of the ingested substance, e.g., a phytoestrogen or polyphenol, that provides an increase, e.g., a beneficial increase, in the activity of the ingested substance, e.g., a phytoestrogen or polyphenol, in the presence of the administered glycan composition; c) administering an ingested substance, such as a phytoestrogen or polyphenol, wherein the subject has already been administered a glycan composition in an amount and for a sufficient time to increase the activity of the ingested substance, such as a phytoestrogen or polyphenol, in the subject at the time of administration of the ingested substance; d) administering an ingestible substance, such as a phytoestrogen or polyphenol, to a subject determined to be in need of a glycan composition; or e) The ingested substance, such as a phytoestrogen or polyphenol, and the glycan composition are administered to the subject in an amount and for a time sufficient to increase the activity of the drug in the subject, wherein the administration of the drug and the glycan composition overlap. Including, i) the glycan preparation comprises a glycan polymer comprising a glycan unit of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; ii) the average degree of branching (DB) of the glycan polymers in the glycan preparation is 0, 0.01-0.6, 0.05-0.5, 0.1-0.4, or 0.15-0.4; iii) at least 50% (at least 60%, 65%, 70%, 75%, 80%, or 85%, or less than 50%) of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, at least 3 and less than 10 glycan units, at least 5 and less than 25 glycan units, or at least 10 and less than 35 glycan units; iv) the average DP (average DP) of the glycan preparation is about 5-8, about 8-13, about 13-25, about 5-15, about 5-20, or about 5-15; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is 0, or about 0.8:1 to about 5:1, about 1:1 to about 5:1, about 1:1 to about 3:1, about 3:2 to about 2:1, or about 3:2 to about 3:1; vi) the glycan preparation contains 15 mol% to 75 mol% (20 mol% to 60 mol%, 25 mol% to 50 mol%, or 30 mol% to 45 mol%) of 1,6 glycosidic bonds; vii) the glycan preparation contains at least one, two, or three 1,2 glycosidic bonds, 1,3 glycosidic bonds, and 1,4 glycosidic bonds in an amount of 1 mol% to 40 mol% (1 mol% to 30 mol%, 5 mol% to 25 mol%, 10 mol% to 20 mol%), respectively; viii) the glycan preparation has a final solubility limit in water of at least about 50 (at least about 60, 70, at least about 75, or less than 50) Brix at 23°C; ix) the glycan preparation has a dietary fiber content of at least 50% (at least 60%, 70%, 80%, or at least 90%, or less than 50%); or x) Any combination of two, three, four, five, six, seven, eight, or nine of i), ii), iii), iv), v), vi), vii), viii), viii), and ix). is The method is characterized.

[0007] In another aspect, the present invention provides a method of reducing the toxic activity of a substance, e.g., a heterocyclic amine (HCA) or a polycyclic aromatic hydrocarbon (PAH), in an ingested substance, e.g., a food, dietary supplement, or medical food, in a subject, e.g., a human subject, comprising: a) administering a glycan composition in an amount and for a period of time effective to reduce the toxic activity of an ingested substance, such as an HCA or PAH, in a subject; b) administering the glycan composition in an amount and for a time sufficient to reduce the toxic activity of the ingested substance, e.g., HCA or PAH, in the subject, wherein the glycan composition is administered in an amount effective to reduce the toxic activity of the ingested substance, e.g., HCA or PAH, in the presence of the administered glycan composition, the subject contains a level of the ingested substance, e.g., HCA or PAH, that provides a reduction, e.g., a beneficial reduction, in the toxic activity of the ingested substance, e.g., HCA or PAH; c) administering an ingested substance, such as an HCA or PAH, wherein the subject has already been administered a glycan composition in an amount and for a sufficient time to reduce the toxic activity of the ingested substance, such as an HCA or PAH, in the subject at the time of administration of the ingested substance, such as an HCA or PAH; d) administering an ingested substance, such as an HCA or PAH, to a subject who is determined to be in need of a glycan composition; or e) administering to the subject an ingested substance, such as an HCA or PAH, and a glycan composition in an amount and for a time sufficient to reduce the toxic activity of the ingested substance, such as an HCA or PAH, in the subject, wherein the administration of the drug and the ingested substance, such as an HCA or PAH composition, overlaps. Including, i) the glycan preparation comprises a glycan polymer comprising a glycan unit of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; ii) the average degree of branching (DB) of the glycan polymers in the glycan preparation is 0, 0.01-0.6, 0.05-0.5, 0.1-0.4, or 0.15-0.4; iii) at least 50% (at least 60%, 65%, 70%, 75%, 80%, or 85%, or less than 50%) of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, at least 3 and less than 10 glycan units, at least 5 and less than 25 glycan units, or at least 10 and less than 35 glycan units; iv) the average DP (average DP) of the glycan preparation is about 5-8, about 8-13, about 13-25, about 5-15, about 5-20, or about 5-15; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is 0, or about 0.8:1 to about 5:1, about 1:1 to about 5:1, about 1:1 to about 3:1, about 3:2 to about 2:1, or about 3:2 to about 3:1; vi) the glycan preparation contains 15 mol% to 75 mol% (20 mol% to 60 mol%, 25 mol% to 50 mol%, or 30 mol% to 45 mol%) of 1,6 glycosidic bonds; vii) the glycan preparation contains at least one, two, or three 1,2 glycosidic bonds, 1,3 glycosidic bonds, and 1,4 glycosidic bonds in an amount of 1 mol% to 40 mol% (1 mol% to 30 mol%, 5 mol% to 25 mol%, 10 mol% to 20 mol%), respectively; viii) the glycan preparation has a final solubility limit in water of at least about 50 (at least about 60, 70, at least about 75, or less than 50) Brix at 23°C; ix) the glycan preparation has a dietary fiber content of at least 50% (at least 60%, 70%, 80%, or at least 90%, or less than 50%); or x) Any combination of two, three, four, five, six, seven, eight, or nine of i), ii), iii), iv), v), vi), vii), viii), viii), and ix). is The method is characterized.

[0008] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (i) a method for modulating the processing of an exogenous substance in a subject (modulation of processing); or (ii) A method for modulating enzyme activity (modulating activity) in the digestive tract of a subject And, a) administering a glycan composition in an amount and for a time sufficient to regulate a process or activity in a subject; b) administering the glycan composition in an amount and for a time sufficient to regulate a process or activity in the subject, wherein the subject contains an exogenous substance or enzyme at the time of administration of the glycan composition; c) administering an exogenous substance, wherein at the time of administration of the exogenous substance, the subject has already been administered a glycan composition in an amount and for a time sufficient to regulate the processing of the exogenous substance in the subject; d) administering an exogenous substance and the subject is determined to be in need of the glycan composition; or e) administering to the subject an exogenous substance and a glycan composition in an amount and for a time sufficient to regulate a process or activity in the subject, wherein the administration of the exogenous substance and the glycan composition overlaps. Including, i) the glycan preparation comprises a glycan polymer comprising a glycan unit of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; ii) the average degree of branching (DB) of the glycan polymers in the glycan preparation is 0, 0.01-0.6, 0.05-0.5, 0.1-0.4, or 0.15-0.4; iii) at least 50% (at least 60%, 65%, 70%, 75%, 80%, or 85%, or less than 50%) of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, at least 3 and less than 10 glycan units, at least 5 and less than 25 glycan units, or at least 10 and less than 35 glycan units; iv) the average DP (average DP) of the glycan preparation is about 5-8, about 8-13, about 13-25, about 5-15, about 5-20, or about 5-15; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is 0, or about 0.8:1 to about 5:1, about 1:1 to about 5:1, about 1:1 to about 3:1, about 3:2 to about 2:1, or about 3:2 to about 3:1; vi) the glycan preparation contains 15 mol% to 75 mol% (20 mol% to 60 mol%, 25 mol% to 50 mol%, or 30 mol% to 45 mol%) of 1,6 glycosidic bonds; vii) the glycan preparation contains at least one, two, or three 1,2 glycosidic bonds, 1,3 glycosidic bonds, and 1,4 glycosidic bonds in an amount of 1 mol% to 40 mol% (1 mol% to 30 mol%, 5 mol% to 25 mol%, 10 mol% to 20 mol%), respectively; viii) the glycan preparation has a final solubility limit in water of at least about 50 (at least about 60, 70, at least about 75, or less than 50) Brix at 23°C; ix) the glycan preparation has a dietary fiber content of at least 50% (at least 60%, 70%, 80%, or at least 90%, or less than 50%); or x) Any combination of two, three, four, five, six, seven, eight, or nine of i), ii), iii), iv), v), vi), vii), viii), viii), and ix). is The method is characterized.

[0009] In another aspect, the invention features a glycan composition disclosed herein.

[0010] In one embodiment, the glycan composition mediates host processing by microorganisms (e.g., gut microorganisms), for example, by affecting the production, level, structure, distribution, effect, or activity of microbial entities, such as enzymes, that act on exogenous substances.

[0011] In one embodiment, the glycan composition alters the way microorganisms (e.g., intestinal microorganisms) mediate processing, for example, by increasing or decreasing the number or abundance of microorganisms in the intestine of a subject. In one embodiment, an increase or decrease in the number or abundance of microorganisms, such as bacterial taxa, is associated with an increase or decrease in the processing activity of, for example, enzymes acting on exogenous substances. In one embodiment, microbial entities, such as enzymes, alter the processing of exogenous compounds, such as drugs, drug metabolites, drug additives, foods, food additives, allergens, toxins, or poisons.

[0012] In one embodiment, the microorganism mediates an alteration in the production, level, structure, distribution, or activity of a host component, e.g., an enzyme (e.g., a mammalian enzyme), made by the subject. In one embodiment, the host entity, e.g., an enzyme, alters the processing of an exogenous compound, e.g., a drug, drug metabolite, drug additive, food, food additive, allergen, toxin, or poison.

[0013] The methods described herein provide for administering a glycan composition having a preselected characteristic, for example, i) the ability to change the number or abundance (relative abundance) of microorganisms, e.g., gut microorganisms, that alter the exogenous substance (e.g., by increasing or decreasing microbial growth), ii) the ability to provide a processing activity (e.g., in the form of a microbial enzyme) of a microorganism, e.g., gut microorganism, that alters the exogenous substance (e.g., by changing the transcription level / expression level of a microbial enzyme in the microorganism), or (iii) the ability to modulate the response of a microorganism, e.g., gut microorganism, to a host subject (e.g., by increasing or decreasing the host processing activity (e.g., in the form of a host enzyme) that alters the exogenous substance (e.g., by changing a metabolite or transmitting an output by the microorganism).

[0014] In some embodiments, the enzyme provided by the microorganism alters (e.g., alters production, levels, structure, distribution, effect, and / or activity) the exogenous compound, e.g., directly. In some embodiments, the enzyme provided by the microorganism alters (e.g., alters production, levels, structure, distribution, effect, and / or activity) the exogenous compound, e.g., indirectly. For example, the enzyme produces a metabolite that alters the exogenous compound or mediates host processing to alter the exogenous compound. For example, an enzyme provided by the microorganism that indirectly alters an exogenous compound can produce a metabolite that competes with a host enzyme, changing how the host enzyme interacts with the exogenous compound, thereby altering the exogenous compound. In another example, an enzyme provided by the microorganism that indirectly alters an exogenous compound can activate or inhibit a host enzyme that processes (e.g., metabolizes) the exogenous compound. In embodiments, an increase or decrease in the number or abundance (e.g., relative abundance) of the microorganism, or its ability to provide enzymatic activity, is associated with an increase or decrease in the activity of an enzyme that interacts with the exogenous substance. In one embodiment, the interaction of an enzyme with an exogenous substance, e.g., a drug, can optimize the efficacy of the drug by, for example, increasing the level of the active form or its bioavailability, or decreasing the level of the inactive form or a toxic intermediate (e.g., produced by drug metabolism (e.g., by host or microbial enzymes)), thereby modulating the subsequent effect of the drug on the host (e.g., therapeutic effect). In one embodiment, the interaction of an enzyme with an exogenous substance, e.g., a toxin or poison, can reduce adverse effects on the subject by increasing processing (e.g., increasing solubility, decreasing reactivity, etc.) to non-toxic or less toxic forms or intermediates that are more rapidly excreted from the subject's body.

[0015] In one embodiment, a glycan composition that promotes the growth of Bacteroides species, Enterococcus faecalis, and / or Lactobacillus species is administered in combination with sulfasalazine to a subject, e.g., a patient with rheumatoid arthritis. Provided herein are methods (e.g., methods for treating rheumatoid arthritis) comprising administering a glycan composition described herein to a subject receiving (or about to receive) sulfasalazine in an amount effective to increase the conversion of the prodrug sulfasalazine to 5-aminosalicylic acid, for example, by increasing the level or activity of microbial azoreductase, thereby increasing the level of 5-aminosalicylic acid. See, e.g., Table 1, column 3.

[0016] In one embodiment, a glycan composition that reduces the growth of intestinal microorganisms (e.g., aerobic enterobacteria or anaerobic bacteria such as Clostridium perfringens) or reduces the production of enzymes that produce p-cresol, e.g., from tyrosine, is administered in combination with acetaminophen / paracetamol. For example, a method is provided that includes administering a glycan composition described herein to a subject receiving (or about to receive) acetaminophen / paracetamol in an amount effective to reduce acetaminophen / paracetamol-induced drug toxicity and / or increase the activity of acetaminophen / paracetamol (e.g., acetaminophen / paracetamol) by reducing the level of p-cresol, which competes with acetaminophen as a substrate for SILT1A1, thereby reducing the interference of p-cresol with the host metabolism of acetaminophen / paracetamol. In one embodiment, a glycan composition that reduces the growth of intestinal microorganisms (e.g., aerobic enterobacteria or anaerobic bacteria such as Clostridium perfringens) or reduces the production of enzymes that produce p-cresol, e.g., from tyrosine, is administered in combination with acetaminophen / paracetamol. For example, a method is provided that includes administering a glycan composition described herein to a subject receiving (or about to receive) acetaminophen / paracetamol in an amount effective to reduce acetaminophen / paracetamol-induced drug toxicity and / or increase the activity of acetaminophen / paracetamol (e.g., acetaminophen / paracetamol). In one embodiment, a pathogenic Firmicutes (e.g., Clostridium difficile) is administered. A glycan composition that inhibits the growth of Bacteroidetes, Actinobacteria, and / or Fusobacteria in combination with tyrosine and / or phenylalanine is administered to a subject, for example, a subject suffering from pain, fever, or drug-induced toxicity (e.g., from acetaminophen). For example, a method is provided that includes administering to a subject a glycan composition described herein in an amount effective to reduce the level of p-cresol by reducing the level or activity of a microbial enzyme that metabolizes the substrate to p-cresol. See, for example, Table 1, column 8.

[0017] In one embodiment, a glycan composition that promotes the growth of gut microorganisms (e.g., Proteobacteria, Firmicutes, or Actinobacteria) is administered in combination with irinotecan to a subject, e.g., a subject with cancer, e.g., colon cancer. For example, a method (e.g., a method for treating cancer) is provided, comprising administering a glycan composition described herein to a subject receiving (or about to receive) irinotecan in an amount effective to reduce the level of a toxic intermediate of irinotecan (e.g., SN-38 glucoronide) by reducing the level or activity of microbial beta-glucuronidase. In one embodiment, a method is provided for treating side effects associated with irinotecan treatment, such as bone marrow suppression, diarrhea, and neutropenia. See, e.g., Table 1, column 5.

[0018] In one embodiment, a glycan composition that promotes the growth of Eggerthella lenta, e.g., strain DSM2243, is administered in combination with digoxin to a patient, e.g., a patient with cardiac disease or heart disease, e.g., cardiac arrhythmia or heart failure. Provided are methods (e.g., methods for treating cardiac disease or heart disease) that include administering a glycan composition described herein to a subject receiving (or about to receive) digoxin in an amount effective to increase drug activity, e.g., by reducing the level or activity of microbial bacterial reductase. See, e.g., Table 1, column 7.

[0019] In one embodiment, a glycan composition that promotes the growth of Enterococcus faecium, Lactobacillus mucosae, Bifidobacterium species, or Eggerthella species is administered in combination with a phytoestrogen (e.g., an isoflavone or lignan), such as a glycosidic isoflavone such as daidzin, to a subject, e.g., a subject with or at risk of breast cancer. For example, a method (e.g., a method for treating breast cancer) is provided, comprising administering a glycan composition described herein to a subject who has received (or will receive) daidzin in an amount effective to increase equol levels by increasing the level or activity of a microbial reductase that catalyzes the cleavage of glycosidic bonds and the reduction of α,β-unsaturated ketones. See, e.g., Table 1, column 14.

[0020] In one embodiment, a glycan composition that promotes the growth of Actinobacteria, Bacteroidetes, and / or Firmicutes is administered in combination with a phytoestrogen (e.g., an isoflavone or lignan), such as a glycoside isoflavone such as daidzin, to a patient, such as a breast cancer patient or a patient at risk of breast cancer. A method (e.g., a method for treating breast cancer) is provided, comprising administering the glycan composition described herein to a subject who has received (or is about to receive) a phytoestrogen in an amount effective to increase the level or activity of a microbial enzyme that enhances the metabolism of the phytoestrogen into a molecule that binds to an estrogen receptor. See, for example, Table 1, column 13.

[0021] In one embodiment, a glycan composition that inhibits or reduces the growth of bacteria having the uidA gene, such as Escherichia coli, is administered in combination with a heterocyclic amine (e.g., produced when grilling meat) (e.g., 2-amino-3-methylimidazo[4,5-f]quinolone (IQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)) to a subject, e.g., a subject at risk of cancer. For example, a method is provided in which a glycan composition described herein is administered to a subject who has received (or is about to receive), e.g., eats (or is about to eat), a heterocyclic amine (e.g., as a component of grilled meat) in an amount effective to reduce the level of a toxic compound, e.g., a carcinogen, by reducing the level or activity of microbial beta-glucuronidase. See, for example, Table 1, column 16.

[0022] In one embodiment, a glycan composition that inhibits or reduces the growth of colonic microorganisms, such as Firmicutes, Proteobacteria, Actinobacteria (e.g., excluding Bacteroides), and / or bacteria having a choline utilization (cut) gene cluster, is administered in combination with a choline-containing compound, such as L-carnitine, to a subject, for example, a subject with or at risk of high cholesterol or heart disease. For example, a method is provided that includes administering a glycan composition described herein to a subject receiving (or about to receive) L-carnitine in an amount effective to reduce the level or activity of microbial glycyl radical enzymes, thereby reducing the level of trimethylamine (TMA). See, for example, Table 1, column 17.

[0023] In one embodiment, a glycan composition that inhibits the growth of Firmicutes (e.g., Lactobacillus) is administered in combination with a taurine-conjugated bile acid (e.g., tauro-beta-muricholic acid) to a subject, e.g., a subject with obesity (e.g., diet-induced obesity). For example, a method is provided in which the glycan composition described herein is administered to a subject in an amount effective to reduce the level of free bile acids and / or taurine-conjugated bile acids (e.g., emulsifying fats and oils) by reducing the level or activity of microbial bile salt hydrolases. See, for example, Table 1, column 10.

[0024] In one embodiment, a glycan composition that inhibits the growth of Actinobacteria, such as Gordonibacter, is administered to a patient in combination with ellagitannin. For example, a method is provided that includes administering to a subject a glycan composition described herein in an amount effective to reduce the level of ellagitannin and / or increase the level of ellagic acid by increasing the level or activity of a microbial enzyme that hydrolyzes ellagitannin to ellagic acid. See, for example, Table 1, columns 11 and 12.

[0025] In one embodiment, a glycan composition that promotes the growth of E. faecalis, E. lenta, Blautia product, Eubacterium limosum, Clostridium scindens, Lactonifactor longoviformis, Clostridium saccharomia, and / or P. producta is administered in combination with a lignan (plant-derived), such as pinoresinol, secoisolariciresinol, to a subject, e.g., a breast cancer patient or a patient at risk of breast cancer. For example, a method (e.g., a method for treating breast cancer) is provided, comprising administering to a subject a glycan composition described herein in an amount effective to increase the level of enterodiol and / or enterolactone by increasing the level or activity of a microbial enzyme that metabolizes pinoresinol and / or secoisolariciresinol to enterodiol and / or enterolactone.See, for example, Table 1, column 15.

[0026] In one embodiment, a glycan composition that promotes the growth of Enterococcus, Clostridium, Corynebacterium, Campylobacter, and / or Escherichia is administered to a subject in combination with a non-caloric artificial sweetener, such as cyclamate, xylitol, or saccharin. For example, a method is provided that includes administering to a subject a glycan composition described herein in an amount effective to reduce the level of toxic conversion products of sweeteners (e.g., the conversion of cyclamate to potentially toxic cyclohexylamine) by reducing the level or activity of microbial enzymes that metabolize artificial sweeteners. See, for example, Table 1, column 18.

[0027] In one embodiment, a glycan composition that inhibits or reduces the growth of intestinal microorganisms, such as Klebsiella terrigena, is administered in combination with melamine, e.g., a food or substance containing melamine, to a subject, e.g., a subject with or at risk of kidney disease (e.g., renal failure). For example, a method is provided comprising administering to a subject a glycan composition described herein in an amount effective to reduce the toxic level of cyanuric acid by reducing the level or activity of a microbial enzyme that metabolizes melamine.

[0028] In one embodiment, a glycan composition that increases the growth of intestinal microorganisms, such as Bifidobacterium, Lactobacillus, and Escherichia, is administered in combination with a conjugated hydroxycinnamic acid ester (e.g., present in foods such as fruits, vegetables, grains, and coffee) to a subject, e.g., a subject with or at risk of inflammation, e.g., an inflammatory disease. For example, a method is provided comprising administering to a subject the glycan composition described herein in an amount effective to increase the level of anti-inflammatory substances and / or the highly oxidative substances caffeic acid, ferulic acid, and p-coumaric acid by increasing the level or activity of microbial enzymes that process these substances.

[0029] In one embodiment, the glycan composition that inhibits or reduces microbial growth is administered in combination with cycasin (e.g., present in some plants) to a subject, such as a subject with cancer or at risk of cancer. For example, a method is provided for administering to a subject the glycan composition described herein in an amount effective to reduce the toxicity of methylazoxymethanol, a carcinogen, by reducing the level or activity of a microbial enzyme that processes the substance.

[0030] In one embodiment, the glycan composition that increases microbial growth is administered to a subject, for example, a subject with cancer or at risk of cancer, in combination with anthocyanins. For example, a method is provided that comprises administering to a subject the glycan composition described herein in an amount effective to increase the level and / or activity of a microbial enzyme that processes aglycones having anti-cancer properties, thereby increasing the level or activity of the substance.

[0031] In one embodiment, a glycan composition that increases the growth of microorganisms, such as Oxalobacter formigenes, is administered in combination with oxalate to a subject, for example, a subject with or at risk of kidney stones, renal failure, hyperoxaluria, and / or cardiac conduction disorders. For example, a method is provided in which the glycan composition described herein is administered to a subject in an amount effective to reduce oxalate levels associated with nephrotoxicity by increasing the level or activity of an oxalate-processing microbial enzyme (e.g., oxalate:formate antiporter, formyl-CoA transferase, or oxalyl-CoA decarboxylase).

[0032] In one embodiment, a glycan composition that increases the growth of microorganisms, such as microorganisms that upregulate the expression of host CYP450 enzymes, is administered in combination with a polycyclic aromatic hydrocarbon (PAH), such as benzo[a]pyrene (e.g., present in some plant and animal foods, e.g., meat cooked over an open flame), to a subject, such as a subject with cancer or at risk of cancer. For example, a method is provided comprising administering to a subject the glycan composition described herein in an amount effective to upregulate host CYP450 enzymes, thereby providing protection against carcinogenic PAHs, by increasing the level or activity of appropriate microbial enzymes.

[0033] In one embodiment, glycan compositions that regulate the growth of microorganisms, such as microorganisms that control the expression of host phase I (CYP) and phase II drug-metabolizing enzymes (e.g., UGT, SULT) involved in drug metabolism, can mediate host drug response. A method is provided comprising administering to a subject the glycan compositions described herein in an amount effective to regulate the level or activity of microorganisms, thereby altering host drug-metabolizing enzymes and thereby increasing the host's ability to respond better to drugs.

[0034] In one embodiment, a glycan composition that reduces the growth of microorganisms, such as microorganisms that produce a metabolite of sorivudine, such as (E)-5-(2-bromovinyl)uracil (BVU), is administered in combination with sorivudine and 5-fluorouracil (5-FU) to a subject, such as a subject with or at risk of a viral infection, such as shingles, for example, a cancer patient with or at risk of shingles. For example, a method is provided comprising administering to a subject the glycan composition described herein in an amount effective to reduce the toxic level of 5-FU by regulating (increasing or decreasing) the level or activity of an appropriate microbial enzyme.

[0035] In one embodiment, a glycan composition that reduces the growth of enterobacteria, such as K. pneumoniae, is administered in combination with sorivudine to a subject, for example, a subject with or at risk of a viral infection, such as shingles or varicella zoster. For example, a method is provided that includes administering to a subject the glycan composition described herein in an amount effective to reduce the inactivation of sorivudine by reducing the level or activity of microbial phosphorylase, such as thymidine phosphorylase or uridine phosphorylase. For example, see Table 1, column 25.

[0036] In one embodiment, a glycan composition that reduces the growth of bacteria, such as bacteria described herein, for example, Gram-negative bacteria, for example, bacteria that produce lipopolysaccharides, is administered to a subject, for example, a subject with cancer or at risk of cancer, in combination with CpG oligonucleotide immunotherapy for cancer. For example, a method is provided that includes administering to a subject a glycan composition described herein in an amount effective to increase the effectiveness of CpG oligonucleotide immunotherapy by regulating the level or activity of an appropriate microbial enzyme. For example, see Table 3, column 2.

[0037] In one embodiment, a glycan composition that reduces the growth of Bacteroides, such as Bacteroides thetaiotaomicron and / or Bacteroides fragilis, is administered in combination with a cytotoxic T-lymphocyte protein 4 (CTLA4) inhibitor (e.g., an antibody) to a subject, such as a subject with or at risk of cancer. For example, methods are provided that include administering to a subject a glycan composition described herein in an amount effective to increase the effectiveness of the CTLA4 inhibitor by regulating the level or activity of an appropriate microbial enzyme. See, for example, Table 3, column 6.

[0038] In one embodiment, the glycan composition that reduces the growth of Staphylococcus is administered to a subject, for example, a subject with or at risk of inflammation or an inflammatory disease, such as inflammatory bowel disease, in combination with, for example, an anti-inflammatory drug, such as a drug for treating inflammatory bowel disease, for example, a tumor necrosis factor (TNF) inhibitor (e.g., an antibody). Methods are provided that include administering to a subject a glycan composition described herein in an amount effective to increase the effectiveness of an anti-inflammatory drug, for example, by regulating the level or activity of an appropriate microbial enzyme. See, for example, Table 3, column 7.

[0039] In one embodiment, a glycan composition that reduces the growth of mucolytic bacteria, such as Bacteroidetes (e.g., Bacteroidales) and / or Ruminococcus gnavus, is administered in combination with an emulsifier, such as carboxymethylcellulose or polysorbate 80, to a subject, e.g., a subject suffering from or at risk of inflammation, inflammatory disease, or metabolic syndrome. For example, by modulating the level or activity of an appropriate microbial enzyme, a method is provided comprising administering to a subject a glycan composition described herein in an amount effective to increase the effectiveness of the emulsifier. See, e.g., Table 3, column 8.

[0040] Examples of other exogenous substances, enzymes, microorganisms, and disorders can be found in Tables 1, 2, and 3.

[0041] The methods described herein include administering a glycan composition that increases the level or abundance (relative abundance) of a microorganism or increases the ability of a microorganism to produce an enzyme that catalyzes the conversion of a drug or prodrug to its active form.

[0042] The methods described herein include administering a glycan composition that reduces the level or abundance (relative abundance) of microorganisms or reduces the ability of microorganisms to produce enzymes that inhibit the conversion of drugs or prodrugs to their active forms.

[0043] The methods described herein include administering a glycan composition that reduces the level or abundance (relative abundance) of a microorganism or reduces the ability of a microorganism to produce an enzyme that converts a drug or prodrug into an undesirable form, such as a toxic intermediate / metabolite.

[0044] The methods described herein include administering a glycan composition that increases the level or abundance (relative abundance) of a microorganism or increases its ability to produce an enzyme that inhibits the conversion of a drug or prodrug to an undesirable form, e.g., a toxic intermediate / metabolite.

[0045] As described herein, the glycan composition may be useful for the treatment of various diseases. Furthermore, the glycan composition may be used in combination with a substance, for example, an exogenous substance processed by a microorganism. Thus, the present invention provides compositions and methods for regulating the processing of exogenous substances, compositions and methods for regulating enzyme activity, compositions and methods for identifying / selecting treatments for subjects, compositions and methods for reducing the toxicity of substances, compositions and methods for increasing the effectiveness of drugs, and compositions and methods for inducing specific chemical modifications or reactions in vivo. [Brief explanation of the drawings]

[0046] [Figure 1A] A series of graphs showing the modification of exogenous substances by glycan-mediated microbiota shift. (*P<0.05, Welch two-sample t-test). [Figure 1B] A series of graphs showing the modification of exogenous substances by glycan-mediated microbiota shift. (*P<0.05, Welch two-sample t-test). [Figure 1C] A series of graphs showing the modification of exogenous substances by glycan-mediated microbiota shift. (*P<0.05, Welch two-sample t-test). [Figure 2] Box plots showing the change in abundance of Bacteroidaceae / Bacteroides microorganisms associated with, for example, sulfasalazine metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 3] Box plots showing the change in abundance of Enterococcaceae / Enterococcus microorganisms associated with, for example, sulfasalazine metabolism, non-caloric artificial sweetener metabolism, and daidzin metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 4] Box plots showing, for example, changes in abundance of bacteria / Firmicutes microorganisms associated with irinotecan / SN-38 glucuronide metabolism, and tyrosine and / or phenylalanine metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 5] Box plots showing the change in abundance of, for example, bacterial / Proteobacterial microorganisms associated with irinotecan / SN-38 glucuronide metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 6] Box plots showing changes in abundance of bacteria / Actinobacteria microorganisms associated with, for example, irinotecan / SN-38 glucuronide metabolism, tyrosine and / or phenylalanine metabolism, and ellagitannin metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 7] Box plots showing the change in abundance of, for example, Eggerthella lenta microorganisms associated with digoxin metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially obtained FOS, and a no-added carbon control. [Figure 8] Box plots showing the change in abundance of, for example, Coriobacteriaceae / Gordonibacter microorganisms associated with ellagitannin metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 9]Box plots showing changes in abundance of bacteria / Bacteroidetes microorganisms associated with, for example, phytoestrogen metabolism and CpG oligonucleotide immunotherapy in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 10] Box plots showing the change in abundance of Bifidobacteriaceae / Bifidobacterium microorganisms associated with, for example, daidzin metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 11] Box plots showing the change in abundance of, for example, Lachnospiraceae / Blautia microorganisms associated with lignan metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 12] Box plots showing the change in abundance of, for example, Erysipelotrichaceae / Clostridium XVIII microorganisms associated with lignan metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 13] Box plots showing the change in abundance of Lactonifactor / longoviformis microorganisms associated with, for example, lignan metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 14]Box plots showing the change in abundance of Enterobacteriaceae / Escherichia / Shigella microorganisms associated with, for example, heterocyclic amine metabolism and non-caloric artificial sweetener metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 15] Box plots showing the change in abundance of Enterobacteriales / Enterobacteriaceae microorganisms associated with, for example, sorivudine metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 16] Box plots showing the change in abundance of Bacteroides / dorei / fragilis microorganisms associated with, for example, cytotoxic T-lymphocyte protein 4 (CTLA4) inhibitor metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 17] Box plots showing the change in abundance of, for example, Ruminococcaceae / Ruminococcus microorganisms associated with emulsifier metabolism in 12 human fecal cultures (from healthy subjects) exposed to various glycan compositions described herein, commercially available FOS, and a no-added carbon control. [Figure 18A] Graph of weight loss over time in mice gavaged with glycan from day -7 to day 6. Mice were administered irinotecan at 200 mg / kg body weight on day 0. [Figure 18B] Graph of weight loss over time in mice gavaged with glycan from day -7 to day 6. Mice were administered irinotecan at 200 mg / kg body weight on day 0. DETAILED DESCRIPTION OF THE INVENTION

[0047] Described herein are methods for regulating the processing of exogenous substances, such as drugs, drug metabolites, drug additives, foods, food additives, allergens, toxins, or poisons. In embodiments, by regulating the processing of exogenous substances, for example, microbially mediated processing, the effect of the exogenous substance or its processed form on a subject can be changed. Also described herein are glycan compositions that regulate the processing of exogenous substances. In embodiments, the glycan compositions are provided as pharmaceutical compositions, medical foods, nutritional compositions, and food ingredients. Additionally, methods are provided that are effective in treating many diseases, disorders, or pathological conditions.

[0048] definition As used herein, the terms "abundance" or "prevalence," when referring to microbial taxa, refer to the presence of one microbial taxon relative to another in a defined microbial niche, such as the GI tract, or in the entire host organism (e.g., human or animal model).

[0049] As the terms are used herein, "obtain" or "obtaining" refers to obtaining a value, e.g., a numerical value, or an image, or a physical entity (e.g., a sample), for example, by "directly obtaining" or "indirectly obtaining" the value or physical entity. "Directly obtaining" means performing a process (e.g., performing a synthetic or analytical method or protocol) to obtain a value or physical entity. "Indirectly obtaining" refers to receiving a value or physical entity from another entity or source (e.g., a third party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change of a physical substance or the use of a machine or device. An example of directly obtaining a value includes obtaining a sample from a human subject. Directly obtaining a value includes performing a process that uses a machine or device, e.g., an NMR spectrometer, to obtain an NMR spectrum.

[0050] As used herein, "antibody" is used in the broadest sense and includes monoclonal antibodies (including full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (so long as they exhibit the desired activity).

[0051] As used herein, the term "cancer" refers to a cell (group of cells) having an abnormal state or appearance (e.g., of a tissue or organ) characterized by an abnormal ability to grow or replicate autonomously and proliferative cell growth. As used herein, "cancer" includes any solid or liquid, benign or malignant, non-invasive or invasive cancer or tumor, such as a hyperplasia, neoplasia, carcinoma, sarcoma, or hematopoietic neoplastic disorder (e.g., leukemia), and precancerous or pre-cancerous lesion.

[0052] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined therapeutic regimen for a particular disease or condition. The therapeutic regimen defines the dosage and periodicity of administration of each agent so that the effects of the separate agents on the subject overlap. In some embodiments, delivery of two or more agents is simultaneous or concurrent, and the agents may be formulated together. In other embodiments, two or more agents are not formulated together but are formulated and administered sequentially as part of a regimen. In some embodiments, the combined administration of two or more agents or treatments results in a reduction in symptoms or other parameters associated with the disease that is greater than would be observed with one agent or treatment delivered alone or in the absence of the other agent. The effects of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent can be by any appropriate route, including oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent of the combination may be administered by intravenous injection, while a second therapeutic agent of the combination may be administered orally. In some embodiments, combination therapy refers to the administration of two (or more) different agents or treatments to a subject as part of a defined treatment regimen in response to a condition associated with the previous administration of one (or more) of the two (or more) different agents. For example, administration of a first agent may cause an undesirable condition in the subject, prompting the administration of a combination therapy comprising the first agent and a second (or additional) agent (taken / prescribed together or separately) that addresses the undesirable condition, e.g., treats, improves, or alleviates the undesirable condition.

[0053] For example, when used herein in relation to a type of glycan polymer, "distinct" means that it is chemically and / or structurally distinct from others. For example, two sugars are "distinct" if they are chemically different (e.g., fucose and xylose) or structurally different (e.g., cyclic vs. acyclic, L vs. D). Two dimers are distinct if they consist of the same two monomers, but one pair contains alpha-1,4 linkages and the other pair contains beta-1,6 linkages. Distinct entities may have any other suitable distinct characteristics or properties known in the art and / or detectable by the methods described herein.

[0054] As used herein, "toxin" refers to a compound that is naturally occurring or made by humans, e.g., introduced into the environment by humans. Examples of toxins include poisons, environmental pollutants (e.g., triclosan, TCDD, pesticides, and arsenic), mushroom toxins, and snake venom. As used herein, an environmental toxin is a toxin that humans commonly encounter in the environment.

[0055] As used herein, a "dosing regimen," "administration regimen," or "therapeutic regimen" is a modality of drug administration that achieves a therapeutic goal. A dosing regimen includes one, two, three, or four of the following definitions: route of administration, unit dose, dosing frequency, or length of treatment.

[0056] "Effective amount" and "therapeutically effective amount," as used herein, refer to an amount of a pharmaceutical composition or agent sufficient to provide a desired effect. In some embodiments, a physician or other medical professional will determine the appropriate amount and administration regimen. An effective amount also refers to an amount of a pharmaceutical composition or agent that prevents the onset or recurrence of a medical condition.

[0057] As used herein, "exogenous substance" refers to a substance introduced from or produced outside an organism, cell tissue, or system (e.g., a subject). In embodiments, an exogenous substance is introduced into a subject, e.g., orally, intranasally, intravenously, or intramuscularly. An exogenous substance can include, for example, a foreign substance not naturally present in a subject. An exogenous substance can include substances that are naturally present in some humans but may not be present in all humans, or substances that are naturally present in some humans at some time but not in other humans throughout their lifetime. In some embodiments, an exogenous substance includes a derivative of an exogenous substance, provided that the derivative is not incorporated into a host macromolecule, e.g., a protein, lipid, polysaccharide, or nucleic acid molecule. In some embodiments, the molecular weight of the derivative does not differ from the molecular weight of the exogenous substance by more than 5%, e.g., more than 5%, more than 10%, more than 15%, or more than 20%. In one embodiment, a derivative does not include normal metabolic products that incorporate atoms from food or other energy sources, vitamins, minerals, etc. Exogenous substances are described in more detail herein.

[0058] As used herein, "glycan unit" refers to an individual unit of a glycan disclosed herein, e.g., a building block that makes up a glycan.

[0059] As used herein, an "isolated" or "purified" glycan composition (or component thereof) is substantially pure and free of contaminants, such as pathogens or other unwanted biological substances, or toxic or other unwanted organic or inorganic compounds. In some embodiments, a pure or isolated compound, composition, or preparation may contain trace amounts of solvents and / or salts (e.g., less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, less than 0.5%, or 0.1% by w / w, w / v, v / v, or mole %). A purified compound or preparation contains at least about 60% (w / w, w / v, v / v, or mole %) of the target compound by w / w, w / v, v / v, or mole %, at least about 75%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%. For example, a purified (substantially pure) or isolated glycan composition is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, 99.5%, 99.8%, 99.9%, or 100% w / w, w / v, v / v, or molar percent of the glycan composition (i.e., free of any solvent, e.g., water, in which the glycan composition can be dissolved), for example, during production, extraction / purification, and / or processing, separated from co-occurring components (e.g., the glycan composition is substantially free of undesirable compounds). Purity can be measured by any suitable standard method, for example, by column chromatography (e.g., size exclusion chromatography (SEC)), thin layer chromatography (TLC), gas chromatography (GC), high performance liquid chromatography (HPLC), or nuclear magnetic resonance (NMR) spectroscopy. Purified or purity may also define the degree of sterility, safe for administration to a human subject, eg, lacking viable infectious or toxic agents.

[0060] As used herein, "microbiome" refers to the genetic content of the microbial community that inhabits both persistently and transiently in and on a subject (e.g., a human subject), including eukaryotes, archaea, bacteria, and viruses (including bacterial viruses (e.g., phages)), where "genetic content" encompasses all genomic DNA, RNA such as ribosomal RNA and messenger RNA, epigenomes, plasmids, and other types of genomic information. In some embodiments, microbiome specifically refers to the genetic content of the microbial community in an ecological niche.

[0061] "Microbiota," as used herein, refers to the community of microorganisms (chronically and transiently) occurring in and on a subject (e.g., a human subject), and includes eukaryotes, archaea, bacteria, and viruses (including bacterial viruses, e.g., phages). In some embodiments, microbiota specifically refers to the community of microorganisms in an ecological niche.

[0062] As used herein, "modulating the microbiota" or "modulating the microbiota" means changing the state of the microbiota. Changing the state of the microbiota can include changing the structure and / or function of the microbiota. A change in the structure of the microbiota is, for example, a change in the relative composition of taxa in one or more regions of the GI tract, such as the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and / or rectum. In one embodiment, a change in the structure of the microbiota includes a change in the abundance of a taxon (e.g., relative to other taxa or relative to what would be observed in the absence of the modulation). Modulation of the microbiota can also, or in addition, include a change in the function of the microbiota, such as a change in gene expression in the microbiota, the level of a gene product (e.g., RNA or protein), or a change in the metabolic output of the microbiota. Modulation of the structure or function of the microbiota can further induce a change in one or more functional pathways of the host (e.g., a change in gene expression, the level of a gene product, and / or the metabolic output of a host cell or host process) as a result of the change in the microbiota or its function.

[0063] As used herein, the term "oligosaccharide" refers to a molecule consisting of multiple (i.e., two or more) covalently linked individual glycan units. Each glycan unit may be linked via glycosidic bonds (e.g., 1->2 glycosidic bonds, 1->3 glycosidic bonds, 1->4 glycosidic bonds, 1->5 glycosidic bonds, or 1->6 glycosidic bonds) that are in either the alpha or beta configuration.

[0064] As used herein, a "pharmaceutical composition" or "pharmaceutical preparation" refers to a composition or preparation having pharmacological activity or other direct effect in the alleviation, treatment, or prevention of disease, and / or a finished dosage form or formulation thereof, and intended for human use. Pharmaceutical compositions or pharmaceutical preparations are typically produced under Good Manufacturing Practice (GMP) conditions. Pharmaceutical compositions or preparations can be sterile or non-sterile. If non-sterile, such pharmaceutical compositions meet the microbiological standards and standards for non-sterile pharmaceutical products set forth in the United States Pharmacopoeia (USP) or the European Pharmacopoeia (EP). Pharmaceutical compositions can further comprise or be co-administered with additional active agents, such as additional therapeutic agents. Pharmaceutical compositions can also include pharmaceutically acceptable excipients, solvents, carriers, filters, or any combination thereof.

[0065] As used herein, the term "polysaccharide" refers to a polymeric molecule composed of multiple covalently linked individual glycan units. In some embodiments, a polysaccharide comprises at least 10 or more glycan units (e.g., at least 10, at least 15, at least 20, at least 25, or at least 50, at least 100, at least 250, at least 500, or at least 1000 glycan units). Each glycan unit may be linked via glycosidic bonds (e.g., 1->2 glycosidic bonds, 1->3 glycosidic bonds, 1->4 glycosidic bonds, 1->5 glycosidic bonds, and 1->6 glycosidic bonds) in either the alpha or beta configuration. In some embodiments, a polysaccharide is a homogeneous polymer with identical repeating units. In other embodiments, a polysaccharide is a heterogeneous polymer with different repeating units. Polysaccharides can be further characterized by the degree of branching (DB, branch points per residue) or degree of polymerization (DP).

[0066] As used herein, the term "subject" or "patient" generally refers to any human subject. The term does not denote a particular age or sex. A subject may include a pregnant woman. A subject may include newborns (preterm, full-term), infants up to 1 year of age, young children (e.g., 1-12 years), teenagers (e.g., 13-19 years), adults (e.g., 20-64 years), and elderly people (65 years and older). Generally, a subject includes a host and its corresponding microbiota.

[0067] A "substantial reduction," as used herein, is a 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.9%, or 100% reduction.

[0068] A "substantial increase," as used herein, is an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, 850%, 900%, 950%, 1000%, or greater than 1000%.

[0069] As used herein, "synthetic material" refers to an artificial compound or preparation, such as a glycan composition, that does not occur in nature. In one embodiment, the polymer catalysts described herein are used to synthesize the glycans of the preparation under suitable reaction conditions, for example, by polymerization reactions that create oligomers and polymers from individual glycan units added to the reaction. In some embodiments, the polymer catalysts can act as hydrolyzing agents, breaking down glycosidic bonds. In other embodiments, the polymer catalysts can form glycosidic bonds.

[0070] As used herein, the terms "treating" and "treatment" refer to the administration of an agent or composition to a subject (e.g., a symptomatic subject suffering from an adverse condition, disorder, or disease) to affect a reduction in the severity and / or frequency of symptoms, eliminate the symptoms and / or their underlying causes, and / or promote the amelioration or repair of damage, and / or prevent an adverse condition, disorder, or disease in an asymptomatic subject who is predisposed to, or who develops or is at risk of developing, a particular adverse condition, disorder, or disease.

[0071] The term "antigen" refers to a substance that elicits an immune response and is usually also the substance used to detect the corresponding antibody by the many in vitro and in vivo immunological methods available to demonstrate antigen-antibody interactions. Similarly, the term allergen is used to denote an antigen that has the ability to induce and bind to antibodies, although this definition does not exclude the possibility that an allergen may also induce antibodies of classes other than IgE.

[0072] As used herein, "derivative" refers to the product of processed exogenous material. Derivatives may include metabolic products and / or products of any of the enzymatic reactions described herein.

[0073] As used herein, "administered in combination" means that two (or more) therapies, e.g., the therapies described herein, are delivered to a patient, e.g., during the course of the patient's illness, including a disorder / condition. For example, two or more therapies are delivered after a subject is diagnosed with a disorder / condition and before the disorder / condition is cured or eliminated, or before the treatments are terminated for other reasons. In embodiments, the delivery of one treatment is still occurring when the delivery of a second treatment begins; i.e., there is overlap in terms of administration. This is sometimes referred to as "simultaneous" or "concurrent delivery." In other embodiments, the delivery of one treatment is stopped before the delivery of the other treatment begins. In either case, in some embodiments, the therapies are more effective due to the combined administration. For example, the second treatment is more effective; e.g., a comparable effect is seen with less (e.g., a lower dose) of the second treatment, or the second treatment results in greater relief of symptoms than would be seen if the second treatment were administered without the first treatment, or a similar condition is seen with the first treatment. In some embodiments, delivery of the therapies results in a reduction in symptoms or other parameters associated with the disorder / condition that is greater than would be observed with one treatment delivered in the absence of the other treatment. In embodiments, the effects of the two therapies may be partially additive, fully additive, or greater than additive. In embodiments, delivery may be such that the effect of the first delivered treatment is still detectable when the second treatment is delivered.

[0074] "Fructooligosaccharides" or "FOS," as these terms are used herein, refer to fructose polymers consisting of the following sequence, optionally including a terminal glucose: (Fru)n-Glc, consisting of one or more of beta-2,1, beta-2,6, alpha-1,2, and beta-1,2 glycosidic linkages (where n is typically 3-10). Variants include inulin-type beta-1,2 and levan-type beta-2,6 linkages between fructosyl units in the backbone. In one embodiment, the FOS is selected from the group consisting of B. macerans, Z. mobilis, L. reutri, A. niger, A. japonicas, A. foetidus, A. sydowi,b, A. pulllans, C. purpurea, F. oxysporum, and the like. In some embodiments, the FOS are produced by enzymes derived from P. rum, P. citrinum, P. frequentans, P. spinulosum, P. rigulosum, P. parasitica, S. brevicaulis, S. cerevisiae, or K. marxianus. In other embodiments, the FOS are produced by the enzymatic action of a fructosyltransferase, β-fructofuranosidase (EC 3.2.1.26), inulosucrase (EC 2.4.1.9), levansucrase (EC 2.4.1.10), or endo-inulinase.

[0075] As used herein, a "glycan polymer preparation" (also referred to as a "glycan polymer preparation," "glycan preparation," or "glycan polymer") is a preparation containing glycan polymers that exhibit a desired effect (e.g., a therapeutic or regulatory effect (e.g., with respect to an exogenous substance) or a beneficial effect (e.g., with respect to the health of a subject)). In some embodiments, the glycan polymer preparation is prepared from one or more naturally occurring oligosaccharides, such as glucooligosaccharides, mannanoligosaccharides, inulin, lycunose, maltotetraose, nigerotetraose, nystose, sesemose, stachyose, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriose, raffinose, kestose, and fructooligosaccharides. , 2'-fucosyllactose, galactooligosaccharide, glycosyl, idraparinux, isomaltooligosaccharide, maltodextrin, xylooligosaccharide, agar, agarose, alginic acid, alguronic acid, alpha-glucan, amylopectin, amylose, arabioxiran, beta-glucan, callose, capsulan, carrageenan, cellodextrin, cellulin, cellulose, chitin, chitin nanofibril, chitin-glucan complex , Chitosan, Chrysolaminarin, Curdlan, Cyclodextrin, Alpha-Cyclodextrin, Dextran, Dextrin, Dialdehyde Starch, Ficoll, Fructan, Fucoidan, Galactoglucomannan, Galactomannan, Galactosaminogalactan, Gellan Gum, Glucan, Glucomannan, Glucuronoxylan, Glycocalyx, Glycogen, Hemicellulose, Hypromellose, Icodextrin, Kefiran, Laminarin Does not contain lentinan, levan polysaccharide, lichenin, mannan, mucus, natural gum, paramylon, pectic acid, pectin, pentastarch, plant glycogen, pullulan, poligeenan, polydextrose, porphyran, pullulan, schizophyllan, sepharose, sinistrin, sizofiran, sugammadex, welan gum, xanthan gum, xylan, xyloglucan, zymosan, etc.In some embodiments, the glycan polymer is present as a salt, e.g., a pharmaceutically acceptable salt. In some embodiments, the glycan preparation does not contain sorbitol. In some embodiments, the glycan preparation does not contain citric acid. In some embodiments, the glycan preparation does not contain cyclic glycans.

[0076] "Increasing drug activity," as used herein, refers to any one or more of the following: a) increasing the therapeutic effect or other beneficial effect of a drug on a weight, mole, number of molecules, or dosage unit basis. For example, if drug activity is increased, administering X mg of drug will have greater activity than administering X mg without the increase. While not wishing to be bound by mechanism, increasing drug activity can include increasing the conversion of an inactive form to an active form, for example, increasing the processing of a drug into a prodrug, decreasing the conversion of an active form of a drug to an inactive form, or decreasing the removal of an active form of a drug (e.g., by excretion); b) increasing the amount of drug that can be administered compared to the amount that can be administered before a non-therapeutic event is reached. Exemplary non-therapeutic events include toxicity, for example, drug toxicity, or toxicity of species resulting from drug metabolism or off-target activity; c) increasing the efficacy of a drug. Here, drug efficacy refers, for example, to the ability of a drug to produce an effect, for example, a desired effect, for example, increased GI motility or reduced cholesterol levels. In embodiments, drug efficacy includes the intrinsic activity of a drug, which can be expressed as the amount of biological effect produced per unit of drug-receptor complex formed. Drug bioavailability refers to the proportion of drug that enters a subject's circulation after administration and is therefore able to elicit an effect. Drug potency refers to a measure of drug activity, expressed as the amount of drug required to produce an effect of a given strength. Drug efficacy can be measured qualitatively and / or quantitatively. In embodiments, drug efficacy can be measured by detecting the improvement (e.g., elimination) of one or more symptoms of the disease / disorder the drug is intended to treat. In embodiments, drug efficacy can be measured in vitro, e.g., in cell or tissue samples, e.g., cell cultures, by determining functional readouts (e.g., protein, e.g., enzyme levels or activity, production of molecules such as second messengers, post-translational modifications such as protein phosphorylation, or changes in gene expression) after incubation of the cell or tissue sample with the drug.In other embodiments, drug efficacy can be measured ex vivo or in vivo, for example, by determining functional readouts after administration of a drug or after ex vivo incubation with a sample from a subject; d) increasing drug potency. Here, drug potency can be measured by determining the EC50 (median effective concentration) of a drug, which is the concentration of a drug at which the effect is 50% of Emax (the maximum possible effect of a drug). The lower the EC50, the higher the drug's potency. The EC50 of a drug can be determined by standard methods, for example, by measuring functional readouts in cells or tissue samples, for example, cell cultures, after administering increasing doses of the drug; or e) increasing drug (bio)availability. Here, drug bioavailability can be measured by determining the area under the plasma concentration-time curve (AUC), which is directly proportional to the total amount of drug (e.g., unmodified drug) that reaches the subject's systemic circulation.

[0077] exogenous substances The methods described herein modulate the processing of exogenous substances. In some embodiments, the methods described herein modulate the ability of the microbiome to mediate the processing of exogenous substances. Exogenous substances can include, for example, various agents, such as pharmaceutical agents, environmental toxins or poisons, dietary components, food additives, drug additives, and / or allergens.

[0078] The pharmaceutical agent may be, for example, a protein / peptide / polypeptide (e.g., an antibody molecule or fragment thereof), a nucleic acid (e.g., DNA, RNA, and / or an inhibitory nucleic acid, e.g., siRNA, RNAi, miRNA), or modified versions thereof, or a small molecule.

[0079] Pharmaceutical agents include enzymes, receptors, antibodies, or adaptor proteins. In embodiments, pharmaceutical agents are FDA-approved drugs, e.g., approved to prevent or treat a disorder, disease, or condition described herein.

[0080] In some embodiments, the pharmaceutical agent is, for example, a prodrug that requires bioactivation by the subject (e.g., by microorganisms in the subject, e.g., intestinal microorganisms in the subject) to become an active drug. Examples of prodrugs are irinotecan, prontosil, or sulfasalazine. For example, the prodrug contains an azo bond, such as prontosil and sulfasalazine.

[0081] Exemplary classes of pharmaceutical agents include, but are not limited to, anti-inflammatory agents, nonsteroidal anti-inflammatory drugs (NSAIDs), statins, antioxidants, antimicrobial agents (e.g., antibiotics or antifungals), cancer treatments, immunotherapy (e.g., for cancer), antibody therapy, protein or peptide therapy, cell-based therapy, nucleic acid therapy, or macrolides.

[0082] Exemplary pharmaceutical agents (and some exemplary processed / metabolized forms thereof) include 5-aminosalicylic acid, 5-fluorouracil, balsalazide, benzylpenicillin, BILR 355, calcitonin, chloramphenicol, clonazepam, deleobvir, diclofenac (glucuronide), digoxin, eltrombopag, flucytosine, glyceryl trinitrate, glycyrrhizin, indocin (n-oxide), indomethacin glucuronide, insulin, isorbidiol dinitrate, ketoprofen (glucuronide), levamisole, levodopa, loperamide (N-oxide), lovastatin, methamphetamine, methotrexate, metronidazole,

[0013] Examples of suitable anti-inflammatory drugs include benzodiazepines, ...

[0083] Exemplary pharmaceutical agents (and some exemplary processed / metabolized forms thereof) include: i) Non-steroidal anti-inflammatory (NSAID) drugs, such as 5-aminosalicylic acid and its derivatives, e.g., balsalazide, olsalazine, sulfasalazine (aminosalicylic acid anti-inflammatory drugs), diclofenac (=>glucuronide) (for pain, migraine and arthritis), indocin (=>N-oxide), indomethacin (=>glucuronide), ketoprofen (=>glucuronide) (propionates), sulindac, etc. ii) Chemotherapeutic drugs, such as 5-fluorouracil and methotrexate (antimetabolites, antineoplastic drugs, and immunosuppressants for cancer), irinotecan (SN-38G) (colon and rectal cancer), etc. iii) Antibiotics / antibacterial agents, such as benzylpenicillin (penicillin-based antibacterial agents), chloramphenicol, metronidazole, prontosil, neoprontosil, sulfapyridine, etc. iv) Antiviral agents, such as BILR 355 and Sorivudine (nucleoside analogue / reverse transcriptase inhibitors, e.g., for HIV), Deleobvir (non-nucleoside polymerase inhibitor for Hepatitis C virus), etc. v) Antifungal agents, such as flucytosine (5-FC) (a pyrimidine analogue) vi) Antinematodes (e.g., antihelminthic drugs), such as levamisole (an immunomodulator for hookworm infections) vii) Hormones, e.g., calcitonin (thyroid hormone, e.g., for osteoporosis, cancer-related bone pain), insulin (blood sugar levels), etc. viii) Sedatives, such as clonazepam (a benzodiazepine for seizures, panic disorder, and anxiety) ix) Cardiac medications / hypertension medications, e.g., cardiac glycosides such as digoxin (antiarrhythmic for heart failure), glyceryl trinitrate (for heart failure and high blood pressure), isosorbide dinitrate (for chest pain (angina)), etc. x) Colony-stimulating factors, such as eltrombopag (a bone marrow stimulating drug for thrombocytopenia and aplastic anemia) xi) Emulsifiers / gel-forming agents, such as glycyrrhizin (saponin, e.g., for food and cosmetics) xii) Dopamine, such as levodopa (a dopamine precursor in Parkinson's disease and parkinsonian-like conditions) xiii) Opioid receptor agonists, e.g. loperamide (=>N-oxide) (for diarrhea) xiv) Statins, such as lovastatin (for high cholesterol and triglyceride levels) xv) CNS stimulants, such as methamphetamine (for ADHD and opiate use) xvi) Sensitizers / radiotherapeutic agents, such as misonidazole (a nitroimidazole that acts as a radiosensitizer in radiotherapy). xvii) Narcotic analgesics, e.g., morphine (=>6-glucuronide), etc. xviii) Hypnotics, such as nitrazepam (benzodiazepines for anxiety, insomnia, amnesia, anticonvulsants and skeletal muscle relaxants) xix) Antacids / proton pump inhibitors, such as nizatidine, ranitidine, and omeprazole (H2 antagonists) (for ulcers, gastroesophageal reflux disease (GERD)) xx) Painkillers, such as phenacetin (pain relief) xxi) Uricase inhibitors, such as potassium oxonate (for preventing 5-fluorouracil-induced gastrointestinal toxicity) xxii) Antipsychotics, such as risperidone (for schizophrenia, bipolar disorder, and autism-related agitation) xxiii) Laxatives, such as sennosides (senna glycosides) and sodium picosulfate (for constipation) xxiv) Sulfonamides, such as succinylsulfathiazole, sulfapyridine, sulfasalazine, etc. xxv) Anticonvulsants, such as zonisamide (for seizures and epilepsy) xxvi) Immunotherapeutic agents, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and CpG oligonucleotides (for cancer).

[0084] In embodiments, dietary components may include substances that are derived from the diet and may be biologically active, eg, may affect the health and / or disease of a subject.

[0085] In embodiments, the dietary ingredient comprises caffeic acid, chlorogenic acid, choline, cycasin, ellagic acid, geniposide, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), quinic acid, ellagitannins (e.g., punicalagin, peduncladin), flavones (e.g., baicalin, catechin / epicatechin, hesperidin, quercetin-3-glucoside), isoflavones (e.g., daidzein, genistein, glycitein), and / or lignans (e.g., pinoresinol, secoisolariciresinol).

[0086] In embodiments, the dietary component comprises a polyphenol, e.g., a polyphenol described herein, e.g., an anthocyanin or proanthocyanidin. In embodiments, the dietary component comprises a phytoestrogen, e.g., a phytoestrogen described herein, e.g., an isoflavone or lignan. In embodiments, the dietary component comprises a heterocyclic amine. In embodiments, the dietary component comprises a choline-containing compound, e.g., L-carnitine or phosphatidylcholine.

[0087] Food and / or drug additives may include chemicals added to foods and / or drugs, for example, to enhance shelf life and / or flavor. Such food and drug additives may interact with intestinal microorganisms. Examples of food additives include artificial sweeteners (e.g., cyclamate, xylitol, saccharin), emulsifiers (e.g., carboxymethylcellulose or polysorbate 80), and / or contaminants (e.g., melamine). Some contaminants in food, such as melamine and its processing intermediates, can be harmful. Examples of food and drug additives include acedobene, cyclamate, lactitol, lactulose, melamine, rebaudioside A, and / or stevioside.

[0088] Environmental toxins and poisons can include chemicals that can affect gut microbes, for example, affecting their growth and / or metabolism. Exemplary environmental toxins can include bisphenol A, oxybenzone, fluoride, parabens, phthalates, butylated hydroxyanisole, perfluorooctanoic acid, perchlorates, decabromodiphenyl ether, and asbestos.

[0089] An allergen is a type of antigen that produces an abnormal and intense immune response and is normally recognized by the body as harmless. Exemplary classes of allergens include animal components, drugs, foods, insect components, mold spores, chemicals, and plant components. Exemplary animal component allergens include Fel d1 (from cats), animal fur, animal dander, cockroach caps, wool, and house dust mite feces. Exemplary drug allergens include penicillin, sulfonamides, and salicylates. Exemplary food allergens include celery, celeriac, corn, maize, eggs (e.g., egg albumin), fruits, legumes (e.g., beans, peas, peanuts, soybeans), milk, seafood, sesame, soybeans, tree nuts (e.g., pecans, almonds), and wheat. Exemplary insect component allergens include bee sting venom, wasp sting venom, and mosquito bite venom. Exemplary chemical allergens include nickel sulfate, balsam of Peru, fragrance, quaternium-15, neomycin, latex, and metals. Exemplary plant component allergens include wood, grasses (e.g., ryegrass or timothy grass), weeds (e.g., ragweed, plantain, nettle, Chenopodium album, sorrel, Artemisia vulgaris), and trees (e.g., birch, alder, hazel, hornbeam, horse chestnut (Aesculus), willow, plane tree (Platanus), linden (Tilia), olive (Olea), poplar, Ash juniper, and Alstonia scholaris).

[0090] Processing of exogenous substances chemical reaction In embodiments, the processing of exogenous substances includes regulating the level of derivatization and / or degradation of exogenous substances. In one embodiment, the glycan composition regulates the ability of microorganisms, such as intestinal microorganisms, to process, for example, derivatize and / or degrade, for example, exogenous substances, such as drugs, or drug metabolites or intermediates, to produce an entity, for example, an enzyme. In embodiments, the processing of exogenous substances includes metabolism (e.g., the production of one or more metabolites or intermediates, for example, from exogenous substances as starting materials).

[0091] In embodiments, the processing of exogenous substances includes reactions such as hydrolysis, oxidation, reduction, aromatization, alkylation, acylation, phosphorylation, glycosylation, sulfation, and / or nitrosylation. In one embodiment, the glycan composition modulates the ability of microorganisms, such as intestinal microorganisms, to produce enzymes that catalyze the hydrolysis, oxidation, reduction, aromatization, alkylation, acylation, phosphorylation, glycosylation, sulfation, and / or nitrosylation of exogenous substances. In embodiments, the exogenous substance is a drug, drug metabolite, drug additive, food, food additive, allergen, toxin, or poison.

[0092] In embodiments, the treatment occurs in vivo, eg, in a host, eg, a subject described herein.

[0093] Provided herein is a method for (i) hydroxylation, (ii) methylation, (iii) sulfonation, (iv) hydrolysis, (v) oxidation, (vi) reduction, (vii) aromatization, (viii) alkylation, (ix) acylation, (x) phosphorylation, (xi) glycosylation, (xii) sulfation, and / or (xiii) nitrosylation of an exogenous substance in a subject in vivo, comprising administering a glycan composition to the subject. In one embodiment, the glycan composition modulates the ability of microorganisms in the microbiome, such as gut microorganisms, to produce enzymes that: i) hydroxylation, (ii) methylation, (iii) sulfonation, (iv) hydrolysis, (v) oxidation, (vi) reduction, (vii) aromatization, (viii) alkylation, (ix) acylation, (x) phosphorylation, (xi) glycosylation, (xii) sulfation, and / or (xiii) nitrosylation of an exogenous substance. In embodiments, the exogenous substance is a drug, a drug metabolite, a drug additive, a food, a food additive, an allergen, a toxin, or a poison.

[0094] In some embodiments, the modification of an exogenous substance can be detected and / or pharmacokinetic parameters can be determined by mass spectrometry, for example, mass spectrometry of a blood, feces, or urine sample taken from a subject. In some embodiments, the modification of an exogenous substance can be detected and / or pharmacokinetic parameters can be determined by in vitro testing, for example, using an isolated biological sample (e.g., a fecal sample such as a fecal slurry), an isolated microorganism (e.g., an isolated bacterial taxon), and / or an isolated enzyme or purified enzyme extract (e.g., a microbial enzyme) that uses the isolated exogenous substance as a substrate and modifies the exogenous substance in vitro, e.g., in a test vessel, optionally using appropriate solvents, buffers, energy sources, and other suitable reaction conditions, and a suitable assay for detecting the modification.

[0095] In embodiments, any one of (i)-(xiii) is performed by a microorganism, e.g., a bacterial taxon. In embodiments, any one of (i)-(xiii) is performed by an enzyme, e.g., a microbial enzyme. In embodiments, any one of (i)-(xiii) is performed by a host enzyme (e.g., a non-microbial, human, or mammalian enzyme). In embodiments, any one of (i)-(xiii) is performed in the gastrointestinal tract, e.g., the stomach, small intestine, and / or large intestine. In embodiments, any one of (i)-(xiii) is performed in a region of the small intestine (e.g., the duodenum, jejunum, or ileum). In embodiments, any one of (i)-(xiii) is performed in a region of the large intestine (e.g., the cecum, colon, or rectum). In embodiments, any one of (i)-(xiii) is substantially performed in the colon.

[0096] Treated enzymes In embodiments, processing of exogenous materials is performed by enzymes, e.g., microbial (e.g., bacterial) enzymes, or host enzymes (e.g., eukaryotic enzymes, e.g., mammalian enzymes, e.g., human enzymes). In embodiments, processing includes derivatization and / or degradation. Processing, e.g., derivatization and / or degradation, can be performed by enzymes described herein. Exemplary enzymes include (i) oxidoreductases (EC1) (e.g., dehydrogenases, oxidases, catalases), (ii) transferases (EC2) (e.g., aminotransferases, peptidyl transferases, glycosyltransferases), (iii) hydrolases (EC3) (e.g., reductases (e.g., metalloreductases), aromatase / cyclases, phosphorylases, glycosidases, cellulases, amylases, ureases, lipases, proteases, peptidases, mannose, etc.). (v) isomerases (EC5) (e.g., epimerases, mutases), (vi) ligases (EC6) (e.g., synthases), (vii) azoreductases (e.g., arylamine N-acetyltransferases), (viii) beta-glucuronidases (e.g., uridine diphosphate (UDP)-glucuronosyltransferases), and / or (ix) carboxylesterases.

[0097] In embodiments, the enzyme acts on one or more of the following types of bonds: (i) ester bonds, (ii) ether bonds, (iii) peptide bonds, (iv) carbon-nitrogen bonds, e.g., non-peptide bonds, (v) acid anhydrides, (vi) carbon-carbon bonds, (vii) halide bonds, (viii) phosphorus-nitrogen bonds, (ix) sulfur-nitrogen bonds, (x) carbon-phosphorus bonds, (xi) sulfur-sulfur bonds, and / or (xii) carbon-sulfur bonds.

[0098] In embodiments, the enzyme comprises a reductase, such as nitrate / nitrite / nitric oxide reductase, arsenate reductase, ferric / ferric reductase, chlorate reductase, fumarate reductase, aldehyde reductase, peroxide reductase, CO2 reductase, morphinone reductase, TMAO reductase, sulfite reductase, DMSO reductase, ribonucleotide reductase, fatty acid reductase, xylose reductase, thioredoxin reductase, chromium reductase, perchlorate reductase, or dihydrofolate reductase.

[0099] In embodiments, the enzyme comprises a hydrolase, such as a carboxylic acid ester hydrolase, a thioester hydrolase, a phosphate mono(di)(tri)ester hydrolase, a sulfate ester hydrolase, a diphosphate monoester hydrolase, a phosphate triester hydrolase, an exodeoxyribonuclease, an exonuclease, an endodeoxyribonuclease, an endoribonuclease, a glycosylase, a glycosidase (O, N, or S glycosidase), a trialkylsulfonium hydrolase, an ether hydrolase, or a peptidase.

[0100] In embodiments, the peptidase comprises an α-amino-acylpeptide hydrolase, a peptidyl-amino acid hydrolase, a dipeptide hydrolase, a peptidyl peptide hydrolase, an aminopeptidase, a peptidyl amino acid hydrolase, an acyl amino acid hydrolase, a dipeptidase, a dipeptidyl peptidase, a tripeptidyl peptidase, a peptidyl dipeptidase, a serine-type carboxypeptidase, a metallocarboxypeptidase, a cysteine-type carboxypeptidase, an omega peptidase, a serine endopeptidase, a cysteine ​​endopeptidase, an aspartic endopeptidase, a metalloendopeptidase, a threonine endopeptidase, or an endopeptidase.

[0101] The enzymes can be produced by any of the exemplary bacterial taxa described herein, for example, in Tables 1-6.

[0102] In embodiments, the enzyme comprises an activity, eg, action on a substrate, as described herein, eg, in Tables 1-3.

[0103] The methods described herein include modifying the activity or level of an enzyme, for example, an enzyme in a microorganism or mammal, using the glycan compositions described herein. In one embodiment, the modification of enzyme activity is an increase in activity due to an increase in the number or abundance (relative abundance) of microorganisms (e.g., microorganisms that contain or can produce enzymes, or microorganisms that produce or can produce entities that increase enzyme activity), or includes such an increase. In one embodiment, the modification of enzyme activity is a decrease in activity due to a decrease in the number or abundance (relative abundance) of microorganisms (e.g., microorganisms that contain or can produce enzymes, or microorganisms that produce or can produce entities that reduce enzyme activity).

[0104] Enzyme activity (or activity of an enzyme) can include the level (e.g., expression level), the activity (e.g., specific activity) of the enzyme, and / or the availability / bioavailability of the enzyme, e.g., the enzyme, in a host. In some cases, increased enzyme activity can be desirable, for example, when the enzyme generates an active drug form from a prodrug or when the enzyme detoxifies a substrate. In embodiments, the method includes increasing enzyme activity, for example, by at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or at least 100%), or at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, at least 1000-fold or more).

[0105] In some cases, reducing enzyme activity may be desirable, for example, when the enzyme produces a toxic product, such as a metabolite or intermediate, or when the enzyme changes the active drug form so that it is more rapidly eliminated (e.g., excreted) or otherwise reduces its bioavailability. In embodiments, the reduction includes, for example, reducing the processing (e.g., the amount of material processed and / or the processing rate of the material) by at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or at least 99%), or at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, at least 1000-fold or more).

[0106] Bacterial taxa that process exogenous substances In embodiments, the exogenous substance is treated by a bacterium, e.g., a bacterial taxon, e.g., an enzyme produced by the bacterial taxon. In embodiments, the exogenous substance is metabolized by the bacterial taxon. In embodiments, the treatment comprises reducing the amount of the exogenous substance or its derivatives / metabolites / intermediates that are toxic to the subject.

[0107] In embodiments, the treatment comprises increasing the excretion of the toxic derivative, for example, decreasing the synthesis of the toxic derivative.

[0108] Exemplary bacterial taxa capable of processing exogenous materials include, for example, those described herein, eg, in Tables 1-6.

[0109] In embodiments, the methods described herein include increasing the treatment (e.g., the amount of material and / or the rate of material treatment), for example, by at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, or at least 100%), or at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, at least 1000-fold or more) relative to a reference level (e.g., the level of treatment occurring in a subject prior to administration of the glycan composition).

[0110] In embodiments, the methods described herein include reducing the processing (e.g., the amount of material processed and / or the rate of material processing), for example, by at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or at least 99%), or at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, at least 1000-fold or more).

[0111] Area of ​​bowel targeted / treated In embodiments, the exogenous substance is present in, passes through, and / or is destined for the gastrointestinal tract (e.g., the stomach, small intestine, and / or large intestine). In embodiments, the exogenous substance is present in, passes through, and / or is destined for a region of the small intestine (e.g., the duodenum, jejunum, or ileum). In embodiments, the exogenous substance is present in, passes through, and / or is destined for a region of the large intestine (e.g., the cecum, colon, or rectum). In embodiments, the exogenous substance is present in, passes through, and / or is destined for the colon. In embodiments, the exogenous substance is present systemically in the subject (e.g., present in, passes through, and / or is destined for the subject's circulation). In embodiments, the exogenous substance accumulates locally in the subject, for example, in an organ (e.g., the liver or kidney).

[0112] In embodiments, the exogenous material is processed (e.g., as described herein) in the gastrointestinal tract (e.g., the stomach, small intestine, and / or large intestine), e.g., in regions of the small intestine (e.g., the duodenum, jejunum, or ileum), or in regions of the large intestine (e.g., the cecum, colon, or rectum). In embodiments, the exogenous material is processed (e.g., as described herein) in the colon.

[0113] Example Treatments and Effects Tables 1, 2, 3, 4, 5, and 6 include exemplary processing enzymes, exemplary exogenous substances, exemplary bacterial taxa, examples of the action of enzymes on exogenous substances, and / or examples of the effects that the glycan compositions described herein may have on the enzymes and / or taxa. These effects include desired effects, such as increased drug efficacy (e.g., when the exogenous substance includes a drug), and / or reduced drug toxicity, and / or reduced exposure to toxic metabolites / substances.

[0114] [Table 1]

[0115] [Table 2]

[0116] [Table 3]

[0117] [Table 4]

[0118] [Table 5]

[0119] [Table 6]

[0120] [Table 7]

[0121] [Table 8]

[0122] [Table 9]

[0123] [Table 10]

[0124] [Table 11]

[0125] [Table 12]

[0126] [Table 13]

[0127] [Table 14]

[0128] Methods that affect drug toxicity / efficacy Bacterial taxa can process substances, such as drugs, (e.g., using bacterial enzymes) to produce or release toxic compounds / molecules. Bacterial taxa can also process toxic substances (e.g., using bacterial enzymes) to make them less toxic, for example, bacterial taxa can detoxify toxic substances. In another example, bacterial taxa can process substances, such as prodrugs (e.g., using bacterial enzymes), to convert them into active forms, e.g., thereby increasing their efficacy. In yet another example, bacterial taxa can process substances, such as drugs, e.g., active drug forms (e.g., using bacterial enzymes) to reduce or eliminate their activity. Provided herein are methods for regulating microbial taxa and microbial activity against exogenous substances, comprising administering a glycan composition described herein in an amount effective to regulate microbial taxa and / or microbial activity against the exogenous substance. The compositions and methods described herein can regulate one or more bacterial taxa and / or one or more bacterial enzymes so that the toxicity of a substance, such as a drug, is reduced and / or the efficacy of the drug is increased. For example, the compositions and methods described herein can reduce the levels of bacterial taxa (and / or reduce the activity of bacterial enzymes) that produce or release toxic compounds / molecules. In some examples, the compositions and methods described herein can increase the levels of bacterial taxa (and / or increase the activity of bacterial enzymes) that detoxify substances. In other examples, the compositions and methods described herein can increase the levels of bacterial taxa (and / or increase the activity of bacterial enzymes) that increase the efficacy of drugs, e.g., convert prodrugs to active forms. In yet other examples, the compositions and methods described herein can reduce the levels of bacterial taxa (and / or reduce the activity of bacterial enzymes) that inactivate drugs or convert drugs to less active (e.g., inactive) forms.

[0129] Provided herein is a method for reducing drug toxicity in a human subject. In an embodiment, the method comprises administering a glycan composition to the subject in an amount effective to reduce the toxicity of the drug. In an embodiment, the subject has previously been administered, is currently being administered, or is scheduled to be administered a drug (e.g., a drug associated with toxicity). In an embodiment, the glycan composition is administered in an amount and / or for a time sufficient to reduce the subject's drug toxicity (and associated symptoms, e.g., cytotoxicity, diarrhea, constipation, nausea, dizziness, weight loss, etc.) (e.g., compared to a reference level, e.g., drug toxicity in the subject prior to administration of the glycan composition). In an embodiment, the method further comprises administering a drug to the subject, for example, in combination with the glycan composition. In embodiments, the drug toxicity is at least 5% (e.g., at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or at least 99%) compared to a reference level (e.g., drug toxicity in a subject prior to administration of the glycan composition), or at least 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 100-fold, 250-fold, 500-fold, at least 1000-fold or more).

[0130] Drug toxicity refers to one or more side effects in a subject resulting from the administration of a drug to the subject. Side effects can range from discomfort (e.g., symptoms such as cytotoxicity, diarrhea, constipation, nausea, dizziness, weight loss, etc.) to, in some cases, death. Drug toxicity can result from many causes, including off-target activity, on-target toxicity, processing of the drug into toxic metabolites or intermediates, inappropriate dosage for the subject (e.g., too high a dosage), long-term use of the drug, and / or interactions between the drug and a second drug or substance. Drug toxicity depends on many factors, including age, pre-existing conditions, genetic makeup, and / or the presence of other drugs or their metabolites in the subject. Mechanistically, drug toxicity can result from the production of toxic metabolites or intermediates of the drug, on-target side effects (e.g., a drug binds to the correct target / receptor but is provided at an inappropriate concentration, exhibits suboptimal kinetics, and / or is used for the wrong symptoms), or off-target side effects (e.g., a drug binds to the wrong target / receptor).

[0131] Drug toxicity can be measured qualitatively and / or quantitatively. In embodiments, methods for measuring drug toxicity (e.g., quantitative methods) include tests (e.g., in vitro tests) that detect apoptosis and / or necrosis of host cells, for example, host cells lining the digestive tract or a portion thereof. In embodiments, the presence of apoptosis and / or necrosis in cells indicates that the drug is toxic. In embodiments, a lower degree of apoptosis and / or necrosis in cells (e.g., fewer apoptotic / necrotic cells) indicates reduced drug toxicity, for example, compared to before treatment with the glycan compositions described herein.

[0132] In embodiments, a method (e.g., a quantitative method) for measuring drug toxicity may include measuring the number or abundance of a particular microbial taxon (e.g., a microbial taxon described herein) in a sample (e.g., a fecal sample) from a subject. In embodiments, a decrease (e.g., a decrease) in the abundance of a microbial taxon and / or a decrease (e.g., a decrease) in the diversity of a microbial taxon indicates cytotoxicity, for example, compared to before treatment with a drug. In embodiments, an increase in the abundance of a microbial taxon and / or an increase in the diversity of a microbial taxon indicates reduced drug toxicity, for example, compared to before treatment with a glycan composition described herein.

[0133] In embodiments, the method for measuring drug toxicity can include measuring the level of one or more inflammatory markers and / or other biomarkers that indicate a response to injury in a subject, for example, a sample from the subject.The level of inflammatory markers and / or other biomarkers can be measured using standard methods.In embodiments, the inflammatory markers include one or more inflammatory cytokines, for example, TNF-α, IL-1, IL-6, and / or IL-10.

[0134] In embodiments, qualitative methods for measuring drug toxicity may include detecting one or more symptoms of drug toxicity in a subject, for example, constipation, diarrhea, inflammation, and / or vomiting.

[0135] Also provided herein is a method for increasing the efficacy, potency, and / or bioavailability of a drug in a subject, comprising administering a glycan composition to the subject. In an embodiment, the subject has previously been administered, is currently being administered, or is scheduled to be administered a drug. In an embodiment, the glycan composition is administered in an amount and / or for a sufficient time to increase the efficacy, potency, and / or bioavailability of the drug in the subject (e.g., compared to a reference level, e.g., the drug toxicity in the subject before administration of the glycan composition).

[0136] Drug efficacy refers to the ability of a drug to produce a desired effect, for example, increasing GI motility or reducing cholesterol levels.In embodiments, drug efficacy includes the intrinsic activity of a drug, which can be expressed as the amount of biological effect produced per unit of drug-receptor complex formed.Drug bioavailability refers to the proportion of drug that enters the subject's circulation after administration and can thereby produce an effect.Drug potency refers to the measure of drug activity, expressed as the amount of drug required to produce a given strength of effect.

[0137] Drug efficacy can be measured qualitatively and / or quantitatively. In embodiments, drug efficacy can be measured by detecting an improvement (e.g., disappearance or milder form) of one or more symptoms of the disease / disorder that the drug is intended to treat. In embodiments, drug efficacy can be measured in vitro, for example, in a cell or tissue sample, for example, in a cell culture, by determining a functional readout (e.g., protein, e.g., enzyme level or activity, production of molecules such as second messengers, post-translational modifications such as protein phosphorylation, or changes in gene expression) after incubation of the cell or tissue sample with the drug. In other embodiments, drug efficacy can be measured ex vivo or in vivo, for example, by determining a functional readout after administration of the drug or after ex vivo incubation with a sample (e.g., a fecal sample) from a subject.

[0138] Drug potency is the amount of max The EC of a drug, the concentration of the drug that is 50% of the maximum possible effect of the drug. 50 The EC (median effective concentration) can be measured by determining the EC 50 The lower the EC, the higher the drug's potency. 50 can be determined by standard methods, for example, by measuring functional readouts in cell or tissue samples, e.g., cell cultures, after administration of increasing doses of a drug.

[0139] The bioavailability of a drug can be measured by determining the area under the plasma concentration-time curve (AUC), which is directly proportional to the total amount of drug (e.g., unmodified drug) that reaches the systemic circulation of a subject.

[0140] In some embodiments, the compositions and methods may achieve one or more desired effects described in Table 1, 2, or 3. In embodiments, the methods include modulating the activity of an enzyme and / or the level of a microorganism described in Table 1, 2, or 3, or Table 4, 5, or 6. In embodiments, the methods include administering a composition to a subject who has been administered, is being administered, or will be administered an exogenous substance described herein, e.g., in Table 1, 2, or 3.

[0141] Also provided herein is a method for identifying or selecting a treatment regimen for a subject. In an embodiment, this method includes: a) obtaining the presence or level of a bacterial taxon or microbial metabolite, or enzyme activity value in a subject; b) selecting a glycan composition for treating the subject according to the value; And c) administering the glycan composition in an amount and / or for a sufficient time to treat the subject.

[0142] In embodiments, the method further comprises, prior to step (a), selecting a subject to which an exogenous substance, e.g., an environmental toxin or poison, a pharmaceutical agent or drug, a dietary component, a food additive, or a drug additive, has been administered, is being administered, or will be administered.

[0143] Also provided herein are methods for selecting a subject for treatment using the glycan compositions described herein. In embodiments, the subject is selected based on exposure to an exogenous substance, such as an exogenous substance described herein. In embodiments, the subject is selected for treatment if the subject has been administered (exposed to or contacted), is being administered (exposed to or contacted), or will be administered (exposed to or contacted) with an exogenous substance (e.g., an environmental toxin or poison, a pharmaceutical or drug, a dietary component, a food additive, or a drug additive). In embodiments, the exogenous substance includes an allergen. In other embodiments, the subject is selected if the subject has a disease / condition, such as an immune disease, an infectious disease, a metabolic disease, a neurodegenerative disease, cancer, an allergy, or other disease or disorder or adverse condition, including a precondition or predisposition to develop a disease or disorder. In embodiments, the subject is selected if the enzymatic activity (e.g., enzyme level and / or enzyme specific activity), for example, microbial enzyme activity, is deficient (e.g., determined to be deficient). In embodiments, a subject is selected if it has (e.g., is determined to have) an excess amount of an enzyme and / or an overactive enzyme, e.g., a microbial enzyme. In embodiments, the enzyme is an enzyme described herein, e.g., in Tables 1, 2, or 3. In embodiments, the enzyme is an enzyme having an activity or catalyzing a reaction described herein, e.g., in the "Treatment of Exogenous Substances" section herein. In embodiments, a subject is selected if it has a deficiency (e.g., is determined to be deficient) of a microbial taxon. In embodiments, a subject is selected if it has an excess (e.g., is determined to be excessive) of a microbial taxon. In embodiments, the bacterial taxon includes a beneficial bacterial taxon, e.g., a bacterial taxon the levels of which are desired to be increased according to Tables 1, 2, 3, and 4-6. In embodiments, the bacterial taxon includes a harmful bacterial taxon, e.g., a bacterial taxon the levels of which are desired to be decreased according to Tables 1, 2, 3, and 4-6.

[0144] Glycan polymer compositions and their production The glycan composition may contain the glycans described herein, dietary fiber, e.g., FOS (fructooligosaccharides), other sugars (e.g., monomers, dimers, e.g., lactulose), and sugar alcohols, and optionally other components, such as polyphenols, fatty acids, peptides, micronutrients, such as those described in WO 2016 / 172658, "MICROBIOME REGULATORS AND RELATED USES THEREOF," and microorganisms such as bacteria.

[0145] The glycan preparations described in WO 2016 / 122889, "GLYCAN THERAPEUTICS AND RELATED METHODS THEREOF" and WO 2016 / 172657, "GLYCAN THERAPEUTICS AND METHODS OF TREATMENT" (which are incorporated by reference in their entireties) are suitable for the methods and compositions described herein.

[0146] Preparations containing glycans can be produced by non-enzymatic catalysts, such as the polymer catalysts described in WO 2012 / 118767, "POLYMERIC ACID CATALYSTS AND USES THEREOF," or other suitable methods. Methods for preparing the polymer catalysts and solid-supported catalysts described herein can be found in WO 2014 / 031956, "POLYMERIC AND SOLID-SUPPORTED CATALYSTS, AND METHODS OF DIGESTING CELLULOSIC MATERIALS USING SUCH CATALYSTS." For example, glycans produced by using catalysts such as those described in WO 2016 / 007778, "OLIGOSACCHARIDE COMPOSITIONS AND METHODS FOR PRODUCING THEREOF," are suitable for the methods and compositions described herein. All patent applications are incorporated herein by reference in their entirety.

[0147] In some embodiments, the glycan polymers are made using glycosidase enzyme molecules under conditions suitable for producing the glycan polymers.

[0148] In some embodiments, glycan polymers are produced by solid-phase oligosaccharide synthesis, e.g., using various protecting groups to achieve glycan polymer synthesis. Exemplary methods are described in "Solid-Phase Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries," Peter H. Seeberger and Wilm-Christian Haase, American Chemical Society, 2000; and "Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research," Thomas J. Boltje et al., Nat. Chem. 2009 November 1;1(8):611-622.

[0149] Glycan preparation characteristics The glycans may have one or more of the characteristics and properties described in WO 2016 / 122889, WO 2016 / 172657, WO 2016 / 007778 and WO 2016 / 172658 (each of which is incorporated by reference in its entirety), as well as the characteristics and properties described herein.

[0150] The glycan polymers produced by the methods described herein can contain oligosaccharides. In some embodiments, the glycan polymers contain homooligosaccharides (or homoglycans), where all monosaccharides in the polymer are of the same type.

[0151] In some embodiments, the glycan polymer comprises a heterooligosaccharide (or heteroglycan), in which multiple types of monosaccharides are present in the polymer. In some embodiments, the glycan polymer has one or more of the properties described herein. In some embodiments, the glycan polymer preparation has one or more of the bulk properties described herein.

[0152] Degree of polymerization (DP) In some embodiments, glycan polymer preparations, such as those produced using the methods described herein, are polydisperse and exhibit a range of degrees of polymerization.

[0153] Optionally, the preparation may be fractionated to represent, for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or greater than 98% short (DP about 1-2), medium (DP about 3-10), long (DP about 11-18), or very long (DP >18) species. In one embodiment, a polydisperse fractionated glycan polymer preparation is provided that comprises at least 85%, 90%, or at least 95% medium length species having a DP of about 3-10. In one embodiment, a polydisperse fractionated glycan polymer preparation is provided that comprises at least 85%, 90%, or at least 95% long species having a DP of about 11-18. In one embodiment, a polydisperse fractionated glycan polymer preparation is provided that comprises at least 85%, 90%, or at least 95% very long species having a DP of about 18-30.

[0154] Optionally, the preparation may be fractionated to represent, for example, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or greater than 98% of the short (DP about 1-2) or medium (DP about 3-10) glycans in the preparation. Alternatively, or in addition to fractionation, the small DP fraction (e.g., monomers and dimers) is subjected to enzymatic fermentation, e.g., using yeast suitable for degrading these sugars. In one embodiment, a polydisperse fractionated glycan polymer preparation comprising at least 85%, 90%, or at least 95% glycans having a DP of about 3-10 is prepared using the methods described herein.

[0155] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymers of the glycan preparation have a DP of at least DP3, DP4, DP5, DP6, or DP7. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymers of the glycan preparation have a DP of about DP3 to about DP10, about DP3 to about DP8, about DP3 to about DP6, about DP3 to about DP5, about DP3 to about DP4, about DP2 to about DP4, about DP2 to about DP5, about DP2 to about DP6, about DP2 to about DP8, or about DP2 to about DP10. In some embodiments, less than 1%, 2%, 3%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, or less than 50% of the glycan polymers of the glycan preparation have a DP of DP2 or less.

[0156] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of 2 to 25, 3 to 25, 4 to 25, 5 to 25, 6 to 25, 7 to 25, 8 to 25, 9 to 25, 10 to 25, 2 to 30, 3 to 30, 4 to 30, 5 to 30, 6 to 30, 7 to 30, 8 to 30, 9 to 30, or 10 to 30. In one embodiment, the glycan polymer preparation has a degree of polymerization (DP) of at least 3 and less than 30 glycan units.

[0157] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of 5 or more and less than 30 glycan units. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of 8 or more and less than 30 glycan units. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of 10 or more and less than 30 glycan units. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of glycan units between 3, 4, 5, 6, 7, 8 and 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of glycan units between 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of between 3, 4, 5, 6, 7, 8, 9, 10 and 20, 21, 22, 23, 24, 25, 26, 27, 28 glycan units. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of at least 2. In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has a DP of at least 3.

[0158] Average DP In some embodiments, the glycan polymer preparation has an average degree of polymerization (average DP) of about DP2, DP3, DP4, DP5, DP6, DP7, DP8, or DP9. In some embodiments, the glycan polymer preparation has an average degree of polymerization (average DP) of about 2 to about 10, about 2 to about 8, about 2 to about 6, about 2 to about 4, about 3 to about 10, about 3 to about 8, about 3 to about 6, or about 3 to about 4.

[0159] In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymer preparation has an average degree of polymerization (average DP) of about DP5, DP6, DP7, DP8, DP9, DP10, DP11, or DP12. In some embodiments, the average DP of the glycan polymer preparation is about DP5-DP10, about DP6-DP10, about DP6-DP12, about DP6-DP14, about DP8-DP12, about DP8-DP14, about DP8-DP16, about DP10-DP16, about DP10-DP18, about DP4-DP18, about DP6-DP18, or about DP8-DP18.

[0160] average molecular weight In some embodiments, about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or about 97% of the glycan polymers of the preparation are at about 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800 g / mol, 400, 500, 600, 700, 80 ... , 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, and 5000 g / mol.

[0161] Degree of branching (DB) In some embodiments, the glycan preparation has a structure that varies from linear to branched. Branched glycans can contain at least one glycan subunit linked via an alpha or beta glycosidic bond to form a branch. The branching rate or degree of branching (DB) can vary so that the glycan polymers of the preparation contain at least one, at least two, at least three, at least four, at least five, or at least about six branching points in the glycan polymer. In some embodiments, the glycan polymers of the glycan preparation are unbranched (DB=0).

[0162] In some embodiments, glycan preparations (e.g., oligosaccharides or polysaccharides) range from linear to highly branched structures. Unbranched glycans may contain only alpha or only beta linkages. Unbranched glycans may contain at least one alpha linkage and at least one beta linkage. Branched glycans may contain at least one glycan unit linked via an alpha or beta glycosidic bond to form a branch. The branching rate or degree of branching (DB) may vary, such that approximately every 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 15th, 20th, 25th, 30th, 35th, 40th, 45th, 50th, 60th, or 70th unit contains at least one branch point. For example, animal glycogen contains a branch point approximately every 10th unit.

[0163] In some embodiments, a preparation of glycan polymers is provided, the preparation comprising a mixture of branched glycans, the average degree of branching (DB, branch points per residue) is 0, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, 0.99, 1, or 2. In some embodiments, a preparation of glycan polymers is provided, the average degree of branching is at least 0.01, 0.05, 0.1, 0.2, 0.3, or at least 0.4. In some embodiments, a preparation of glycan polymers is provided, the average degree of branching is about 0.01-0.1, 0.01-0.2, 0.01-0.3, 0.01-0.4, 0.01-0.5, 0.01-0.6, or about 0.01-0.7. In some embodiments, a preparation of glycan polymers is provided, the average degree of branching is about 0.05-0.1, 0.05-0.2, 0.05-0.3, 0.05-0.4, 0.05-0.5, 0.05-0.6, or about 0.05-0.7. In some embodiments, a preparation of glycan polymers is provided, the average degree of branching is not zero. In some embodiments, a preparation of glycan polymers is provided, the average degree of branching is not greater than 0.1 and less than 0.4, or not greater than 0.2 and less than 0.4. In some embodiments, the glycan polymer preparation comprises linear glycans. In some embodiments, the preparation of glycan polymers comprises glycans that exhibit branched or branch-on-branch structures.

[0164] In some embodiments, a preparation of glycan polymers is provided, wherein the average degree of branching (DB) is not 0, is at least 0.01, 0.05, 0.1, or at least 0.2, or is in the range of about 0.01 to about 0.2 or about 0.05 to 0.1.

[0165] Glycosidic bonds and glycosidic linkages The linkages between individual glycan subunits found in preparations of glycan polymers can include alpha 1->2, alpha 1->3, alpha 1->4, alpha 1->5, alpha 1->6, alpha 2->1, alpha 2->3, alpha 2->4, alpha 2->6, beta 1->2, beta 1->3, beta 1->4, beta 1->5, beta 1->6, beta 2->1, beta 2->3, beta 2->4, and beta 2->6.

[0166] In some embodiments, the glycan polymer preparation comprises only alpha linkages. In some embodiments, the glycan polymer comprises only beta linkages. In some embodiments, the glycan polymer comprises a mixture of alpha and beta linkages.

[0167] In some embodiments, the ratio of alpha-glycosidic linkages to beta-glycosidic linkages in the preparation is about 1:1, 2:1, 3:1, 4:1, or 5:1. In some embodiments, the ratio of beta-glycosidic linkages to alpha-glycosidic linkages in the preparation is about 1:1, 2:1, 3:1, 4:1, or 5:1.

[0168] In some embodiments, the ratio of alpha-glycosidic bonds to beta-glycosidic bonds in the preparation is about 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.7:1, 2:1, 2.2:1, 2.5:1, 2.7:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or about 10:1.

[0169] In some embodiments, the glycan polymers of the glycan polymer preparation contain both alpha and beta glycosidic linkages selected from the group consisting of 1->2 glycosidic linkages, 1->3 glycosidic linkages, 1->4 glycosidic linkages, 1->5 glycosidic linkages, and 1->6 glycosidic linkages. In some embodiments, the glycan polymer preparation contains at least two, or at least three, alpha and beta 1->2 glycosidic linkages, alpha and beta 1->3 glycosidic linkages, alpha and beta 1->4 glycosidic linkages, alpha and beta 1->5 glycosidic linkages, and / or alpha and beta 1->6 glycosidic linkages.

[0170] In some embodiments, the glycan polymers of the glycan preparation comprise substantially all glycan subunits of the alpha or beta configuration, optionally each comprising about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the other configurations.

[0171] In some embodiments, the preparation of glycan polymers comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, at least 99.9%, or even 100% glycans having alpha glycosidic linkages. In some embodiments, the preparation of glycan polymers comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, at least 99.9%, or even 100% glycans having beta-glycosidic linkages. In some embodiments, a preparation of glycan polymers is provided in which at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% of the glycans having glycosidic linkages are alpha-glycosidic, and at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% of the glycans having glycosidic linkages are beta-glycosidic, and the ratio of alpha-glycosidic and beta-glycosidic linkages does not exceed 100%.

[0172] In some embodiments, a preparation of glycan polymers is provided in which at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, at least 99.9%, or even 100% of the glycan glycosidic linkages are one or more of 1->2 glycosidic linkages, 1->3 glycosidic linkages, 1->4 glycosidic linkages, and 1->6 glycosidic linkages. In some embodiments, a preparation of glycan polymers is provided in which at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, at least 20%, or 25% of each of the glycan glycosidic linkages are 1->2, 1->3, 1->4, and 1->6 glycosidic linkages. Optionally, the glycan polymer preparation further comprises at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or at least 85% of glycan glycosidic linkages selected from the group consisting of alpha 2->1, alpha 2->3, alpha 2->4, alpha 2->6, beta 2->1, beta 2->3, beta 2->4, and beta 2->6 glycosidic linkages.

[0173] In some embodiments, the glycan polymers of the glycan preparation are alpha 1->2 and alpha 1->3, alpha 1->2 and alpha 1->4, alpha 1->2 and alpha 1->6, alpha 1->2 and beta 1->2, alpha 1->2 and beta 1->3, alpha 1->2 and beta 1->4, alpha 1->2 and beta 1->6, alpha 1->3 and alpha 1->4, alpha 1->3 and alpha 1->6, alpha 1->3 and beta 1->2, alpha 1->3 and beta 1->3, alpha 1->3 and beta 1->4, alpha 1->3 and beta 1->6, alpha 1->4 and alpha 1 ->6, alpha 1->4 and beta 1->2, alpha 1->4 and beta 1->3, alpha 1->4 and beta 1->4, alpha 1->4 and beta 1->6, alpha 1->6 and beta 1->2, alpha 1->6 and beta 1->3, alpha 1->6 and beta 1->4, alpha 1->6 and beta 1->6, beta 1->2 and beta 1->3, beta 1->2 and beta 1->4, beta 1->2 and beta 1->6, beta 1->3 and beta 1->4, beta 1->3 and beta 1->6, and beta 1->4 and beta 1->6.

[0174] L-type and D-type In some embodiments, a preparation of glycan polymers is provided in which at least one glycan subunit is an L-type sugar. In some embodiments, a preparation of glycans is provided in which at least one glycan subunit is a D-type sugar. In some embodiments, a preparation of glycans is provided in which the glycan subunits are naturally occurring or more common (e.g., D-glucose, D-xylose, L-arabinose) L- or D-type sugars.

[0175] In some embodiments, the glycan polymer preparations (e.g., oligosaccharides and polysaccharides) contain a desired mixture of L- and D-type glycan subunits, for example, a desired ratio of L- to D-type or D- to L-type, such as 1:1, 1:2, 1:3, 1:4, 1:5, etc.

[0176] In some embodiments, the glycan polymer preparation comprises a desired mixture of L- and D-type glycan units, for example, a mixture of L-type to D-type or D-type to L-type in a desired ratio of 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:100, 1:150, etc.

[0177] In some embodiments, the glycan polymer preparation comprises glycans having substantially all L- or D-type glycan subunits, optionally containing about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of each of the other types.

[0178] Glycan unit content In some embodiments, a glycan polymer preparation is provided in which at least one glycan subunit is a tetrose, pentose, hexose, or heptose. Optionally, the glycan subunits involved in forming the glycans of the glycan polymer preparation are varied. Examples of monosaccharide glycan subunits include hexoses such as glucose, galactose, and fructose, and pentoses such as xylose. Monosaccharides generally have the chemical formula: Cx(H2O)y, where x is typically ≥ 3. Monosaccharides can be classified by the number of carbon atoms they contain, x, for example, diose (2), triose (3), tetrose (4), pentose (5), hexose (6), and heptose (7). Monosaccharide glycan subunits can exist in acyclic (open-chain) forms. Open-chain monosaccharides with the same molecular graph can exist as two or more stereoisomers. Monosaccharides can also exist in cyclic forms via a nucleophilic addition reaction between a carbonyl group and one of the hydroxyls of the same molecule. The reactants form a ring of carbon atoms closed by a single bridging oxygen atom. In these cyclic forms, the ring usually has five atoms (furanose) or six atoms (pyranose).

[0179] In some embodiments, the glycan polymer preparation comprises a desired mixture of different monosaccharide glycan subunits, such as a mixture of diose (2), triose (3), tetrose (4), pentose (5), hexose (6), or heptose (7). In some embodiments, the glycan polymers of the glycan polymer preparation comprise a desired mixture of pentose (5) and hexose (6).

[0180] In some embodiments, the glycan polymer preparation comprises a desired mixture of two, three, four, or five different glycan subunits, for example, one or more glycan subunits selected from i) monosaccharides selected from glucose, galactose, arabinose, mannose, fructose, xylose, fucose, and rhamnose, ii) acarviosin, n-acetyllactosamine, allolactose, cellobiose, chitobiose, galactose-alpha-1,3-galactose, gentiobiose, isomalt, isomaltose, isomaltulose, kojibiose, lactitol, lactobionic acid, lactose ... ii) one or more glycan subunits selected from disaccharides selected from tulose, laminaribiose, maltitol, maltose, mannobiose, melibiose, melibiulose, neohesperidose, nigerose, robinose, rutinose, sambubiose, sophorose, sucralose, sucrose, sucrose acetate isobutyrate, octaacetylsucrose, trehalose, turanose, vicianose, and xylobiose; and iii) acarbose, N-acetylemannosamine, N-acetylmuramic acid, N-acetylneuraminic acid, N-acetyletalosaminuronic acid. acid), arabinopyranosyl-N-methyl-N-nitrosourea, D-fructose-L-histidine, N-glycolylneuraminic acid, ketosamine, kidamycin, mannosamine, 1B-methylseleno-N-acetyl-D-galactosamine, muramic acid, muramyl dipeptide, phosphoribosylamine, PUGNAc, sialyl-Lewis A, sialyl-LewisX), validamycin, voglibose, N-acetylgalactosamine, N-acetylglucosamine, aspartylglucosamine, bacillithiol, daunosamine, desosamine, fructosamine, galactosamine, glucosamine, meglumine, and perosamine; iv) one or more glycan subunits selected from amino sugars selected from 1-5-ahydroglucitol, cladinose, colitose, 2-deoxy-D-glucose, 3-deoxyglucasone, deoxyribose, dideoxy v) one or more glycan subunits selected from deoxysugars selected from nucleotides, digitalose, fludeoxyglucose, sarmentose, and sulfoquinovose; v) one or more glycan subunits selected from iminosugars selected from castanospermine, 1-deoxynojirimycin, miglitol, miglustat, and swainsonine, N-acetylneuraminic acid, N-acetyltalosamnuronic acidacid), aldaric acid, aldonic acid, 3-deoxy-D-manno-octo-2-urosonic acid, glucuronic acid, glucosamineuronic acid, glyceric acid, N-glycolylneuraminic acid, iduronic acid, isosaccharinic acid, pangamic acid, sialic acid, threonic acid, urosonic acid, uronic acid, xylonic acid, gluconic acid, ascorbic acid, ketodeoxyoctulosonic acid, galacturonic acid, galactosaminuronic acid, mannuronic acid, mannosaminuronic acid, tartaric acid, mucic acid, saccharic acid, lactic acid, oxalic acid, succinic acid, hexanoic acid, fumaric acid, maleic acid, butyric acid, citric acid, glucosamine acid, malic acid, succinamic acid, sebacic acid, and capric acid vi) one or more glycan subunits selected from a sugar acid selected from formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, and isovaleric acid; and vii) one or more glycan subunits selected from a sugar alcohol selected from methanol, ethylene glycol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, mannitol, sorbitol, galactitol, iditol, volemitol, fucitol, inositol, maltotriitol, maltotetriitol, and polyglycitol.

[0181] Exemplary glycans are described by a three-letter code representing the monomeric sugar components, followed by a number out of 100 reflecting the proportion of the material the monomer comprises. Thus, "glu100" refers to a glycan produced from an input of 100% D-glucose (glycan unit), and "glu50gal50" refers to a glycan produced from an input of 50% D-glucose and 50% D-galactose (glycan unit), or alternatively, from an input of lactose dimers (glycan unit). As used herein, xyl = D-xylose, ara = L-arabinose, gal = D-galactose, glu = D-glucose, rha = L-rhamnose, fuc = L-fucose, man = D-mannose, sor = D-sorbitol, gly = D-glycerol, and neu = NAc-neuraminic acid.

[0182] In some embodiments, the glycan polymer preparation comprises one glycan unit A selected from i) to vii) above, wherein the glycan unit A comprises 100% of the glycan unit input. For example, in some embodiments, the glycan polymer preparation is selected from homoglycans xyl100, rha100, ara100, gal100, glu100, and man100. In some embodiments, the glycan preparation is selected from homoglycans fuc100 and fru100.

[0183] In some embodiments, the glycan polymer preparation comprises a mixture of two glycan units A and B independently selected from i) to vii) above, wherein A and B can be selected from the same or different groups i) to vii), and A and B can be selected in any desired ratio (e.g., in the range of 1 to 99% A and 99 to 1% B, but not exceeding 100%).

[0184] For example, in some embodiments, the glycan polymer preparation comprises heteroglycans ara50gal50, ara50gal50, xyl75gal25, ara80xyl20, ara60xyl40, ara50xyl50, glu80man20, glu60man40, man80glu20, man60glu40, xyl75ara25, gal75xyl25, Man80gal20, gal75xyl25, Man66gal33, Man75gal25, glu80gal20, glu60gal40, glu40gal60, glu20gal80, gal80man20, gal60man40, gal40man60, glu80xyl20, glu and man62glu38.

[0185] In some embodiments, the glycan polymer preparation comprises a mixture of three glycan units A, B, and C independently selected from i) to vii) above, wherein A, B, and C can be selected from the same or different groups in i) to vii), and A, B, and C can be selected in any desired ratio (e.g., not exceeding 100%, 1 to 99% A, 1 to 99% B, and 1 to 99% C).

[0186] For example, in some embodiments, the glycan polymer preparation comprises heteroglycans xyl75glu12gal12, xyl33glu33gal33, xyl75glu12gal12, glu33gal33fuc33, glu33gal33nman33, glu33gal33xyl33, glu33gal33ara33, gal33man33xyl33, gal33man33ara33, man52glu29gal19, Glu33Man33Xyl33, Glu33Man33Ara33, Glu33Xyl33Ara33, Gal33Man33Xyl33, Gal33Man33Ara33, Gal33Xyl33Ara33, Man33Xy and Glu45Gal45Man10.

[0187] In some embodiments, the glycan polymer preparation comprises a mixture of four glycan units A, B, C, and D independently selected from i) to vii) above, wherein A, B, C, and D can be selected from the same or different groups in i) to vii), and A, B, C, and D can be selected in any desired ratio (e.g., not exceeding 100%, 1 to 99% A, 1 to 99% B, 1 to 99% C, and 1 to 99% D).

[0188] In some embodiments, the glycan polymer preparation comprises a mixture of five glycan units A, B, C, D, and E independently selected from i) to vii) above, wherein A, B, C, D, and E can be selected from the same or different groups in i) to vii), and A, B, C, D, and E can be selected in any desired ratio (e.g., not exceeding 100%, 1 to 99% A, 1 to 99% B, 1 to 99% C, 1 to 99% D, and 1 to 99% E).

[0189] In some embodiments, a preparation of glycan polymers is provided, wherein at least one glycan subunit is selected from the group consisting of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, and rhamnose.

[0190] In some embodiments, the preparation of glycan polymers is selected from a group consisting of, for example, glucose and galactose, glucose and arabinose, glucose and mannose, glucose and fructose, glucose and xylose, glucose and fucose, glucose and rhamnose, galactose and arabinose, galactose and mannose, galactose and fructose, galactose and xylose, galactose and fucose, and galactose and rhamnose, arabinose and mannose, arabinose and fructose, arabinose and xylose, arabinose and fucose, and arabinose and rhamnose, mannose and fructose, mannose and xylose, mannose and fucose, and A desired mixture of two different monosaccharide glycan subunits, such as mixtures of mannose and rhamnose, fructose and xylose, fructose and fucose, and fructose and rhamnose, xylose and fucose, xylose and rhamnose, and fucose and rhamnose, can be prepared in a ratio of, for example, 1:1, 1:2, 1:3, 1:4, or 1:5 or in a mixture of two different monosaccharide glycan subunits. or in the inverse ratios thereof, or 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:14, 1:16, 1:18, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, or 1:100, or in the inverse ratios thereof.

[0191] In some embodiments, the glycan polymer preparation contains a desired mixture of three different monosaccharide glycan subunits, e.g., for a glucose-containing glycan preparation, glucose, galactose, and arabinose; glucose, galactose, and mannose; glucose, galactose, and fructose; glucose, galactose, and xylose; glucose, galactose, and fucose; glucose, galactose, and rhamnose; glucose, arabinose, and mannose; glucose, arabinose, and fructose; glucose, arabinose, and xylose; glucose, arabinose, and fucose; glucose, arabinose, and rhamnose; glucose, mannose, and fructose; glucose, mannose, and xylose; glucose, mannose, and fucose; glucose, mannose. Rhamnose; glucose, fructose, and xylose; glucose, fructose, and fucose; glucose, fructose, and rhamnose; mixtures of glucose, fucose, and rhamnose, etc., may be used in ratios of, for example, 1:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1:1:3, 1:2:3, 1:3:3, 1:1:4, 1:2:4, 1:1:5, 1:2:5, etc., or in ratios of 1:1:1, 1:2:1, 1:3:1, 1:4:1, 1:5:1, 1:6:1, 1:7:1, 1:8:1, 1:9:1, 1:10:1, 1:12:1, 1: 14:1, 1:16:1, 1:18:1, 1:20:1, 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1:5:2, 1:6:2, 1:7:2, 1:8:2, 1:9:2, 1:10:2, 1:1:3, 1:2:3, 1:3:3, 1:4:3, 1:5:3, 1:6:3, 1:7:3, 1:8:3, 1:9 :3, 1:10:3, 1:1:4, 1:2:4, 1:3:4, 1:4:4, 1:5:4, 1:6:4, 1:7:4, 1:8:4, 1:9:4, 1:10:4, 1:1:5, 1:2:5, 1:3:5, 1:4:5, 1:5:5, 1:6:5, 1:7:5, 1:8:5, 1:9:5, 1:10:5, etc.

[0192] In some embodiments, the glycan polymer preparation does not contain N-acetylgalactosamine or N-acetylglucosamine. In some embodiments, the glycan preparation does not contain sialic acid. In some embodiments, the glycan polymer preparation does not contain lipids or fatty acids. In some embodiments, the glycan polymer preparation does not contain amino acids.

[0193] Furanose: Pyranose In some embodiments, a preparation of glycan polymers is provided in which at least one glycan subunit is a furanose sugar. In some embodiments, a preparation of glycans is provided in which at least one glycan subunit is a pyranose sugar. In some embodiments, the glycan polymer comprises a mixture of furanose and pyranose sugars. In some embodiments, the ratio of furanose sugars to pyranose sugars in the preparation is about 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.2:1, 1.5:1, 1.7:1, 2:1, 2.2:1, 2.5:1, 2.7:1, 3:1, 4:1, 5:1, or about 6:1, or the ratio of furanose sugars to pyranose sugars in the preparation is about 7:1, 8:1, 9:1, or about 10:1.

[0194] In some embodiments, the glycan polymer preparation comprises substantially all furanose or pyranose sugars, optionally containing about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of each of the other sugars.

[0195] In some embodiments, the glycan polymer preparation comprises substantially all pyranose sugars, and the furanose-type glycan units in the preparation are less than about 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, or 5%. In some embodiments, less than 3%, 2%, or 1% of the monomeric glycan units in the preparation are furanose-type.

[0196] salt In some embodiments, the glycan polymer preparation comprises one or more glycan subunits present in a salt form (e.g., a pharmaceutically acceptable salt form), such as, for example, hydrochloride, hydroiodide, hydrobromide, phosphate, sulfate, methanesulfate, acetate, formate, tartrate, malate, citrate, succinate, lactate, gluconate, pyruvate, fumarate, propionate, aspartate, glutamate, benzoate, etc.

[0197] Derivatization If necessary, the monosaccharide or oligosaccharide glycan subunits of the glycan can be further substituted or derivatized, for example, the hydroxyl group can be etherified or esterified. For example, the glycan (e.g., oligo- or polysaccharide) can contain modified saccharide units, such as 2'-deoxyribose, in which the hydroxyl group is removed, 2'-fluororibose, in which the hydroxyl group is replaced with fluorine, or N-acetylglucosamine, nitrogen-containing forms of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose). The degree of substitution (DS, the average number of hydroxyl groups per glycosyl unit) can be 1, 2, or 3, or another suitable DS. In some embodiments, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the glycan subunits are substituted or derivatized. In some embodiments, the degree of substitution varies between subunits, for example, a certain percentage is not derivatized, exhibits a DS of 1, exhibits a DS of 2, and exhibits a DS of 3. Any desired mixture can be produced, for example, 0-99% of the subunits are underivatized, 0-99% of the subunits exhibit a DS of 1, 0-99% of the subunits exhibit a DS of 2, and 0-99% of the subunits exhibit a DS of 3, totaling 100%. The degree of substitution can be controlled by adjusting the average number of moles of substituents (molar substitution (MS)) added to the glycosyl moiety. The distribution of substituents along the length of the glycan oligosaccharide or polysaccharide chain can be controlled by adjusting the reaction conditions, reagent type, and extent of substitution. In some embodiments, the monomeric subunits are substituted with one or more of acetate ester, sulfate half ester, phosphate ester, or pyruvyl cyclic acetal groups.

[0198] solubility In some embodiments, the glycan polymer in the preparation is highly soluble. In some embodiments, the glycan polymer preparation can be concentrated to at least 55 Brix, 65 Brix, 60 Brix, 65 Brix, 70 Brix, 75 Brix, 80 Brix, or at least 85 Brix at 23 ° C. (final solubility limit) without significant solidification or crystallization. In some embodiments, the glycan polymer preparation can be concentrated to at least about 0.5 g / ml, 1 g / ml, 1.5 g / ml, 2 g / ml, 2.5 g / ml, 3 g / ml, 3.5 g / ml, or at least 4 g / ml at 23 ° C. (final solubility limit) without significant solidification or crystallization.

[0199] In some embodiments, the glycan polymer preparation (e.g., oligosaccharides) is branched, e.g., has an average DB of at least 0.01, 0.05, or 0.1, and has a final solubility limit in water at 23°C of at least about 70 Brix, 75 Brix, 80 Brix, or at least about 85 Brix, or at least about 1 g / ml, 2 g / ml, or at least about 3 g / ml.

[0200] In some embodiments, the preparation of glycan polymers has a concentration of at least 0.001 g / L, 0.005 g / L, 0.01 g / L, 0.05 g / L, 0.1 g / L, 0.2 g / L, 0.3 g / L, 0.4 g / L, 0.5 g / L, 0.6 g / L, 0.7 g / L, 0.8 g / L, 0.9 g / L, 10 g / L, 11 g / L, 12 g / L, 13 g / L, 14 g / L, 15 g / L, 16 g / L, 17 g / L, 18 g / L, 19 g / L, 20 g / L, 21 g / L, 22 g / L, 23 g / L, 24 g / L, 25 g / L, 26 g / L, 27 g / L, 28 g / L, 29 g / L, 30 g / L, 31 g / L, 32 g / L, 33 g / L, 34 g / L, 35 g / L, 36 g / L, 37 g / L, 38 g / L, 39 g / L, 40 g / L, 41 g / L, 42 g / L, 43 g / L, 44 g / L, 45 g / L, 46 g / L, 47 g / L, 48 g / L, 49 g / L, 50 g / L, 51 g / L, 52 g / L, 53 g / L, 54 g / L, 55 g / L, 56 g / L, 57 g / L, 58 g / L, 59 g / L, 60 g / L, 61 g / L, 62 g / L, 63 g / L, 64 g / 400g / L, 500g / L, 600g / L, 700g / L, 800g / L, 900g / L, and 1000g / L. In some embodiments, the glycan polymer preparation is more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or more than 99.5% soluble and has a solubility of 0.001 g / L, 0.005 g / L, 0.01 g / L, 0.05 g / L, 0.1 g / L, 0.1 g / L, 0.2 g / L, 0.3 g / L, 0.4 g / L, 0.5 g / L, 0.6 g / L, 0.7 g / L, 0.8 g / L, 0.9 g / L, 10 g / L, 11 g / L, 12 g / L, 13 g / L, 14 g / L, 15 g / L, 16 g / L, 17 g / L, 18 g / L, 19 g / L, 20 g / L, 21 g / L, 22 g / L, 23 g / L, 24 g / L, 25 g / L, 26 g / L, 27 g / L, 28 g / L, 29 g / L, 30 g / L, 31 g / L, 32 g / L, 33 g / L, 34 g / L, 35 g / L, 36 g / L, 37 g / L, 38 g / L, 39 g / L, 40 g / L, 41 g / L, 42 g / L, 43 g / L, 44 g / L, 45 g / L, 46 g / L, 47 g / L, 48 g / L, 49 g / L, 50 g / L, 51 g / L, 52 g / L, 5 g / L, 0.2 g / L, 0.3 g / L, 0.4 g / L, 0.5 g / L, 0.6 g / L, 0.7 g / L, 0.8 g / L, 0.9 g / L, 1 g / L, 5 g / L, 10 g / L, 20 g / L, 30 g / L, 40 g / L, 50 g / L, 100 g / L, 200 g / L, 300 g / L, 400 g / L, 500 g / L, 600 g / L, 700 g / L, 800 g / L, 900 g / L, 1000 g / L.

[0201] Sweetness In some embodiments, the glycan polymer preparation has a desired sweetness. For example, sucrose (table sugar) is the prototypical sweet substance. Sucrose in solution has a sweetness perception rating of 1, and other substances are rated relative to this (e.g., fructose is rated at 1.7 times the sweetness of sucrose). In some embodiments, the sweetness of the glycan polymer preparation ranges from 0.1 to 500,000 relative to sucrose. In some embodiments, the relative sweetness is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 25000, 50000, 75000, 100000, 150000, 200000, 250000, 300000, 350000, 40000, 450000, 500000, or greater than 500,000 (sucrose is scored as 1). In some embodiments, the glycan polymer preparation is mildly sweet or both sweet and bitter.

[0202] In some embodiments, a preparation of glycan polymers, e.g., a preparation that is substantially DP2+ or DP3+ (e.g., at least 80%, 90%, or at least 95% DP2+ or DP3+, or a fractionated preparation), is substantially insensitive to sweetness, having a relative sweetness of about 0, 0.0001, 0.001, 0.005, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or about 0.8 compared to sucrose (sucrose is scored as 1).

[0203] The glycan polymer preparation can be characterized by any suitable method, including, for example, the methods described in WO 2016 / 122889, WO 2016 / 172657, WO 2016 / 007778, and WO 2016 / 172658, which are incorporated herein by reference.

[0204] In embodiments, the glycan compositions and glycan preparations may include one or more (e.g., two, three, four, five, six, or more) of the following properties (including bulk properties): a) a glycan polymer comprising at least one of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; b) a high degree of polymerization (DP), e.g., at least about 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% of the polymers have a DP in the range of about 30-100,000, about 30-50,000, about 30-10,000, about 30-5,000, about 30-1,000, about 30-500, about 30-200, about 30-100, or about 3-50; c) low degree of polymerization, e.g., at least about 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% of the polymers have a DP in the range of about 2-29, about 2-25, about 2-20, about 2-15, about 2-10, about 2-8, about 2-6, about 3-8, or about 4-8; d) high viscosity, for example, in the range of about 100 to 10,000 mPas, 100 to 5,000 mPas, 100 to 1,000 mPas, or 100 to 500 mPas in water at 20°C; e) low viscosity, for example in the range of about 1 to 99 mPas, 1 to 50 mPas, 1 to 10 mPas, 1 to 5 mPas, 25 to 75 mPas, or 10 to 50 mPas in water at 20°C; f) a high ultimate solubility limit in water of at least about 60, 70, or at least about 75 Brix at 23°C; g) low final solubility limit in water of less than 5, 10, 20, 30, 40, 50 Brix at 23°C, or insoluble (less than 0.1 Brix); h) Calorie values ​​of approximately 0.1 calorie / g to 3 calorie / g, 0.1 calorie / g to 2 calorie / g, 0.1 calorie / g to 1.5 calorie / g, 0.1 calorie / g to 1 calorie / g, 0.1 calorie / g to 0.5 calorie / g, i) non-caloric value (e.g., about 0 cal / g to 0.09 cal / g, 0 cal / g to 0.05 cal / g, or about 0 cal / g to 0.01 cal / g, j) low digestibility, less than about 30%, 20%, 10%, 5%, 1%, 0.5% of the glycan polymers are digestible by human glucosylases (e.g., alpha-amylase); k) high digestibility, where at least 50%, 60%, 70%, 80%, 90%, 95% of the glycan polymers are digestible by human glucosylases (e.g., alpha-amylase); l) low fermentability, less than about 40%, 30%, 20%, 10%, 5%, 1%, 0.5% of the glycan polymers are fermentable by the human (e.g., colonic) microbial community or a single bacterial strain; m) high fermentability, where at least 50%, 60%, 70%, 80%, 90%, 95% of the glycan polymers are fermentable by the human (e.g., colonic) microbial community or a single bacterial strain; n) slow fermentation rate, where less than about 0.5%, 1%, 2%, 5%, 10%, or 15% of the glycan polymer is fermented by the human (e.g., colonic) microbial community or a single bacterial strain in 12-24 hours; o) a fast fermentation rate, where at least about 15%, 20%, 30%, 40%, or 50% of the glycan polymers are fermented by a human (e.g., colonic) microbial community or a single bacterial strain in 12 to 24 hours; p) high gastrointestinal tolerance (e.g., the subject tolerates a high daily dose, e.g., at least about 5 g / day, 10 g / day, 15 g / day, 20 g / day, 30 g / day, 40 g / day, 50 g / day, 60 g / day, or 70 g / day, without experiencing substantial side effects such as bloating, excessive gas, GI discomfort, diarrhea, constipation, etc.).

[0205] The glycan compositions described herein may contain one or more sugars and / or sugar alcohols. The compositions may contain monosaccharides (e.g., monosaccharides, disaccharides, trisaccharides, tetrasaccharides, or pentasaccharides), sugar alcohols, or any combination thereof. In some embodiments, the compositions contain metabolizable sugars or metabolizable sugar alcohols, where the sugars or sugar alcohols are metabolized in the host's digestive tract. The sugars and sugar alcohols disclosed in WO 2016 / 172658 (incorporated herein by reference) are suitable for use in the methods and compositions described herein. In embodiments, the compositions described herein, for example, the glycan compositions described herein, may contain polyphenols, fatty acids (e.g., short-chain fatty acids), amino acids, peptides, and micronutrients, for example, as described herein and in WO 2016 / 172658, which is incorporated herein by reference, and Table 7.

[0206] [Table 15]

[0207] [Table 16]

[0208] Probiotics In embodiments, the compositions described herein, such as the glycan compositions described herein, may include probiotic or probiotic bacterial taxa, such as bacteria listed in Tables 4-6, and generally recognized as safe (GRAS) bacteria, or known probiotic or probiotic microorganisms. In embodiments, the compositions described herein, such as the glycan compositions described herein, may include bacterial taxa listed in Tables 1-3. In some embodiments, a probiotic or probiotic bacterial taxa (or a preparation thereof) may be administered to a subject receiving a glycan preparation.

[0209] In some embodiments, the composition further comprises at least about 1% (w / w) probiotic or probiotic bacteria or a combination thereof (e.g., at least about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more).

[0210] Probiotic microorganisms may also be included in the glycan composition or used in combination with the glycan compositions described herein. Probiotic microorganisms are also referred to as probiotics. Probiotics may include metabolic products produced by probiotic microorganisms during fermentation. These metabolic products may be released into the fermentation medium, for example, into the host organism (e.g., the subject), or may be stored within the microorganism. Probiotic microorganisms include, for example, bacteria, bacterial homogenates, bacterial proteins, bacterial extracts, bacterial fermentation supernatants, and combinations thereof, which, when administered in therapeutic doses, perform beneficial functions for the host animal.

[0211] Useful probiotic microorganisms include bacteria that produce at least one lactic acid and / or acetic acid and / or propionic acid, for example, microorganisms that produce lactic acid and / or acetic acid and / or propionic acid by decomposing carbohydrates such as glucose and lactose.Preferably, the probiotic microorganisms are lactic acid bacteria.In embodiments, the lactic acid bacteria include bacteria of the genus Lactobacillus, Leuconostoc, Pediococcus, Streptococcus, and Bifidobacterium. Suitable probiotic microorganisms also include other microorganisms that beneficially affect the host by improving the host's intestinal microbial balance, for example, but not limited to, yeasts such as Saccharomyces, Debaromyces, Candida, Pichia, and Torulopsis, molds such as Aspergillus, Rhizopus, Mucor, and Penicillium and Torulopsis, and bacteria such as, but not limited to, Clostridium, Fusobacterium, and the like. Other bacteria such as Bacillus subtilis, Bacillus anguilliformis, Bacillus spp. ...

[0212] Non-limiting examples of lactic acid bacteria useful in the disclosure herein include Streptococcus lactis, Streptococcus cremoris, Streptococcus diacetylactis, Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus, Lactobacillus helveticus, Lactobacillus bifidus, Lactobacillus casei, Lactobacillus lactis, Lactobacillus plantarum, and the like. plantarum, Lactobacillus rhamnosus, Lactobacillus delbruekii, Lactobacillus thermophilus, Lactobacillus fermentii, Lactobacillus salivarius, Lactobacillus paracasei, Lactobacillus brevis, Bifidobacterium longum, Bifidobacterium infantis, Bifidobacterium bifidum, Bifidobacterium animalis animalis), Bifidobcterium lactis, Bifidobcterium brevebreve, Bifidobcterium adolescentis and Pediococcus cerevisiae, and combinations thereof, particularly strains of the genera Lactobacillus, Bifidobacterium and combinations thereof.

[0213] Probiotic microorganisms that are particularly useful in the present disclosure include those that are of human origin (for human administration) (or of mammalian origin to which the probiotic microorganism is administered), are non-pathogenic to the host, can withstand technological processes (i.e., can remain viable and active during processing and delivery), are resistant to gastric acidity and bile toxicity, adhere to intestinal epithelial tissue, have the ability to colonize the gastrointestinal tract, produce antimicrobial substances, modulate the immune response in the host, and affect metabolic activities (e.g., cholesterol assimilation, lactase activity, vitamin production).

[0214] The probiotic microorganisms may be included in the glycan preparation as a single strain or a combination of multiple strains, wherein the total number of bacteria in the dose of probiotic microorganisms is about 1 x 10 per dose. 3 ~Approx. 1×10 14 , or about 1 × 10 to about 1 × 10 12 , or approximately 1 × 10 7 ~Approx. 1×10 11 It is a CFU.

[0215] Probiotic microorganisms can be incorporated into glycan preparations while they are alive but in a "suspended" or lethargic state. Once freeze-dried, live cultures of probiotic microorganisms are handled to minimize exposure to moisture that would otherwise revive the culture. This is because, once revived, the cultures may experience high morbidity unless they are immediately cultured in a high-moisture environment or medium. Additionally, the cultures are handled to reduce the likelihood of exposure to high temperatures (especially in the presence of moisture) to reduce morbidity.

[0216] The probiotic microorganisms can be used in the form of a dry powder. The probiotic microorganisms can also be administered in a glycan preparation, or in a separate glycan preparation administered at the same time as the glycan preparation or at a different time.

[0217] Examples of probiotics include, but are not limited to, those that acidify the colon, such as those derived from Lactobacillus or Bifidobacterium, which are thought to maintain a healthy balance of the gut microbiota by producing organic acids (lactic and acetic), hydrogen peroxide, and bacteriocins, which have been reported to inhibit enteric pathogens.

[0218] Other Lactobacillus bacteria that can be used include, but are not limited to, L. crispatus, L. casei, L. rhamnosus, L. reuteri, L. fermentum, L. plantarum, L. sporogenes, and L. bulgaricus. Other probiotic bacteria suitable for the glycan composition include Bifidobacterium lactis, B. animalis, B. bifidum, B. longum, B. adolescentis, and B. infantis.

[0219] In embodiments, probiotic microbial taxa that may be used in and / or in combination with the compositions described herein include Akkermansia, Anaerococcus, Bacteroides, Bifidobacterium (e.g., Bifidobacterium lactis), and the like. lactis, B. animalis, B. bifidum, B. longum, B. adolescentis, B. breve, and B. infantis), Blautia, Clostridium, Corynebacterium, Dialister, Eubacterium, Faecalibacterium, Finegoldia, Fusobacterium, Lactobacillus (e.g., L. acidophilus), cidophilus, L. helveticus, L. bifidus, L. lactis, L. fermentii, L. salivarius, L. paracasei, L. brevis, L. delbruekii, L. thermophiles, L. crispatus, L. casei, L. rhamnosus, L. reuteri, L. fermentum, L. plantarum, L. sporogene, and L. bulgaricus.bulgaricus), Peptococcus, Peptostreptococcus, Peptoniphilus, Prevotella, Roseburia, Ruminococcus, Staphylococcus, and / or Streptococcus (e.g., S. lactis, S. cremoris, S. diacetylactis, S. thermophiles).

[0220] In embodiments, probiotic bacterial taxa, e.g., GRAS strains, that can be used in and / or in combination with the compositions described herein include Bacillus coagulans GBI-30, 6086; Bifidobacterium animalis subsp. lactis BB-12; Bifidobacterium breve Yakult; Bifidobacterium infantis 35624; Bifidobacterium animalis subsp. lactis UNO 19 (DR10); Bifidobacterium longum BB536; Escherichia coli M-17; Escherichia coli M-17; coli Nissle 1917; Lactobacillus acidophilus DDS-1; Lactobacillus acidophilus LA-5; Lactobacillus acidophilus NCFM; Lactobacillus casei DN 114-001 {Lactobacillus casei Immunitas / Defensis); Lactobacillus casei CRL431; Lactobacillus casei F19; Lactobacillus paracasei Stl l (or NCC2461); Lactobacillus johnsonii johnsonii) Lai (Lactobacillus LCI, Lactobacillus johnsonii NCC533); Lactococcus lactis L1A;Lactobacillus plantarum 299V; Lactobacillus reuteri ATTC 55730 (Lactobacillus reuteri SD2112); Lactobacillus rhamnosus ATCC 53013; Lactobacillus rhamnosus LB21; Saccharomyces cerevisiae {boulardii} lyo; a mixture of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14; Lactobacillus acidophilus a mixture of Lactobacillus acidophilus NCFM and Bifidobacterium lactis BB-12 or BL-04; a mixture of Lactobacillus acidophilus CL1285 and Lactobacillus casei; and a mixture of Lactobacillus helveticus R0052, Lactobacillus rhamnosus R0011, and / or Lactobacillus rhamnosus GG (LGG);

[0221] Synbiotics Combinations of microorganisms (e.g., bacterial taxa) are provided herein, for example, with the glycan compositions disclosed herein, which the microorganisms can use as a growth substrate. Exogenously introduced microorganisms, such as those listed in Tables 1-3, can provide many beneficial effects. This can occur by promoting the growth of the microorganisms (using glycans), thereby encouraging the growth of other bacteria at the colonization site.

[0222] The methods provided herein include administering to a subject one or more (e.g., one or more, two or more, three or more, four or more, etc.) bacterial taxa, such as those listed in Tables 1-3 or Tables 4-6, in combination with a glycan composition. Such combinations may increase, suppress, and / or modify specific bacterial taxa. Provided herein are methods for regulating the processing of exogenous substances described herein, including administering one or more (e.g., one or more, two or more, three or more, four or more, etc.) bacterial taxa. The subject may include a subject who has taken, is taking, or is about to take an antibiotic. The subject may include a subject who has not taken or has never taken an antibiotic.

[0223] Prebiotics In some embodiments, the glycan composition comprises a prebiotic substance. In some embodiments, a prebiotic can be administered to a subject receiving the glycan preparation. Prebiotics are substances that, when ingested, can provide beneficial physiological effects to the host by selectively stimulating the growth or activity of a limited number of resident bacteria in the intestine (Gibson GR, Roberfroid M BJ Nutr. (1995) 125: 1401-12.). Prebiotics, such as dietary fiber or prebiotic oligosaccharides (e.g., crystalline cellulose, wheat bran, oat bran, corn fiber, soybean fiber, beet fiber, etc.), can also promote the growth of probiotic and / or commensal bacteria in the intestine by providing bacteria with fermentable carbohydrates and increasing the levels of these microbial populations (e.g., Lactobacillus and Bifidobacteria) in the digestive tract.

[0224] Prebiotics include, but are not limited to, various galactan and carbohydrate-based gums, such as psyllium, guar, carrageen, gellan, lactulose, and konjac. In some embodiments, prebiotics include galactooligosaccharides (GOS), lactulose, raffinose, stachyose, lactosucrose, fructo-oligosaccharides (FOS, e.g., oligofructose or oligofructans), inulin, isomalto-oligosaccharides, xylo-oligosaccharides (XOS), palatinose oligosaccharides, isomaltose oligosaccharides (IMOS), transgalactosylated oligosaccharides (e.g., transgalacto-oligosaccharides), transgalactosylated disaccharides, soybean oligosaccharides (e.g., soybean oligosaccharides), chitosan oligosaccharides (thioses), gentio-oligosaccharides, soybean and pectic oligosaccharides. The sugars and / or mixtures thereof include one or more of oligosaccharides, gluco-oligosaccharides, pectin oligosaccharides, palatinose polycondensates, difructose anhydride III, sorbitol, maltitol, lactitol, polyols, polydextrose, linear and branched dextrans, pullalan, hemicellulose, reduced palatinose, cellulose, beta-glucose, beta-galactose, beta-fructose, verbascose, galactinol, xylan, inulin, chitosan, beta-glucan, guar gum, gum arabic, pectin, high sodium alginate, and lambda carrageenan, or mixtures thereof.

[0225] Prebiotics can be found in certain foods, for example, chicory root, Jerusalem artichoke, dandelion greens, garlic, leek, onion, asparagus, wheat bran, wheat flour, banana, milk, yogurt, sorghum, burdock, broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, radish, and rutabaga, and miso.In some embodiments, the microbiome regulator described herein is administered to subject with a diet that includes foods rich in prebiotics.Suitable sources of soluble and insoluble fiber are commercially available.

[0226] In some embodiments, the glycan composition comprises at least about 1% (w / w) prebiotic material (e.g., at least about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or more). In an embodiment, the glycan composition comprises FOS. In an embodiment, the glycan composition comprises lactulose.

[0227] Changes in bacterial populations can be measured by the "prebiotic index." The prebiotic index considers an increase in the growth rate of bifidobacteria, eubacteria, and lactic acid bacteria to be a positive effect, and an increase in Clostridia, bacteriodes, sulfate-reducing bacteria, and Escherichia coli to be a negative effect. The prebiotic index (PI) refers to the sum of (bifidobacteria / total bacteria) + (lactic acid bacteria / total bacteria) - (bacteroides / total bacteria) - (clostridia / total bacteria) (see Palframan et al., 2003, Lett Appl Microbiol 37:281-284). In embodiments, administering a glycan composition to a subject can result in an increase in the prebiotic index. Administration of the glycan composition to a subject may result in an increase in the following: Bacteroides, Blautia, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, Akkermansia, Faecalibacterium, Roseburia, Prevotella, Bifidobacterium, Lactobacillus, Christensenella minuta, or Christensenellaceae.

[0228] In some embodiments, the glycan composition comprises an antibiotic, antifungal, antiviral, or anti-inflammatory agent (e.g., cytokine, hormone, etc.).

[0229] In some embodiments, the glycan composition further comprises a second therapeutic agent, such as a drug, or a preparation thereof.

[0230] For example, the second therapeutic agent is an anti-cancer agent. Examples of anti-cancer agents include checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, anti-CTLA4, anti-TIM-3, anti-LAG-3, etc.), vaccines (e.g., autologous cancer vaccines, allogeneic cancer vaccines, neoantigen cancer vaccines, shared antigen cancer vaccines (e.g., NY-ESO-1), targeted kinase inhibitors (e.g., imatinib mesylate, ibrutinib, neratinib, palpocilib, erlotinib, lapatinib, etc.), antibodies (e.g., bevacizumab, trastuzumab, rituximab, cetuximab, etc.), chemotherapeutic agents (e.g., irinotecan, 5-fluorouracil, lenalidomide, capecitabine, docetaxel, etc.), antibody-drug conjugates (e.g., trastuzumab emtansine), and other anti-cancer agents mentioned elsewhere herein.

[0231] For example, the second therapeutic agent is a pain management drug. In some embodiments, the pain management drug is an opioid, such as codeine, fentanyl, hydrocodone, hydrocodone / acetaminophen, hydromorphone, meperidine, methadone, morphine, oxycodone, oxycodone and acetaminophen, or oxycodone and naloxone. In other embodiments, the pain management drug is a non-opioid, such as acetaminophen, or a non-steroidal anti-inflammatory drug (NSAID), such as aspirin and ibuprofen.

[0232] For example, the second therapeutic agent is a cardiac glycoside, a sulfonamide (sulfa drug), a nucleoside analog, or an aminosalicylate.

[0233] In some embodiments, the cardiac glycoside is digoxin, digitoxin, convallatoxin, anthialin, or oleandrin.

[0234] In some embodiments, the sulfonamide (sulfonamide) is an antimicrobial agent, e.g., a short-acting antimicrobial agent, such as sulfafurazole, sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole (sulfisoxazole), or sulfisomidine (sulfaisodimidine). In some embodiments, the sulfonamide (sulfonamide) is an antimicrobial agent, e.g., an intermediate-acting antimicrobial agent, e.g., sulfadoxine, sulfamethoxazole, sulfamoxole, or sulfanitran. In some embodiments, the sulfonamide (sulfonamide) is an antimicrobial agent, e.g., a long-acting antimicrobial agent, e.g., sulfadimethoxine, sulfamethoxypyridazine, or sulfamethoxydiazine. In some embodiments, the sulfonamide (sulfonamide) is an antimicrobial agent, e.g., an ultra-long-acting antimicrobial agent, e.g., sulfadoxine, sulfamethopyrazine, or terephthyl. In some embodiments, the sulfonamide (sulfonamide) is a sulfonylurea, e.g., an antidiabetic drug, e.g., acetohexamide, carbutamide, chlorprotamide, glibenclamide (glyburide), glibornuride, gliclazide, glyclopyramide, glimepiride, glipizide, gliquidone, glisoxepide, tolazamide, or tolbutamide. In some embodiments, the sulfonamide (sulfonamide) is a diuretic, e.g., acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, or xipamide. In some embodiments, the sulfonamide (sulfonamide) is an antispasmodic, e.g., ethoxzolamide, sulthiame, topiramate, or zonisamide. In some embodiments, the sulfonamide (sulfa drug) is an antiretroviral drug, such as amprenavir (HIV protease inhibitor), darunavir (HIV protease inhibitor), delavirdine (non-nucleoside reverse transcriptase inhibitor), fosamprenavir (HIV protease inhibitor), or tipranavir (HIV protease inhibitor).In some embodiments, the sulfonamide (sulfa drug) is a hepatitis C antiviral, such as asunaprevir (NS3 / 4A protease inhibitor), beclabuvir (NS5B RNA polymerase inhibitor), dasabuvir (NS5B RNA polymerase inhibitor), grazoprevir (NS3 / 4A protease inhibitor), paritaprevir (NS3 / 4A protease inhibitor), or simeprevir (NS3 / 4A protease inhibitor). In some embodiments, the sulfonamide (sulfa drug) is, for example, apricoxib (COX-2 inhibitor), bosentan (endothelin receptor antagonist), brinzolamide (carbonic anhydrase inhibitor for glaucoma), celecoxib (COX-2 inhibitor), dofetilide (class III antiarrhythmic), dorzolamide (anti-glaucoma carbonic anhydrase inhibitor), dronedarone (class III antiarrhythmic), ibutilide (class III antiarrhythmic), parecoxib (COX-2 inhibitor), probenecid (uricosuria), sotalol (beta-blocker), sulfasalazine (anti-inflammatory drug and DMARD), sumatriptan (anti-migraine triptan), tamsulosin (alpha-blocker), or udenafil (PDE5 inhibitor).

[0235] In some embodiments, the nucleoside analog is a deoxyadenosine analog, such as didanosine (ddI) (HIV) or vidarabine (antiviral drug). In some embodiments, the nucleoside analog is an adenosine analog (e.g., BCX4430 (Ebola)). In some embodiments, the nucleoside analog is a deoxycytidine analog, such as cytarabine (chemotherapy), gemcitabine (chemotherapy), emtricitabine (FTC) (HIV), lamivudine (3TC) (HIV, hepatitis B), or zalcitabine (ddC) (HIV). In some embodiments, the nucleoside analog is a guanosine or deoxyguanosine analog, such as abacavir (HIV), acyclovir, or entecavir (hepatitis B). In some embodiments, the nucleoside analog is a thymidine or deoxythymidine analog, such as stavudine (d4T), telbivudine (hepatitis B), or zidovudine (azidothymidine or AZT) (HIV). In some embodiments, the nucleoside analog is a deoxyuridine analog, such as idoxuridine or trifluridine. In some embodiments, the nucleoside analog is a pyrimidine analog, such as 5-fluorouracil (5FU), cytarabine (cytosine arabinoside), or 6-azauracil (6-AU). In some embodiments, the nucleoside analog is a purine analog, such as azathioprine, mercaptopurine, thiopurine, fludarabine, or pentostatin. In some embodiments, the aminosalicylate is 4-aminosalicylic acid, balsalazide, olsalazine, sulfasalazine, or mesalazine (5-aminosalicylic acid).

[0236] For example, the second therapeutic agent is an antiproliferative agent, antineoplastic agent, or an antitumor agent or treatment. In some embodiments, such drugs or treatments include chemotherapeutic agents, e.g., cytotoxic agents (e.g., alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, corticosteroids); cancer growth inhibitors such as tyrosine kinase inhibitors and proteasome inhibitors; L-asparaginase and bortezomib (Velcade®), anticancer agents, e.g., checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L Other chemical drugs such as anti-CTLA4, anti-TIM-3, anti-LAG-3, etc.; vaccines (e.g., autologous cancer vaccines, allogeneic cancer vaccines, neoantigen cancer vaccines, shared antigen cancer vaccines (e.g., NY-ESO-1), etc.); targeted kinase inhibitors (e.g., imatinib mesylate, ibrutinib, neratinib, palpocilib, erlotinib, lapatinib, etc.); or antibodies (e.g., bevacizumab, trastuzumab, rituximab, cetuximab, etc.). Hormonal therapy (or antihormonal therapy) can be used, for example, for hormone-sensitive cancers.

[0237] For example, the second therapeutic agent is a drug known to induce diarrhea or a drug known to induce constipation. In some embodiments, drugs known to induce diarrhea include 5-fluorouracil (5-FU), methotrexate, irinotecan, taxanes, monoclonal antibodies, and hormonal agents. In some embodiments, drugs known to induce constipation include vinca alkaloids, platinum (e.g., cisplatin), thalidomide, and hormonal agents.

[0238] Pharmaceutical compositions, medical foods, dietary supplements, food ingredients, and unit dosage forms Provided herein is a pharmaceutical composition comprising a glycan composition. Further provided herein is a medical food comprising a glycan composition. Further provided herein is a dietary supplement comprising a glycan composition. Further provided herein is a food ingredient comprising a glycan composition.

[0239] Optionally, the composition comprises one or more of the following: i) a prebiotic substance, such as dietary fiber; ii) a bacterial taxon, such as probiotic bacteria; iii) a micronutrient, such as a vitamin, mineral, or polyphenolic compound; iv) an anti-cancer drug, a pain management drug, a drug that manages side effects of treatment, a drug that manages metabolism, an anti-inflammatory drug, or an antimicrobial agent.

[0240] Pharmaceutical compositions, medical foods, dietary supplements, and unit dosage forms suitable for use in the methods and compositions described herein can be found in WO 2016 / 122889, WO 2016 / 172657, and WO 2016 / 172658, which are incorporated herein by reference.

[0241] In some embodiments, the glycan composition does not contain prebiotic substances. In some embodiments, the glycan composition does not contain probiotic bacteria.

[0242] In some embodiments, the glycan composition comprises one or more of the glycan preparations described herein.

[0243] The glycan polymer preparations described herein can be formulated for any suitable dosage form, for example, nasal, oral, rectal, or intragastric administration. In some embodiments, the glycan polymer preparations described herein can be formulated for enteral administration. In some embodiments, the glycan polymer preparations described herein can be formulated for tube feeding (nasogastric tube, oral gastric tube, or gastric tube feeding). The dosage forms described herein can be prepared using methods known to those skilled in the art.

[0244] The dosage form may be, for example, a packet containing the glycan polymer preparation in the form of a liquid (wash / rinse), gel, cream, ointment, powder, tablet, pill, capsule, repository, disposable applicator, or medical device (e.g., syringe). Also provided are articles of manufacture, such as a container containing a unit dosage form of the glycan polymer preparation and a label containing instructions for use of the glycan polymer.

[0245] Orally usable composition forms include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl methylcellulose, inert diluents, preservatives, antioxidants, disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose), or a lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can optionally be coated or scored and can be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets can optionally be provided with an enteric coating, to provide release in a part of the intestine (e.g., colon, lower intestinal tract). All formulations for oral administration can be in a dosage suitable for such administration. Push-fit capsules The capsules may contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound and / or other agents (e.g., prebiotics or probiotics) may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0246] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water-soluble carrier, such as polyethylene glycol, or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0247] In one embodiment, the provided glycan polymer preparation comprises a softgel formulation. The softgel can comprise a gelatin-based shell surrounding a liquid fill. The shell can be made of gelatin, a plasticizer (e.g., glycerin and / or sorbitol), a modifier, water, a colorant, an antioxidant, or a flavoring. The shell can be made of starch or carrageenan. The outer layer can be enteric coated. In one embodiment, the softgel formulation can comprise a water- or oil-soluble fill solution or a suspension of the composition covered by a gelatin layer.

[0248] Oral solid formulations can include an enteric coating, which can control the location where the glycan polymer preparation is absorbed in the digestive system. For example, the enteric coating can be designed so that the glycan polymer preparation does not dissolve in the stomach, but rather moves to the small intestine and dissolves there. The enteric coating is stable at low pH (e.g., in the stomach) and can dissolve at higher pH (e.g., in the small intestine). Materials that can be used for enteric coating include, for example, alginic acid, cellulose acetate phthalate, plastic, wax, shellac, and fatty acids (e.g., stearic acid, palmitic acid).

[0249] The preparation for oral use can also be provided in liquid dosage form.Liquid preparation can be, for example, in the form of aqueous or oily suspension, solution, emulsion, syrup or elixir, or can be provided as a dry product that is reconstituted with water or other suitable vehicle before use.Such liquid preparation can contain suspending agent, for example, sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fat; emulsifier, for example, lecithin, sorbitan monooleate, acacia gum; non-aqueous vehicle (can contain edible fat), for example, almond oil, oily ester (such as glycerin, propylene glycol or ethyl alcohol); preservative, for example, methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid, and if necessary, conventional flavoring or coloring agent. In some embodiments, liquid formulations may contain, for example, a drug in water solution and / or suspension form; and a vehicle comprising polyethoxylated castor oil, alcohol, and / or polyoxyethylated sorbitan monooleate, with or without flavoring.Each dosage form may contain an effective amount of glycan polymer, and may optionally contain pharmaceutically inactive agents such as conventional excipients, vehicles, fillers, binders, disintegrants, pH adjusters, buffers, solvents, solubilizers, sweeteners, colorants, and any other inactive agents that can be included in pharmaceutical dosage forms for administration.Examples of such vehicles and additives can be found in Remington's Pharmaceutical Sciences, 17th edition (1985).

[0250] The pharmaceutical compositions provided herein may be in unit-dosage or multi-dosage form. As used herein, unit-dosage form refers to a physically discrete unit suitable for administration to a human in need thereof. In one embodiment, the unit-dosage form is provided in a package. Each unit dose may contain a predetermined quantity of the active ingredient sufficient to produce the desired therapeutic effect, together with other pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. A unit-dosage form may be administered in fractions or multiples thereof. A multi-dosage form is a plurality of identical unit-dosage forms packaged in a single container and may be administered as separate unit-dosage forms. Examples of multi-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, the multi-dosage form contains different pharmaceutically active agents. For example, a multi-dose dosage form may be provided that includes a first dosage element containing a composition comprising a glycan polymer and a second dosage element containing a prebiotic, a therapeutic agent, and / or a probiotic (which may be in modified release form). In this example, a pair of dosage elements may constitute a single unit dosage. In one embodiment, a kit is provided that includes multiple unit dosages, each unit including a first dosage element containing a composition comprising a glycan polymer preparation and a second dosage element (which may be in modified release form) containing a probiotic, a medicinal agent, a prebiotic, or a combination thereof. In another embodiment, the kit further includes a set of instructions.

[0251] In some embodiments, the unit dosage form contains about 1 mg to about 100 g of a glycan polymer preparation (e.g., a glycan polymer described herein). For example, the unit dosage form may contain about 50 mg to about 50 g, about 500 mg to about 50 g, about 5 g to about 50 g, about 100 mg to about 100 g, about 1 g to about 100 g, about 10 g to about 100 g, about 1 g to about 10 g, about 1 g to about 20 g, about 1 g to about 30 g, about 1 g to about 40 g, about 1 g to about 50 g, about 1 g to about 60 g, about 1 g to about 70 g, about 1 g to about 80 g, about 1 g to about 90 g, about 1 g to about 100 g, about 1 g to about 150 g, or about 1 g to about 200 g of glycan polymer.

[0252] In other embodiments, the unit dosage form contains from about 0.001 mL to about 1000 mL of a glycan polymer (eg, a glycan polymer described herein). For example, the unit dosage form may contain about 0.001 mL to about 950 mL, about 0.005 mL to about 900 mL, about 0.01 mL to about 850 mL, about 0.05 mL to about 800 mL, about 0.075 mL to about 750 mL, about 0.1 mL to about 700 mL, about 0.25 mL to about 650 mL, about 0.5 mL to about 600 mL, about 0.75 mL to about 550 mL, about 1 mL to about 500 mL, about 2.5 mL to about 450 mL, about 5 mL to about 400 mL, about 7.5 mL to about 350 mL, about 10 mL to about 300 mL, about 12.5 mL to about 250 mL, about 15 mL to about 200 mL, about 17.5 mL to about 150 mL, about 20 mL to about 100 mL, or about 25 mL to about 75 mL of glycan polymer.

[0253] In certain embodiments, the unit dosage form contains about 0.001 mL to about 10 mL, about 0.005 mL to about 7.5 mL, about 0.01 mL to about 5 mL, about 0.05 mL to about 2.5 mL, about 0.1 mL to about 1 mL, about 0.25 mL to about 1 mL, or about 0.5 mL to about 1 mL of glycan polymer. In other embodiments, the unit dosage form contains about 0.01 mL to about 10 mL, about 0.025 mL to about 7.5 mL, about 0.05 mL to about 5 mL, or about 0.1 mL to about 2.5 mL of glycan polymer. In other embodiments, the unit dosage form contains about 0.1 mL to about 10 mL, about 0.25 mL to about 7.5 mL, about 0.5 mL to about 5 mL, about 0.5 mL to about 2.5 mL, or about 0.5 mL to about 1 mL of glycan polymer.

[0254] In some embodiments, the unit dosage form, e.g., a tablet, capsule (e.g., a hard capsule, a push-fit capsule, or a soft capsule), or softgel, has a length of about 0.1 inches to about 1.5 inches (e.g., about 0.5 inches and about 1 inch), or about 5 mm to about 50 mm (e.g., about 10 mm to about 25 mm). In some embodiments, the unit dosage form, e.g., a tablet, capsule (e.g., a hard capsule, a push-fit capsule, or a soft capsule), or softgel, has an outer diameter of about 0.05 inches to about 1 inch (e.g., about 0.1 inches to about 0.5 inches), or about 1 mm to about 25 mm (e.g., about 5 mm to about 10 mm).

[0255] Each unit dosage form of the glycan polymer can have a caloric value of about 0.01 kcal to about 1000 kcal. For example, the unit dosage form can have a caloric value of about 0.01 kcal to about 100 kcal, about 0.05 kcal to about 50 kcal, about 0.1 kcal to about 10 kcal, about 0.25 kcal to about 2.5 kcal, about 0.5 kcal to about 5 kcal, about 0.75 kcal to about 7.5 kcal, about 1 kcal to 10 kcal, about 5 kcal to about 50 kcal, or about 10 kcal to about 100 kcal. In certain embodiments, the unit dosage form of the glycan polymer has a caloric value of 10 kcal to about 500 kcal. In certain embodiments, the unit dosage form of the glycan polymer has a caloric value of 1 kcal to about 100 kcal. In certain embodiments, the unit dosage form of the glycan polymer has a caloric value of 0.1 kcal to about 10 kcal.

[0256] In still other embodiments, the unit dosage form may have a caloric value of about 0.001 kcal to about 10 kcal, about 0.005 kcal to about 10 kcal, about 0.01 kcal to about 10 kcal, about 0.025 kcal to about 25 kcal, about 0.05 kcal to about 50 kcal, about 0.075 kcal to about 75 kcal, about 0.1 kcal to 100 kcal, about 0.25 kcal to about 10 kcal, about 0.5 kcal to about 5 kcal, about 0.25 kcal to about 25 kcal, or about 0.1 kcal to about 1 kcal.

[0257] The unit dosage form of the glycan polymer can be formulated to dissolve in an aqueous solution (e.g., water, milk, juice, etc.) and orally administered as a drink, syrup, solution, or suspension. For example, the unit dosage form of the glycan polymer can include cubes, packets, lozenges, pills, tablets, capsules, candies, powders, elixirs, or concentrated syrups formulated to dissolve in an aqueous solution prior to oral administration. In other embodiments, the unit dosage form of the glycan polymer can include cubes, packets, lozenges, pills, tablets, capsules, candies, powders, elixirs, or concentrated syrups formulated to dissolve in vivo, for example, in the mouth, stomach, intestines, or colon of a subject upon oral administration.

[0258] In some embodiments, the glycan polymer preparation is administered enterally. This preferably includes oral administration or administration by oral or nasogastric tube (including nasojejunal tube, oral gastric tube or oral jejunal tube). In other embodiments, administration includes rectal administration (including enema, suppository, or colonoscopy).

[0259] The dosage forms described herein can be manufactured using methods known to those skilled in the art. For example, in tablet production, an effective amount of prebiotics can be uniformly dispersed in one or more excipients or additives, for example, by high-shear granulation, low-shear granulation, fluidized-bed granulation, or by blending for direct compression. Excipients and additives include diluents, binders, disintegrants, dispersants, lubricants, glidants, stabilizers, surfactants, anti-adherents, adsorbents, sweeteners, and colorants, or combinations thereof. Diluents, also known as fillers, can be used to increase the bulk of the tablet so that it provides a practical size for compression. Non-limiting examples of diluents include lactose, cellulose, microcrystalline cellulose, mannitol, dry starch, hydrolyzed starch, powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, alumina, and kaolin. Binders can impart cohesion to tablet formulations and can be used to help the tablet remain intact after compression. Non-limiting examples of suitable binders include starch (including corn starch and pregelatinized starch), gelatin, sugars (e.g., glucose, dextrose, sucrose, lactose, and sorbitol), cellulose, polyethylene glycol, alginic acid, dextrin, casein, methylcellulose, waxes, natural and synthetic gums, such as acacia, tragacanth, sodium alginate, arabic, xanthan gum, and synthetic polymers such as polymethacrylic acid, polyvinyl alcohol, hydroxypropyl cellulose, and polyvinylpyrrolidone. Lubricants can also facilitate tablet manufacture, non-limiting examples of which include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.Disintegrants can facilitate the disintegration of the tablet after administration, non-limiting examples of which include starch, alginic acid, cross-linked polymers such as, for example, cross-linked polyvinylpyrrolidone, e.g., cross-linked polyvinylpyrrolidone, croscarmellose sodium, potassium starch glycolate or sodium starch glycolate, clay, cellulose (e.g., carboxymethylcellulose (e.g., carboxymethylcellulose (CMC), CMC-Na, CMC-Ca)), starch, gums, etc. Non-limiting examples of suitable glidants include silicon dioxide, talc, etc. Stabilizers can inhibit or retard drug degradation reactions, including oxidative reactions. Surfactants can also be included and can be anionic, cationic, amphoteric, or nonionic. Exemplary sweeteners can include stevia extract, aspartame, sucrose, alitame, saccharin, etc. Optionally, the tablets may also contain non-toxic auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting agents, or emulsifying agents, solubilizing agents, coating agents, flavoring agents (e.g., mint, cherry, anise, peach, apricot, licorice, raspberry, vanilla), and the like.Additional excipients and additives include aluminum acetate, benzyl alcohol, butylparaben, butylated hydroxytoluene, calcium disodium EDTA, calcium hydrogen phosphate dihydrate, dibasic calcium phosphate, tribasic calcium phosphate, candelilla wax, carnauba wax, hydrogenated castor oil, cetylpyridine chloride, citric acid, colloidal silicon dioxide, copolyvidone, corn starch, cysteine ​​HCl, dimethicone, disodium hydrogen phosphate, erythrosin sodium, ethylcellulose, gelatin, glycerin, glyceryl monooleate, glyceryl monostearate, glycine, HPMC pthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, red iron oxide or ferric oxide, yellow iron oxide, iron oxide or ferric oxide, magnesium carbonate, magnesium oxide, magnesium stearate, methionine, methacrylic acid copolymer, methylparaben, silicified microcrystalline cellulosic The additives may include sucrose, mineral oil, phosphoric acid, regular calcium phosphate, anhydrous calcium phosphate, polaxamer 407, polaxamer 188, regular polaxamer, polyethylene oxide, polyoxyethylene 140 stearate, polysorbate 80, potassium bicarbonate, sodium sorbate, potato starch, povidone, propylene glycol, propylene paraben, propyl paraben, retinyl palmitate, sodium saccharin, selenium, silica, silica gel, fumed silica, sodium benzoate, sodium carbonate, sodium citrate dihydrate, crossmellose sodium, sodium laurin sulfate, sodium metabisulfite, sodium propionate, sodium starch, sodium starch glycolate, sodium stearyl fumarate, sorbic acid, sorbitol, sorbitan monooleate, pregelatinized starch, succinic acid, triacetin, triethyl citrate, vegetable stearin, vitamin A, vitamin E, vitamin C, or combinations thereof. The amounts of these excipients and additives may be appropriately selected based on their relationship to the other components and the characteristics of the formulation and production method.

[0260] An immediate release formulation of an effective amount of a glycan polymer preparation may include one or more combinations of excipients that allow for rapid release of the pharmaceutically active agent (e.g., 1 minute to 1 hour after administration). A controlled release formulation (also referred to as sustained release (SR), extended release (ER, XR, or XL), time-release or timed-release, controlled release (CR), or sustained release) refers to the release of the glycan polymer preparation from the dosage form at a specific desired time point after the dosage form is administered to a subject.

[0261] In one embodiment, a controlled-release dosage form begins its release and continues its release over an extended period of time. Release can begin almost immediately or can be sustained. Release can be constant, increase or decrease over time, be pulsed, continuous or intermittent, etc. In one embodiment, a controlled-release dosage form refers to the release of a drug from a composition or dosage form in which the drug is released according to a desired profile over an extended period of time. In one aspect, controlled release refers to the delayed release of a drug from a composition or dosage form in which the drug is released according to a desired profile in which release occurs after a period of time.

[0262] Pharmaceutical carriers or vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art to be suitable for a particular mode of administration. In addition, the composition may contain one or more components that do not impair the desired action, or components that complement the desired action or have another action.

[0263] In a further embodiment, the dosage form may be an effervescent dosage form. Effervescent means that the dosage form generates gas when mixed with liquids, including water and saliva. Some effervescent agents (or effervescent couples) generate gas through a chemical reaction that occurs upon exposure of the effervescent disintegrant to water or saliva in the oral cavity. This reaction may be the result of a reaction between a soluble acid source and a source of alkaline monocarbonate or alkaline carbonate. The reaction of these two common compounds produces carbon dioxide gas upon contact with water or saliva. The effervescent couple (or individual acids and bases individually) can be coated with a solvent-protecting coating or an enteric coating to prevent premature reaction. Such couples can also be mixed with pre-lyophilized particles (e.g., glycan polymers). The acid source may be any that is safe for human consumption and generally includes food acids, acids, and hydrite antacids, such as citric acid, tartaric acid, amaric acid, humic acid, adipic acid, and succinic acid. Carbonate sources include dry solid carbonates and bicarbonates, such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate, etc. Also included are reactants that evolve oxygen or other gases and are safe for human consumption. In one embodiment, citric acid and sodium bicarbonate are used.

[0264] In another aspect, the dosage form can be in the form of a candy (e.g., a matrix), such as a lollipop or lozenge. In one embodiment, an effective amount of glycan polymer is dispersed in the candy matrix. In one embodiment, the candy matrix contains one or more sugars (e.g., dextrose or sucrose). In another embodiment, the candy matrix is ​​a sugar-free matrix. The selection of a particular candy matrix can vary widely. Conventional sweeteners (e.g., sucrose), sugar alcohols suitable for use by diabetics (e.g., sorbitol or mannitol), or other sweeteners (e.g., those described herein) can be used. The candy matrix can be very soft and quickly dissolving, or hard and more slowly dissolving. Various forms will have advantages in different situations.

[0265] A candy mass composition containing an effective amount of glycan polymers can be orally administered to a subject in need thereof, including a human adult or child, such that the effective amount of glycan polymers is released into the subject's oral cavity as the candy mass dissolves and is swallowed.

[0266] The dosage forms described herein can also be in the form of pharmaceutical particles produced by a variety of methods, including, but not limited to, high-pressure homogenization, wet or dry ball milling, or small particle precipitation (e.g., nGimat's NanoSpray). Other methods useful for making suitable powder formulations are to prepare a solution of the active ingredient and excipients, followed by precipitation, filtration, and micronization, or by removal of the solution by lyophilization, followed by micronization of the powder to the desired particle size. In one embodiment, the pharmaceutical particles have a final size of 3-1000 microns, e.g., up to 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 microns. In another embodiment, the pharmaceutical particles have a final size of 10-500 microns. In another embodiment, the pharmaceutical particles have a final size of 50-600 microns. In another embodiment, the pharmaceutical particles have a final size of 100-800 microns.

[0267] In another aspect, the present disclosure provides a method for making a unit dosage form described herein, comprising providing a glycan polymer (e.g., a glycan polymer described herein); formulating the glycan polymer into a unit dosage form (e.g., a unit dosage form described herein); packaging the unit dosage form; labeling the packaged, packaged unit dosage form, and / or selling or offering for sale the packaged and labeled unit dosage form.

[0268] The unit dosage forms described herein can also be processed.In one embodiment, this processing includes one or more of the following: processing the dosage form into a pharmaceutical composition, for example, formulating and mixing with a second component, such as an excipient or buffer; dividing into smaller or larger aliquots; disposing of the dosage form into a container, for example, an airtight or liquid-tight container; packaging; integrating a label; shipping or transferring to a different location.In one embodiment, this processing includes one or more of the following: sorting, selecting, accepting or discarding, releasing or withholding, processing into a pharmaceutical composition, shipping or transferring to a different location, formulating, labeling, packaging, releasing into commerce, or selling or offering for sale, depending on whether a predetermined threshold is met.In some embodiments, the processed dosage form comprises the glycan polymer described herein.

[0269] In some embodiments, the processing includes one or more of: processing the dosage form into a pharmaceutical composition, e.g., formulating and mixing with a second component, e.g., an excipient or buffer; dividing into smaller or larger aliquots; processing into a container, e.g., an airtight or liquid-tight container; packaging; associating with a label; shipping or transferring to a different location. In one embodiment, the processing includes one or more of: sorting, selecting, accepting or discarding, releasing or withholding, processing into a pharmaceutical composition, shipping or transferring to a different location, formulating, labeling, packaging, releasing into commerce, or selling or offering for sale, and responding to a decision.

[0270] In another embodiment, an oral dosage form comprising a glycan polymer preparation is provided, wherein the oral dosage form is a syrup. The syrup may contain about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85% solids. The syrup may contain about 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% liquid, such as water. The solid may comprise the glycan polymer preparation. The solid may be, for example, about 1-96%, 10-96%, 20-96%, 30-96%, 40-96%, 50-96%, 60-96%, 70-96%, 80-96%, or 90-96% glycan polymer preparation. In another embodiment, the glycan polymer preparation is formulated as a viscous fluid.

[0271] In one embodiment, the composition includes an effervescent component, a neutralizing component, or a water-insoluble dietary fiber. The effervescent component may be at least one member selected from the group consisting of sodium bicarbonate, sodium carbonate, and calcium carbonate. In one embodiment, the neutralizing component may be at least one member selected from the group consisting of citric acid, L-tartaric acid, fumaric acid, L-ascorbic acid, DL-malic acid, acetic acid, lactic acid, and anhydrous citric acid. In one embodiment, the water-insoluble dietary fiber may be at least one member selected from the group consisting of crystalline cellulose, wheat bran, oat bran, corn fiber, soybean fiber, and beet fiber. The formulation may include sucrose fatty acid esters, powdered sugar, fruit juice powder, and / or flavoring materials.

[0272] In some embodiments, the dosage form is formulated to release a pharmaceutical composition comprising a glycan polymer preparation in a specific region of the GI tract, such as the small intestine or large intestine. In some embodiments, the dosage form is formulated to release a pharmaceutical composition comprising a glycan polymer preparation in a specific region of the GI tract, such as the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and / or rectum.

[0273] In some embodiments, the dosage form for the glycan polymer preparation described herein is an enzyme-responsive delivery system. For example, trypsin-responsive polymers can be made using hydrogels cross-linked with peptides that are degraded by trypsin. Trypsin is active in the small intestine. Trypsin-responsive delivery systems can be used to target the delivery of glycan polymer preparations to the small intestine. In another example, an enzyme-digestible hydrogel made of poly(vinylpyrrolidone) cross-linked with albumin is degraded in the presence of pepsin.

[0274] In some embodiments, the dosage form for the glycan polymer preparation described herein is a delivery device that allows for long-term retention at a specific site in the GI tract. For example, a gastroretentive delivery system allows for long-term release of the glycan polymer preparation into the stomach. Gastroretentive delivery can be used for glycan polymer preparations that regulate the bacteria in the stomach or upper small intestine.

[0275] In some embodiments, the dosage form for the glycan polymer preparations described herein is a mucoadhesive delivery system that adheres to the mucosal surface of the stomach. These are typically composed of polymers with multiple hydrogen-bonding groups, such as cross-linked polyacrylic acid, sodium carboxymethylcellulose, sodium alginate, carrageenan, Carbopol 934P, or thiolated polycarbophil.

[0276] In some embodiments, the dosage form for the glycan polymer preparations described herein is an expanding delivery system that rapidly increases in size in the stomach, slowing passage through the pylorus. Such systems include systems that expand within the stomach. For example, geometric shapes such as tetrahedrons, rings, and discs can be packed into gelatin capsules. The shape expands as the capsule dissolves. This system can be composed of one or more erodible polymers (e.g., hydroxypropyl cellulose) and one or more non-erodible polymers (e.g., polyolefins, polyamides, polyurethanes). The glycan polymer can then be dispersed within the polymer matrix. Retention time can be fine-tuned by blending polymers. Alternatively, devices made from elastic polymers that are stable at the acidic pH of the stomach but dissolve in the neutral / alkaline conditions along the GI tract can be used. Such polymer formulations can prevent ileus when the device exits the stomach. Supramolecular polymer gels crosslinked by hydrogen bonds between carboxyl groups, such as poly(acryloyl 6-aminocaproic acid) (PA6ACA) and poly(methacrylic acid-co-ethyl acrylate) (EUDRAGIT L 100-55), can also be used. Other systems include swellable excipients such as collagen sponges. For example, hydrogel matrices (e.g., swellable cores: polyvinylpyrrolidone XL, Carbopol 934P, calcium carbonate) swell 2–50 times in the stomach. Superporous hydrogel composites swell to hundreds of times their original volume within minutes. Some systems, such as carbon dioxide-generating inflatable systems surrounded by a hydrophilic membrane, utilize gas generation to achieve expansion.

[0277] In some embodiments, the dosage form for the glycan polymer preparations described herein is a density-controlled delivery system. These systems are designed to float or sink in gastric fluid, which delays their discharge from the stomach. For example, high-density systems cause the device to sink below the pylorus, at the fundus of the stomach, thereby preventing gastric emptying. Other systems are low-density / floating systems. Such devices may contain air trapped in a hollow chamber or low-density materials such as fats, oils, or foam powders. Low density can be achieved, for example, by swelling; for example, hydrocolloid-containing capsules dissolve upon contact with gastric fluid, causing the hydrocolloid to swell and form a viscous liquid. Other polymers include chitosan, sodium alginate, and glycerol monooleate matrices. Low density can also be achieved by gas generation. For example, tablets loaded with carbonate and, optionally, citric acid generate carbon dioxide upon contact with an acidic aqueous medium. The generated carbon dioxide is trapped within the gelling hydrocolloid, causing the system to float. Hydrocolloids include hydroxypropyl methylcellulose and Carbopol 934P.

[0278] In some embodiments, the dosage forms for the glycan polymer preparations described herein are designed to retain the device in the small or large intestine. The location specificity of the device is provided by specific triggering methods, such as pH or enzymes. These include systems designed for mucoadhesion, as well as microneedle pills. Microneedle pills contain a drug reservoir encapsulated in a pH-responsive coating with microneedles. When the pill reaches the desired location in the GI tract and the coating dissolves, the microneedles adhere the pill to the GI tract lining. In other embodiments, the microneedle pill contains a capsule consisting of two chemical compartments, one filled with citric acid and the other with sodium bicarbonate. As the pill dissolves in the digestive system, the barrier between the two substances erodes, causing them to mix and initiate a chemical reaction that pushes the sugar microneedles through the outer layer of the capsule and into the lining of the small intestine. The sugar needles can be filled with a drug that is delivered to nearby blood vessels as the sugar is absorbed.

[0279] In some embodiments, the dosage form for the glycan polymer preparation described herein uses a pH-sensitive polymer coating. For example, a pH-dependent polymer (biphasic or triphasic) may be insoluble at low pH levels (e.g., acid-resistant in the stomach, acid-resistant in the stomach at pH 1-2) and exhibit increased solubility as the pH increases, for example, to about pH 5.5-6.2 in the duodenum, about pH 5.7 in the ascending colon, about pH 6.4 in the cecum, about pH 6.6 in the transverse colon, about pH 7.0 in the descending colon, about pH 7.2-7.5 in the ileum, or about pH 7.5 in the distal small intestine. In one example, TARGIT TM The technology can be used for site-specific delivery of glycan polymer preparations in the gastrointestinal (GI) tract. This system uses a pH-sensitive coating on injection-molded starch capsules to target the terminal ileum and colon.

[0280] In some embodiments, the dosage form for the glycan polymer preparations described herein is a delayed-release or time-controlled release system. Such systems typically use an enteric coating that can be combined with pH sensitivity and time-release functions. For example, an ETP (enteric-coated time-release press-coated) tablet can be used, which consists of three components: a glycan polymer-containing core tablet (rapid-release function), a press-coated swellable hydrophobic polymer layer (e.g., a hydroxypropyl cellulose (HPC) layer), and a time-release function. The duration of the lag phase can be controlled by the weight or composition of the polymer layer and the enteric coating layer (acid-resistant function).

[0281] In some embodiments, the dosage forms for the glycan polymer preparations described herein use Eudragit® enteric coatings for tablets and capsules. Other suitable synthetic polymers include shellac, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose, polyvinyl acetate phthalate, and polyglutamic acid coatings such as poly-γ-glutamic acid (γ-PGA). These coatings combine both mucoadhesive and pH-dependent release strategies. To enhance colon-targeted delivery, Eudragits® are methacrylic copolymers with various side group compositions that change the pH at which they are soluble. For example, the Eudragit® coating system does not result in significant drug release in the stomach (e.g., pH 1.4) and small intestine (e.g., pH 6.3), while significant drug release is observed in the ileocecal junction at pH 7.8.

[0282] In some embodiments, the dosage form for the glycan polymer preparations described herein is a microbial trigger system, such as a polysaccharide-based delivery system. Polysaccharide-based delivery systems include biodegradable, mucoadhesive polymer coatings, such as coatings composed of chitosan and pectin. Other suitable natural polymers include, for example, guar gum, inulin, cyclodextrin, dextran, amylase, chondroitin sulfate, and locust bean gum. These delivery systems can be used to target the delivery of glycan polymer preparations to the small intestine. Coatings made from naturally occurring polysaccharides, such as guar gum, xanthan gum, chitosan, and alginate, are degraded by enzymes in the colonic intestinal microflora, such as xylosidase, arabinosidase, and galactosidase. For example, CODES TM This technology can be used to deliver glycan polymer preparations. This system combines a polysaccharide coating with a pH-sensitive coating. In some embodiments, this system consists of a core tablet coated with three layers of polymer coating: the outer coating is composed of Eudragit L. This coating dissolves in the duodenum, exposing the next coating. The next coating is composed of Eudragit E. This layer allows the release of lactulose present in the inner core. Lactulose is metabolized into short-chain fatty acids, which lower the surrounding pH at which the Eudragit E layer dissolves. The dissolution of Eudragit E results in the exposure of the glycan polymers. Bacteria present in the colon are responsible for the degradation of the polysaccharides released from the core tablet. The degradation of the polysaccharides can result in the formation of organic acids, which lower the pH of the contents surrounding the tablet.

[0283] In some embodiments, the dosage form for the glycan polymer preparation described herein is a pressure-controlled delivery system. This system takes advantage of the fact that the colon experiences higher pressure than the small intestine. For example, in a water-insoluble ethylcellulose system, the pressure in the lumen of the colon results in the disintegration of the water-insoluble polymer capsule, followed by the release of the glycan polymer. The release profile can be adjusted by changing the thickness of the ethylcellulose, the size of the capsule, and / or the density of the capsule.

[0284] In some embodiments, the dosage form for the glycan polymer preparation described herein is a pulsatile colon-targeted delivery system. For example, this system can be a pulsincap system. The capsule used contains a plug placed within the capsule that controls the release of the glycan polymer. A swellable hydrogel (e.g., hydroxypropylmethylcellulose (HPMC), polymethylmethacrylate, or polyvinyl acetate) seals the drug contents. When the capsule comes into contact with fluid, the plug is extruded from the capsule, releasing the glycan polymer. The release profile can be controlled by varying the length and / or intersection point of the plug with the capsule body. Another system is a port system. The capsule body is surrounded by a semipermeable membrane. The insoluble plug consists of an osmotically active agent and a glycan polymer. When the capsule comes into contact with fluid, the semipermeable membrane allows the fluid to enter, increasing pressure within the capsule body. This extrudes the plug and releases the glycan polymer.

[0285] In some embodiments, the dosage form for the glycan polymer preparations described herein is an osmotically controlled colon-targeted delivery system. An exemplary system, OROS-CT, consists of an osmotic unit (up to 5 or 6 push-pull units) encapsulated in a hard gelatin capsule. The push-pull unit is bilayered with an outer intestinal-impermeable membrane and an inner semipermeable membrane. The inner central portion of the push-pull unit consists of a drug layer and a push layer. The glycan polymer is released through the semipermeable membrane. The capsule body surrounding the push-pull unit dissolves immediately after administration. In the GI tract, the intestinal-impermeable membrane prevents water absorption. The enteric coating dissolves in the small intestine (higher pH, >7), allowing water to enter the unit through the semipermeable membrane, swelling the push layer and forcing the glycan polymer out.

[0286] In some embodiments, the dosage form for the glycan polymer preparations described herein is a "smart pill" that can be used to release the glycan polymer just before it reaches the ileocecal valve.

[0287] In some embodiments, the dosage form for the glycan polymer preparation described herein is a rectal administration formulation. For example, an enema introduces a liquid formulation of the glycan polymer preparation into the rectum. The administered volume is usually less than 10 mL. A suppository introduces the glycan polymer preparation into the rectum. A suppository is a solid dosage form that melts or dissolves when inserted into the rectum and releases the glycan polymer. Common excipients for suppository formulations include cocoa butter, polyethylene glycol, and agar.

[0288] Dosage form The glycan polymer preparations described herein can be formulated into any suitable dosage form, for example, for oral or enteral administration, or for injection. Suitable dosage forms for use in the methods and compositions described herein can be found in WO 2016 / 122889, WO 2016 / 172657, and WO 2016 / 172658, which are incorporated herein by reference in their entirety.

[0289] The dosage forms described herein can be prepared using methods known to those skilled in the art. The dosage forms can be suitable for any route of administration, e.g., oral or parenteral, e.g., intravenous, intramuscular, subcutaneous, intraorbital, intracapsular, intraperitoneal, intrarectal, intracisternal, intratumoral, intravascular, intradermal, or passive or enhanced absorption through the skin.

[0290] The dosage form may be, for example, a liquid (wash / rinse), solid, gel, cream, ointment, powder, tablet, pill, capsule, lozenge, suppository, repository, disposable applicator, soft gel, or medical device (e.g., syringe) containing the glycan composition in the form of any individual container, such as a packet. Also provided are products such as a container containing a unit dosage form of the glycan composition and a label containing instructions for use of the glycan composition.

[0291] The compositions provided herein may be in unit-dosage or multi-dosage form. As used herein, unit-dosage refers to a physically separate unit suitable for administration to a person in need thereof. In one embodiment, the unit-dosage is provided in a package. Each unit dose may contain a predetermined amount of an active ingredient sufficient to produce a desired therapeutic effect, together with other pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit-dosage form may be administered in part or in multiples. A multi-dosage form is a package of multiple identical unit-dosage forms in a single container, and may be administered in separate unit-dosage forms.

[0292] kit Kits are also contemplated. For example, the kit may include a unit-dose glycan polymer preparation and a package insert containing instructions for using the glycan polymer in the treatment of gastrointestinal disorders or conditions. The kit includes the glycan polymer preparation in a suitable package for use by a subject in need thereof. Any of the compositions described herein can be packaged in the form of a kit. The kit may contain a sufficient amount of glycan polymer preparation (optionally, additionally containing prebiotics, probiotic bacteria, and / or a second therapeutic agent) for a full course of treatment or a portion of a course of treatment. The dosage of the glycan polymer preparation may be individually packaged, or the glycan polymer preparation may be provided in bulk, or a combination thereof. Thus, in one embodiment, the kit provides individual doses of the glycan polymer preparation corresponding to the administration points in a treatment regimen in suitable packaging, with the doses packaged in one or more packets.

[0293] In one embodiment, the glycan polymer preparation can be provided in bulk in a single container, or in two, three, four, five, or more than five containers. For example, each container can contain enough glycan polymer preparation for a specific week of a one-month treatment program. When multiple bulk containers are provided, the bulk containers can be suitably packaged together to provide enough glycan polymer preparation for all or part of the treatment period. One or more of these containers can be labeled with information useful to the subject in need or the physician administering the treatment protocol, such as the administration schedule.

[0294] The glycan polymer preparation can be packaged with other suitable substances, such as probiotic bacteria, prebiotic substances, or other substances, as described herein. The other substances can be packaged separately from the glycan polymer preparation, mixed with the glycan polymer preparation, or a combination thereof. Thus, in one embodiment, the kit includes all components intended for use in a course of treatment or part of a course of treatment, such as the glycan polymer preparation, and, optionally, a dosage form containing a probiotic, prebiotic, or polymer agent, such as a buffer, excipient, etc. In one embodiment, the glycan polymer preparation is packaged in one package or a set of packages, and additional components, such as probiotic bacteria, prebiotics, and therapeutic agents, are packaged separately from the glycan polymer preparation.

[0295] The kit may further include materials, such as instructions, expected results, testimonials, explanations, warnings, clinical data, information for medical professionals, etc. In one embodiment, the kit includes a label or other information indicating that the kit is to be used only under the direction of a medical professional. The container may further include a spoon, syringe, bottle, cup, applicator, or other measuring or serving device.

[0296] medical foods Also provided herein are glycan polymer preparations formulated as medical foods. Any of the glycan polymer preparations described herein can be formulated as medical foods and pharmaceutical compositions containing the glycan polymer preparation.

[0297] Medical foods are defined in Section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)). Medical foods are formulated to be ingested (oral intake) or administered enterally (e.g., via feeding / nasogastric tube) under medical supervision, e.g., by a physician. They are intended for the specific dietary management of a disease or condition, such as dysbiosis or GI tract disease. As used herein, medical foods do not include foods that are simply recommended by a physician as part of an overall diet to manage symptoms or reduce the risk of a disease or condition. Medical foods containing glycan polymer preparations are synthetic foods (e.g., formulated and / or processed products, such as those prescribed for partial or total nutritional support of patients via oral intake or enteral feeding via tube), not naturally occurring foods used in their natural state.

[0298] In some embodiments, the subject has limited or impaired ability to ingest, digest, absorb, or metabolize normal foods or specific nutrients. In other embodiments, the subject has other special medically determined nutritional requirements and cannot achieve their nutritional management by changing their normal diet alone. A medical food containing a glycan polymer preparation is administered to a subject in need thereof under medical supervision (which may be ongoing), and the subject will usually receive instructions on the use of the medical food. A medical food may contain one or more food additives, color additives, GRAS excipients, and other drugs or substances suitable for medical foods. A medical food preparation may be a nutritionally complete or incomplete formula.

[0299] nutritional supplements Any of the glycan polymer preparations described herein can be formulated as dietary supplements, for example, for use in the methods described herein. Dietary supplements are regulated by the Dietary Supplement Health and Education Act (DSHEA) of 1994. Dietary supplements are orally ingested products containing "dietary ingredients" intended to supplement the diet. In addition to the glycan polymer preparations described herein, the "dietary ingredients" in these products can include one or more of the following substances: vitamins, minerals, herbs or other plants, amino acids, and enzymes, organ tissues, glands, and metabolites. Dietary supplements can also be extracts or concentrates, and can be found in many forms, such as tablets, capsules, softgels, gel caps, liquids, or powders. They can also be in other forms, such as bars, but in that case, the information on the label must not represent the product as a conventional food or a separate item of diet. DSHEA requires that all dietary supplements be labeled as dietary supplements, not as general foods.

[0300] food ingredients Any of the glycan polymer preparations described herein can be formulated as a food ingredient or food additive, for example, for use in the methods described herein. Food ingredients may be generally recognized as safe (GRAS) or require FDA approval. The glycan polymer preparations can be added to any desired food, such as beverages (e.g., fruit juice), dairy products (e.g., milk, yogurt, cheese), cereals (any grain product), bread, spreads, etc.

[0301] The glycan preparation may be formulated as a food. The term "food," as defined in the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(a)(f)), refers to articles used in food or drink for humans or other animals, chewing gum, and articles used as ingredients in such articles. The food is formulated to be ingested (ingested orally). In addition to the glycan preparation, the food may contain one or more food additives, color additives, GRAS excipients, and other agents or substances suitable for food. The food preparation may be a nutritionally complete or incomplete formula.

[0302] Methods for regulating microbial taxa The compounds and compositions provided herein can be used in methods for modulating bacterial taxa (e.g., one, two, three, four, five, or more taxa) present in a subject's microbiota. In some embodiments, modulation involves a change in the structure of the microbiota, such as a change in the relative composition of taxa or a change in the relative abundance of taxa (e.g., relative to other taxa, or relative to what would be observed in the absence of such modulation). In other embodiments, modulation can involve a change in the function of the microbiota, such as a change in gene expression, a change in the level of a gene product (e.g., RNA or protein), or a change in the metabolic output of the microbiota, or a change in a functional pathway of the host (e.g., a change in gene expression, a change in the level of a gene product, or a change in the metabolic output of the microbiota of a host cell or host process). The methods for modulating microbial taxa disclosed in WO 2016 / 122889 and WO 2016 / 172657 (which are incorporated herein by reference) are suitable for use in the methods described herein.

[0303] The methods described herein include, for example, administering to a subject a composition described herein comprising a glycan composition described herein in an amount effective for regulating a taxon. In some embodiments, when the composition is administered, the abundance of the bacterial taxon can be increased relative to other taxa (or from one time point to another), where the increase can be at least 5%, 10%, 25%, 50%, 75%, 100%, 250%, 500%, 750%, or at least 1000%. When the composition is administered, the decrease can be at least 5%, 10%, 25%, 50%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or at least 99.9%, where the abundance of the bacterial taxon can also be decreased relative to other taxa (or from one time point to another). By administering the composition, the abundance of desired and / or undesired bacterial taxa in the subject's gastrointestinal microbiota can be regulated.

[0304] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, may be found, for example, in the GI tract. Modulate (e.g., increase or decrease) the growth of one or more bacteria, such as those belonging to the genera Bacteroides, Odoribacter, Parabacteroides, Alistipes, Blautia, Clostridium, Coprococcus, Dorea, Eubacterium, Lachnospira, Roseburia, Ruminococcus, Faecalibacterium, Oscillospira, and Subdoligranulum. In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are selected from the group consisting of Akkermansia, Anaerofilum, Bacteroides, Blautia, Bifidobacterium, Butyrivibrio, Clostridium, Coprococcus, Dialister, Dorea, and the like. rea), Fusobacterium, Eubacterium, Faecalibacterium, Lachnospira, Lactobacillus, Phascolarctobacterium, Peptococcus, Peptostreptococcus, Prevotella, Roseburia,One or more bacteria of the genera Ruminococcus and Streptococcus, and / or Akkermansia municiphilia, Christensenella minuta, Clostridium coccoides, Clostridium leptum, Clostridium scindens, Dialister invisus, Eubacterium rectal, Eubacterium eligens, Faecalibacterium prausnitzii, modulates (e.g., increases or decreases) the growth of one or more of the species Streptococcus prausnitzii, Streptococcus salivarius, and Streptococcus thermophilus;

[0305] In some embodiments, for example, the compositions described herein, including the glycan compositions described herein, are selected from the group consisting of Prevotella, Akkermansia, Bacteroides, Clostridium (Erysipelotrichaceae), Clostridium (Clostridiaceae), Bifidobacterium, Aggregatibacter, Clostridium (Peptostreptococcaceae), Parabacteroides, Lactobacillus, and Enterococcus. Modulates (e.g., increases or decreases) the growth of at least two bacterial taxa selected from the group consisting of Bacterium, Bifidobacterium, Aggregatibacter, Clostridium (Peptostreptococcaceae), Parabacteroides, Lactobacillus, and Enterococcus.

[0306] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are effective against Bacteroides, Odoribacter, Parabacteroides, Alistipes, Blautia, Clostridium, Coprococcus, Dorea, and other species that can be found, for example, in the GI tract. and modulating (e.g., increasing or decreasing) the growth of one or more bacterial taxa present in the GI tract, such as those belonging to the genera Dorea, Eubacterium, Lachnospira, Roseburia, Ruminococcus, Faecalibacterium, Oscillospira, and Subdoligranulum. In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are selected from the group consisting of one or more bacterial taxa, such as those believed to be associated with healthy gastrointestinal conditions, e.g., Akkermansia, Anaerofilum, Bacteroides, Blautia, Bifidobacterium, Butyrivibrio, Clostridium, Coprococcus, Dextrococcus, and the like. Dialister, Dorea, Fusobacterium, Eubacterium, Faecalibacterium, Lachnospira, Lactobacillus, Phascolarctobacterium, Peptococcus, Peptostreptococcus, Prevotella,One or more species of the genera Roseburia, Ruminococcus, and Streptococcus, and / or Akkermansia municiphilia, Christensenella minuta, Clostridium coccoides, Clostridium leptum, Clostridium scindens, Dialister invisus, Eubacterium rectal, Eubacterium eligens, Faecalibacterium prausnitzii, The growth of one or more of the species Streptococcus prausnitzii, Streptococcus salivarius, and Streptococcus thermophilus is modulated (e.g., increased or decreased). In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate (e.g., increased or decreased) the growth of one or more bacterial taxa, such as taxa of the Verrucomicrobia phylum, e.g., taxa of the genus Akkermansia.

[0307] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, regulate (e.g., increase or decrease) the growth of one or more bacterial taxa primarily present in the small intestine. For example, the compositions described herein, including, for example, the glycan compositions described herein, regulate one or more (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa primarily present in the small intestine, such as Actinobacteria, Firmicutes (Bacilli, Clostridia), and Proteobacteria (Alphaproteobacteria, Betaproteobacteria). In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate one or more (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa predominantly present in the small intestine selected from the following genera: Cryocola, Mycobacterium, Enterococcus, Lactococcus, Streptococcus, Turicibacter, and the like. cibacter, Blautia, Coprococcus, Holdemania, Pseudoramibacter, Eubacterium, Agrobacterium, Sphingomonas, Achromobacter, Burkholderia and Ralstonia.

[0308] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, regulate (e.g., increase or decrease) the growth of one or more bacterial taxa predominantly present in the large intestine. For example, the compositions described herein, including, for example, the glycan compositions described herein, regulate one or more (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa predominantly present in the large intestine, such as Bacteroidetes, Firmicutes (Clostridia), Verrucomicrobia, and Proteobacteria (Deltaproteobacteria). In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, regulate one or more (2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa predominantly present in the large intestine selected from the following genera: Bacteroides, Butyricimonas, Odoribacter, Parabacteroides, Prevotella, Anaerotruncus, Phascolarctobacterium, Ruminococcus, Bilophila, and Akkermansia.

[0309] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate (e.g., increase or decrease) the growth of one or more bacterial taxa predominantly present in the cecum, such as Actinobacteria, Bacteroides, Bacilli, Clostridia, Mollicutes, Alpha Proteobacteria, and Verrucomicrobia.

[0310] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are capable of modulating (e.g., increasing or decreasing) the growth of one or more bacterial taxa predominantly present in the ascending colon, such as Actinobacteria, Bacteroides, Bacilli, Clostridia, Fusobacteria, Beta Proteobacteria, Delta / Epsilon Proteobacteria, Gamma Proteobacteria, and Verrucomicrobia.

[0311] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate (e.g., increase or decrease) the growth of one or more bacterial taxa predominantly present in the transverse colon, such as Actinobacteria, Bacteroides, Clostridia, Mollicutes, Fusobacteria, and Gamma Proteobacteria.

[0312] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate (e.g., increase or decrease) the growth of one or more bacterial taxa predominantly present in the descending colon, such as Bacteroides, Clostridia, Mollicutes, Fusobacteria, Delta / Epsilon Proteobacteria, and Verrucomicrobia.

[0313] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are capable of modulating (e.g., increasing or decreasing) the growth of one or more bacterial taxa predominantly present in the sigmoid colon, such as Actinobacteria, Bacteroides, Bacilli, Clostridia, Mollicutes, Alpha Proteobacteria, Beta Proteobacteria, and Verrucomicrobia.

[0314] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, modulate (e.g., increase or decrease) the growth of one or more bacterial taxa predominantly present in the rectum, such as Bacteroides, Clostridia, Mollicutes, Alpha Proteobacteria, Gamma Proteobacteria, and Verrucomicrobia.

[0315] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are selected from the group consisting of, for example, Alistipes, Akkermansia, Anaerofilum, Bacteroides, Blautia, Bifidobacterium, Butyrivibrio, Clostridium, Coprococcus, Dialister, Dorea, Fusobacterium, Eubacterium, Faecalibacterium, Lachnospira ... and modulating (e.g., stimulating / increasing or inhibiting / decreasing) the growth of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa of genera such as Lactobacillus, Odoribacter, Oscillospira, Parabacteroides, Phascolarctobacterium, Peptococcus, Peptostreptococcus, Prevotella, Roseburia, Ruminococcus, and Streptococcus and Subdoligranulum.

[0316] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, are selected from the group consisting of Akkermansia, Anaerofilum, Bacteroides, Blautia, Bifidobacterium, Butyrivibrio, Clostridium, Coprococcus, Dialister, Dorea, Fusobacterium, Eubacterium, and the like. The genera Actinobacterium, Faecalibacterium, Lachnospira, Lactobacillus, Phascolarctobacterium, Peptococcus, Peptostreptococcus, Prevotella, Roseburia, Ruminococcus, and Streptococcus, as well as Akkermansia munisifila, municiphilia species, Christensenella minuta species, Clostridium coccoides species, Clostridium leptum species, Clostridium scindens species, Dialister invisus species, Eubacterium rectal species, Eubacterium eligens species, Faecalibacterium prausnitzii, Streptococcus salivariusModulate (e.g., stimulate / increase or inhibit / decrease) the growth of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) microbial taxa of: Bacillus salivarius; and Streptococcus thermophilus.

[0317] In some embodiments, for example, the compositions described herein, including the glycan compositions described herein, modulate (e.g., substantially increase or substantially decrease) the growth (and total number) of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa listed in Tables 1-3 or Tables 4-6 (or substantially increase or substantially decrease) their relative representation / abundance in the total (gastrointestinal) community.

[0318] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, substantially increase the growth, e.g., total number, or relative representation / abundance in the total (gastrointestinal) community, of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa listed in Tables 1-3 or Tables 4-6.

[0319] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, substantially reduce the growth, e.g., total number, or relative representation / abundance in the total (gastrointestinal) community, of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa listed in Tables 1-3 or Tables 4-6.

[0320] In some embodiments, the compositions described herein, including, for example, the glycan compositions described herein, substantially increase or decrease the growth, e.g., total number, or relative expression / abundance in the total (gastrointestinal) community, of one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) bacterial taxa listed in Tables 1-3 or Tables 4-6.

[0321] In certain embodiments, the ratio or relative abundance of certain bacterial taxa can be shifted. Such a shift can be measured relative to the ratio present in the subject prior to administration of the glycan pharmaceutical composition, or relative to a control group that does not receive the glycan pharmaceutical composition.

[0322] Proteome analysis of microbial communities Glycan compositions can be prepared based on their ability to regulate the expression of microbial proteins, e.g., enzymes, associated with the processing of exogenous substances, as described, for example, in Tables 1-3. Suitable methods for proteome analysis of microbial populations can be found in WO 2016 / 122889 and WO 2016 / 172657, which are incorporated herein by reference. In some embodiments, proteome analysis can be performed according to the protocol described, for example, in Cordwell, Exploring and Exploring Bacterial Proteomes, Methods in Molecular Biology, 2004, 266:115.

[0323] Identification of microbial (e.g., bacterial) components For example, the modulation of microorganisms (e.g., taxon expression / abundance) by the glycan compositions described herein occurring in vivo in the GI tract can be analyzed using a number of methods known in the art and described herein. Suitable methods can be found in WO 2016 / 122889, WO 2016 / 172657, and WO 2016 / 172658 (which are incorporated herein by reference). In some embodiments, quantitative PCR (qPCR) can be used as a method to determine whether a glycan composition can cause a shift in bacterial populations in the GI tract.

[0324] In some embodiments, microbial components can be identified by characterizing the DNA sequence of the microbial 16S small subunit ribosomal RNA gene (16S rRNA gene). In other embodiments, microbial compositions can be identified by characterizing nucleotide markers or genes, particularly highly conserved genes (e.g., "housekeeping" genes), or combinations thereof, or by whole genome shotgun sequencing (WGS).

[0325] Administration to subjects The glycan compositions, pharmaceutical compositions, and therapeutic agents described herein can be administered to a subject in need thereof (e.g., systemically or locally) by various routes, including, for example, oral or parenteral, e.g., intravenous, intramuscular, subcutaneous, intraorbital, intracapsular, intraperitoneal, intrarectal, intracisternal, intratumoral, intravascular, intradermal, or passive or enhanced absorption through the skin. Therapeutic agents can be administered intravenously or intraarterially to the site of a pathological condition, for example, into a blood vessel supplying a tumor. In some embodiments, the glycan composition is administered enterally. This includes oral administration or administration via an oral or nasal tube (including a nasogastric tube, a nasojejunal tube, an oral gastric tube, or an oral jejunal tube). In other embodiments, administration includes rectal administration (including an enema, a suppository, or a colonoscopy). Methods of administering to a subject suitable for use in the methods and compositions described herein can be found in WO 2016 / 122889, WO 2016 / 172657, and WO 2016 / 172658, which are incorporated herein by reference in their entireties.

[0326] The active compound and pharmaceutical agent, such as a prebiotic substance, probiotic bacteria or drug, can be administered separately, for example, before, simultaneously with, or after administration of the glycan composition, rather than as part of a pharmaceutical composition or medical food or dietary supplement (e.g., as a co-formulation). In some embodiments, the pharmaceutical composition or medical food containing the glycan composition preparation is administered in combination with a recommended or prescribed diet, such as a diet rich in probiotics and / or prebiotic-containing foods, as determined by a physician or other healthcare professional.

[0327] Treatment method Provided herein are methods for treating a disease, disorder, condition, or pathological condition, comprising administering a glycan composition, such as a glycan composition described herein, to a subject in need thereof. Also provided herein are exogenous substances (e.g., pharmaceutical agents) for use in any of the methods described herein. The exogenous substance can be included in a composition containing the glycan composition, or can be administered / formulated separately. In embodiments, the pharmaceutical agent is used to treat a disease, disorder, condition, or pathological condition described herein.

[0328] Diseases and disorders that can be treated with the methods and compositions described herein can be found in WO 2016 / 122889, WO 2016 / 172657, and WO 2016 / 172658, which are incorporated by reference in their entireties. Exemplary diseases, disorders, conditions, or pathological states can include, but are not limited to, proliferative diseases (e.g., cancer), dysbiosis, infectious diseases, metabolic diseases, neurodegenerative diseases, allergies, and the like.

[0329] Diseases, disorders, and conditions that can be treated with the methods described herein include pain, migraine, arthritis, cancer, colon and rectal cancer, bacterial infections, viral infections, HIV, hepatitis, hepatitis C, fungal infections, worm infections, hookworm infections, osteoporosis, cancer-related pain, diabetes, blood sugar imbalance, seizures, panic disorder, anxiety, heart disease, heart failure, cardiac arrhythmias, high blood pressure, tonsillitis, chest pain, thrombocytopenia, aplastic anemia, Parkinson's disease and parkinsonian symptoms, diarrhea, high cholesterol and triglyceride levels, ADHD, recreational drug use, insomnia, ulcers, gastroesophageal reflux disease (GERD), heartburn, drug toxicity (e.g., 5-fluorouracil-induced gastrointestinal toxicity), schizophrenia, bipolar disorder, hypersensitivity caused by autism, constipation, and epilepsy.

[0330] In some embodiments, the pharmaceutical composition containing the glycan composition is administered before, concurrently with, or after administration of a (e.g., anti-cancer) drug or non-drug (e.g., anti-cancer) treatment whose administration induces symptoms.

[0331] In one embodiment, a method for reducing the toxicity of drug treatment (e.g., anti-cancer drug treatment) in a subject is provided. The method includes: a) administering a pharmaceutical composition comprising a glycan composition to a subject receiving drug treatment; b) administering drug treatment to a subject treated with a pharmaceutical composition comprising a glycan composition; or c) administering a pharmaceutical composition comprising a glycan composition to a subject and administering drug treatment, thereby treating the subject. In some embodiments, the toxicity is dose-limiting toxicity. In some embodiments, the method increases the subject's resistance to drug treatment, for example, anti-cancer drug treatment.

[0332] In some embodiments, dose-limiting toxicity prevents a subject from being treated with the maximum effective dose of a drug. As an example of dose-limiting toxicity, diarrhea may be caused by the chemotherapy drugs irinotecan and 5-fluorouracil. In some embodiments, the glycan composition is administered to treat dose-limiting toxicity, for example, to increase the dose that a subject can tolerate. In some embodiments, tolerability is increased by limiting one or more digestive disorders associated with each effective drug dose.

[0333] All publications, patents, and patent applications cited or referenced in this specification are herein incorporated by reference to the same extent as if each individual publication or patent document was specifically and individually indicated to be incorporated by reference. [Example]

[0334] The present invention is further illustrated by the following examples. The examples are provided for illustrative purposes only and should not be construed as limiting the scope or content of the present invention in any way. The practice of the present invention will employ, unless otherwise specified, conventional methods of protein chemistry, biochemistry, recombinant DNA technology, and pharmacology within the skill of the art. Such techniques are fully explained in the literature. See, for example, TECreighton, Proteins: Structures and Molecular Properties (WH Freeman and Company, 1993); Green & Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th Edition (Cold Spring Harbor Laboratory Press, 2012); Colowick & Kaplan, Methods In Enzymology (Academic Press); Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, 2012); and Sundberg & Carey, Advanced Organic Chemistry: Parts A and B, 5th Edition (Springer, 2007).

[0335] Example 1: Effect of glycans on microbial populations ex vivo To determine the desired composition of glycans, bacterial cultures were grown in the presence of candidate glycans and assayed for growth, community composition (e.g., by 16S rRNA gene sequencing), metabolite production, and phenotypic or transcriptomic characteristics. Desired glycans were selected based on their ability to induce the desired characteristics in bacterial cultures. Bacterial cultures include monocultures, mixed cultures, cultures isolated from humans or experimental animal models, cultures isolated from humans or experimental animal models and supplemented with an isolate or group of isolates, or cultures isolated from humans or experimental animal models and depleted of a group of species (e.g., by application of antibiotics). This assay can be performed in the presence of antibiotics or other test compounds. Results obtained from in vitro assays are compared to results obtained after treating humans with the glycans or administering the glycans to experimental animals to establish in vitro-in vivo correlations of results.

[0336] Example 2: Growth of beta-glucuronidase related, unrelated, and other gut commensal strains on several glycans An in vitro assay was conducted to evaluate the ability of various bacterial strains (including gastrointestinal commensals) to utilize different glycans as growth substrates. The assay was designed to assess the ability of selected glycans to promote the growth of microbiota associated with beta-glucuronidase production, microbiota not associated with beta-glucuronidase production, and other gut commensals. Lactobacillus gasseri was handled aerobically, while all other bacterial strains were handled throughout the experiment in an anaerobic chamber (AS-580, Anaerobe Systems) featuring a palladium catalyst. The chamber was initially made anaerobic by purging with an anaerobic gas mixture consisting of 5% hydrogen, 5% carbon dioxide, and 90% nitrogen, and then maintained in anaerobic conditions using this same anaerobic gas mixture. The anaerobic status of the chamber was confirmed daily using Oxoid anaerobic indicator strips, which change color in the presence of oxygen. All culture media, assay plates, other reagents, and plastic consumables were pre-reduced in an anaerobic chamber for 24–48 h before contact with the bacteria. The glycans glu33gal33fuc33, gal100, glu50gal50, man80gal20, man60glu40, man80gal20, glu100, man100, man52glu29gal19, man66gal33, xyl75ara25, glu80man20, and glu60man40, as well as the commercial control, FOS (Nutraflora FOS; NOW Foods, Bloomingdale, IL), and dextrose were prepared at 5% w / v in water, filter-sterilized, and added to a Costar 3370 assay plate to a final concentration of 0.5% w / v in the assay. Each glycan was assayed in two to four nonadjacent wells. Dextrose and water served as positive and negative controls.

[0337] Bacterial isolates were obtained from the American Type Culture Collection (ATCC) and the Leibniz Institute DSMZ-German Institute of Microorganisms and Cell Cultures (DSMZ). Ruminococcus obeum ATCC 29714 "ROB.74" strain, Bacteroides caccae ATCC 43185 "BCA.26" strain, Bacteroides thetaiotaomicron ATCC 29741 "BTH.8" strain, Bacteroides cellulosilyticus DSM14838 "BCE.71" strain, Parabacteroides distasonis ATCC 8503 "PDI.6" strain, Bacteroides vulgatus ATCC 8482 "BVU.10" strain, Clostridium scindens ATCC Cultures of strains 35704 "CSC.32," Dorea formicigenerans ATCC 27755 "DFO.36," and the bifidobacteria Bifidobacterium longum ATCC 15707 "BLO.16" and Bifidobacterium longum DSM 20088 "BLO.83" were grown anaerobically at 37°C for 18–48 h in Chopped Meat Glucose Broth (CMG, Anaerobe Systems), a pre-reduced enrichment medium containing lean ground beef, enzymatic digest of casein, yeast extract, potassium phosphate, dextrose, cysteine, hemin, and vitamin K1. Cultures of Lactobacillus gasseri ATCC 33323 "LGA.44" were grown aerobically in CMG at 37°C for 18–48 h.Inocula were prepared by measuring the optical density of each culture at 600 nM (OD) in Costar 3370 polystyrene 96-well flat-bottom assay plates using a Biotek Synergy 2 plate reader with Gen5 2.0 All-In-One Microplate Reader Software according to the manufacturer's protocol, and diluting the cells to a final OD of 0.01 in defined and semi-defined media prepared without sugar. B. vulgatus, D. formicigenerans, P. distasonis, and B. longum isolates were cultured in a medium containing 0–5% (v / v) CMG supplemented with 900 mg / L sodium chloride, 26 mg / L calcium chloride dihydrate, 20 mg / L magnesium chloride hexahydrate, 10 mg / L manganese chloride tetrahydrate, 40 mg / L ammonium sulfate, 4 mg / L iron sulfate heptahydrate, 1 mg / L cobalt chloride hexahydrate, and 3 mg / L ammonium sulfate. The nutrient content was 100 mg / L dibasic potassium phosphate, 1.5 g / L dibasic sodium phosphate, 5 g / L sodium bicarbonate, 0.125 mg / L biotin, 1 mg / L pyridoxine, 1 m / L pantothenate, 75 mg / L histidine, 75 mg / L glycine, 75 mg / L tryptophan, 150 mg / L arginine, 150 mg / L methionine, 150 mg / L threonine, 225 mg / L valine, 225 mg / L isoleucine, 300 mg / L leucine, 400 mg / L cysteine, and 450 mg / L proline (Theriot CM et al. Nat Commun. 2014;5:3114).B. thetaiotaomicron, B. caccae, and B. cellulosyliticus were tested in 100 mM potassium phosphate buffer (pH 7.2), 15 mM sodium chloride, 8.5 mM ammonium sulfate, 4 mM L-cysteine, 1.9 μM hematin, 200 μM L-histidine, 100 μM magnesium chloride, 1.4 μM ferrous sulfate heptahydrate, 50 μM calcium chloride, 1 μg / mL vitamin K3, and 5 ng / mL vitamin B12 (Martens EC et al. Cell Host & Microbe 2008;4,447-457). L. gasseri, C. scindens, and R. obeum were cultured in a medium containing 0-5% CMG supplemented with 10 g / L tryptone peptone, 5 g / L yeast extract, 0.5 g / L L-cysteine ​​hydrochloride, 0.1 M potassium phosphate buffer pH 7.2, 1 μg / mL vitamin K3, 0.08% w / v calcium chloride, 0.4 μg / mL ferrous sulfate heptahydrate, 1 μg / mL resazurin, 1.2 μg / mL hematin, 0.2 mM histidine, and 0.05% Tween. 80, 0.5% meat extract (Sigma), 1% trace mineral supplement (ATCC), 1% vitamin supplement (ATCC), 0.017% v / v acetic acid, 0.001% v / v isovaleric acid, 0.2% v / v propionic acid, and 0.2% v / v N-butyric acid (Romano KA et al. mBio 2015;6(2):e02481-14). Bacteria were anaerobically exposed to the glycans ara50gal50, glu33gal33fuc33, glu50gal50, gal100, glu100, xyl100, ara100, ara60xyl40, glu80man20, glu60man40, man52glu29gal19, man100, xyl75ara25, commercial FOS, and dextrose at a final concentration of 0.5% w / v in a final volume of 200 μL per well in 96-well microplates for 18–48 h at 37°C. At the end of the incubation period, OD600 measurements for each isolate were obtained using a Biotek Synergy2 reader with Gen5 2.0 software according to the manufacturer's specifications.

[0338] To facilitate comparison of glycan utilization by strains growing within significantly different OD600 ranges, measurements were normalized by dividing the OD600 readout of the isolates on the test glycans by the average OD600 of the isolates in medium supplemented with 0.5% w / v dextrose. Table 8 summarizes the results obtained.

[0339] [Table 17]

[0340] L. gasseri, R. obeum, and B. longum belong to the same species or genus as reported β-glucuronidase-producing bacteria and are therefore associated with β-glucuronidase production (Russell, W. M., and Klaenhammer, Tridentification and cloning of gusA, encoding a new β-glucuronidase from Lactobacillus gasseri ADH. Appl Environ. Microbiol. 2001; Beaud et al., Genetic characterization of the β-glucuronidase enzyme from a human intestinal bacterium, Ruminococcus gnavus. Microbiology 2005; Roy, D., & Ward, P. Rapid detection of Bifidobacterium dentium by enzymatic hydrolysis of β-glucuronide substrates. J Food Protect. 1992). B. thetaiotaomicron and B. vulgatus have been reported to have no detectable β-glucuronidase activity in vitro (Dabek et al., Distribution of β-glucosidase activity and of β-glucuronidase gene gus in human colonic bacteria. FEMS Microbiol Ecol 2008), and Dorea species, such as D. formicigenerans, do not contain β-glucuronidase in the NCBI protein database. Therefore, these three isolates are not considered to be related to β-glucuronidase production.

[0341] In this assay, many glycans supported the growth of non-β-glucuronidase-associated strains and other gut commensal strains better than β-glucuronidase-associated strains, resulting in relatively low mean normalized growth values ​​for β-glucuronidase-associated strains.

[0342] In this assay, Glu33gal33fuc33 and gal100 did not support the growth of any of the β-glucuronidase-associated strains but supported the growth of 5–6 non-β-glucuronidase-associated strains and other gut commensal strains, with average normalized growth values ​​exceeding 0.15. In this assay, glu50gal50, man80glu20, man60glu40, man80gal20, glu100, man100, man52glu29gal19, and man66gal33 supported normalized growth values ​​of at least 0.3 for non-β-glucuronidase-associated strains, B. thetaiotaomicron, and 1–3 other gut commensal strains, whereas they provided relatively weak or no support for the growth of β-glucuronidase-producing bacteria, with average normalized growth values ​​of <0.3 for L. gasseri and <0.15 for R. obeum and B. longum.

[0343] Bacterial β-glucuronidase has been linked to the toxicity of several drugs. For example, microbial β-glucuronidase in the intestine converts the non-toxic form of the cancer drug irinotecan into a form that is toxic to intestinal epithelial cells (Spanogiannopoulos P. et al. The microbial pharmacists within us: a metagenomics view of xenobiotic metabolism. Nature Reviews Microbiology vol. 14, May 2016). Administering glycans that selectively support the growth of non-β-glucuronidase-associated strains to patients receiving irinotecan chemotherapy can reduce the relative abundance of β-glucuronidase-producing strains in the intestine, thereby reducing irinotecan-associated diarrhea.

[0344] [Table 18]

[0345] [Table 19]

[0346] Example 3: Glycan-supported growth of bacteria involved in phytoestrogen metabolism An in vitro assay was conducted to evaluate the ability of various bacterial strains, including gastrointestinal commensal strains, to utilize different glycans as growth substrates. This assay was designed to assess the ability of selected glycans to promote the growth of microbiota associated with phytoestrogen metabolism, which has been linked to protective effects against breast cancer. Bacterial strains were handled throughout the experiment in an anaerobic chamber (AS-580, Anaerobe Systems) featuring a palladium catalyst. The chamber was first made anaerobic by purging with an anaerobic gas mixture consisting of 5% hydrogen, 5% carbon dioxide, and 90% nitrogen, and then maintained in anaerobic conditions using this same anaerobic gas mixture. The anaerobic status of the chamber was confirmed daily using Oxoid anaerobic indicator strips, which change color in the presence of oxygen. All culture media, assay plates, other reagents, and plastic consumables were pre-reduced in the anaerobic chamber for 24–48 h before contact with the bacteria. The glycans glu80man20, glu60man40, glu100, gal100, man80glu20, glu33gal33fuc33, man60glu40, man80gal20, man66gal33, man100, man52glu29gal19, xyl75ara25, and xyl100 were prepared at 5% w / v in water, filter-sterilized, and added to a Costar 3370 assay plate to a final concentration of 0.5% w / v in the assay; each glycan was assayed in two non-adjacent wells; dextrose and water served as positive and negative controls.

[0347] Bacterial isolates were obtained from the American Type Culture Collection (ATCC) and the Leibniz Institute DSMZ-German Institute of Microorganisms and Cell Cultures (DSMZ). Cultures of Blautia producta ATCC 27340 "BPR.22", Clostridium scindens ATCC 35704 "CSC.32", Enterococcus faecium ATCC 700221 "EFM.66", and the bifidobacteria Bifidobacterium longum ATCC 15707 "BLO.16" and Bifidobacterium longum DSM 20088 "BLO.83" were grown in a pre-reduced enrichment medium containing ground lean beef, enzymatic digest of casein, yeast extract, potassium phosphate, dextrose, cysteine, hemin, and vitamin K1, called Chopped Meat. The cells were grown anaerobically in glucose broth (CMG, Anaerobe Systems) at 37°C for 18–48 h. The cells were assayed at 600 nM (OD ) in Costar 3370 polystyrene 96-well flat-bottom assay plates using a Biotek Synergy 2 plate reader with Gen5 2.0 All-In-One Microplate Reader Software according to the manufacturer's protocol. 600 The optical density of each culture was measured at 0°C, and the final OD was measured in the defined and semi-defined media prepared without sugar. 600Inocula were prepared by diluting cells to 0.01. B. producta, E. faecium, and B. longum isolates were cultured in a 1000 ml / min culture medium supplemented with 0–5% (v / v) CMG, 900 mg / L sodium chloride, 26 mg / L calcium chloride dihydrate, 20 mg / L magnesium chloride hexahydrate, 10 mg / L manganese chloride tetrahydrate, 40 mg / L ammonium sulfate, 4 mg / L iron sulfate heptahydrate, 1 mg / L cobalt chloride hexahydrate, 300 mg / L potassium phosphate dibasic, and 1 mg / L sodium hydroxide. Tested in 5 g / L sodium phosphate dibasic, 5 g / L sodium bicarbonate, 0.125 mg / L biotin, 1 mg / L pyridoxine, 1 m / L pantothenate, 75 mg / L histidine, 75 mg / L glycine, 75 mg / L tryptophan, 150 mg / L arginine, 150 mg / L methionine, 150 mg / L threonine, 225 mg / L valine, 225 mg / L isoleucine, 300 mg / L leucine, 400 mg / L cysteine, and 450 mg / L proline (Theriot CM et al. Nat Commun. 2014;5:3114). C. scindens was cultured in a medium containing 10 g / L tryptone peptone, 5 g / L yeast extract, 0.5 g / L L-cysteine ​​hydrochloride, 0.1 M potassium phosphate buffer pH 7.2, 1 μg / mL vitamin K3, 0.08% w / v calcium chloride, 0.4 μg / mL ferrous sulfate heptahydrate, 1 μg / mL resazurin, 1.2 μg / mL hematin, 0.2 mM histidine, 0.05% Tween 80, 0.5% meat extract (Sigma), 1% trace mineral supplement (ATCC), 1% vitamin supplement (ATCC), 0.017% v / v acetic acid, 0.001% v / v isovaleric acid, 0.2% v / v propionic acid, and 0.2% v / v N-butyric acid (Romano KA et al. mBio 2015;6(2):e02481-14).Bacteria were anaerobically exposed to glu80man20, glu60man40, glu100, gal100, man80glu20, glu33gal33fuc33, man60glu40, man80gal20, man66gal33, man100, man52glu29gal19, xyl75ara25, xyl100, and dextrose at a final concentration of 0.5% w / v in a final volume of 200 μL per well in 96-well microplates for 18 to 48 hours at 37°C. At the end of the incubation period, the OD for each isolate was measured. 600 Measurements were taken using a Biotek Synergy2 reader with Gen5 2.0 software according to the manufacturer's specifications. 600 To facilitate comparison of glycan utilization by strains growing within a range, the OD of the isolates on the test glycans 600 The readout was calculated as the mean OD of the isolates in medium supplemented with 0.5% w / v dextrose. 600 The measurements were normalized by dividing by . Table 11 summarizes the results obtained.

[0348] [Table 20]

[0349] [Table 21]

[0350] Bifidobacterium species and E. faecium have been reported to metabolize the phytoestrogen daidzin (an isoflavone) to a similar extent. B. producta, C. scindens, and Enterococcus faecalis have been reported to metabolize plant lignans, a different class of phytoestrogens, to enterodiol and enterolactone (Spanogiannopoulos P. et al. The microbial pharmacists within us: a metagenomics view of xenobiotic metabolism. Nature Reviews Microbiology vol. 14, May 2016). Thus, B. longum, B. producta, C. scindens, and E. faecalis have been associated with phytoestrogen metabolism.

[0351] In this assay, different glycans supported different levels of growth for a variety of bacterial strains related to phytoestrogen metabolism. In this assay, glu80man20, glu60man40, and glu100 supported the growth of 4–5 of the 5 strains, resulting in average normalized growth values ​​of at least 0.15. In this assay, Glu100 and gal100 supported the growth of three strains, resulting in average normalized growth values ​​of at least 0.15. In this assay, Glu33gal33fuc33, man60glu40, man80gal20, man66gal33, man100, and man52glu29gal19 supported the growth of two strains, and xyl75ara25 and xyl100 supported the growth of one strain.

[0352] The metabolism of phytoestrogens, such as plant lignans and isoflavones, into molecules that bind to estrogen receptors by gut bacteria may have a preventive effect against breast cancer (Mabrook, HB et al. Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Carcinogenesis 33, 203-208 (2012)). Therefore, administration of glycans that promote the growth of bacterial species associated with phytoestrogen metabolism may induce a preventive effect against breast cancer and / or other types of cancer in humans.

[0353] [Table 22]

[0354] Example 4: Modification of exogenous substances by microbiota Untargeted metabolomics was performed on 30–50 mg of cecal contents from mice fed a high-fat diet (Research Diets D12492) or a high-fat diet plus glycans using Metabolon's LC-MS-based DiscoveryHD4 platform.

[0355] Three exogenous substances, enterolactone, stachydrine, and quinic acid, were identified as being modified by the microbiota following the addition of 1% man52glu29gal19 to drinking water (see Figures 1A, 1B, and 1C).

[0356] Enterolactone, a mammalian lignin formed by the action of intestinal bacteria from plant lignin precursors present in the diet, was increased in animals treated with man52glu29gal19. It is believed that enterolactone may have beneficial health effects in humans. Decreased enterolactone levels have been associated with many human pathologies. For example, it has been demonstrated that individuals with type 2 diabetes have significantly reduced urinary enterolactone levels compared to healthy controls (Sun et al., Diabetes Care, 2014). Enterolactone has also been shown to have some anti-carcinogenic effects, as administration of enterolactone has been shown to inhibit or slow the growth of experimental breast cancer (Saarinen et al., Molecular Nutrition & Food Research, 2013). Epidemiological studies have observed lower enterolactone levels in breast cancer patients compared to healthy controls, which may suggest that enterolactone has anti-carcinogenic properties. Enterolactone and lignans may also prevent cardiovascular disease.

[0357] Furthermore, stachydrine was reduced by the addition of 1% man52glu29gal19 to drinking water. Stachydrine is also known as proline betaine. Proline betaine is a glycine betaine analog present in many citrus foods. Stachydrine has been shown to be a marker of dietary citrus intake (Guertin et al. AJCN, 2014). Elevated levels of proline betaine in human urine have been found after the consumption of citrus fruits and juices.

[0358] Furthermore, quinic acid was found to increase when glu100 or man52glu29gal19 was added to a high-fat diet. Quinic acid is an abundant plant product that is used as a carbon source by many microorganisms (Teramoto, et al., Appl. Environ. Microbiol., 2009). These data suggest that the microbial turnover of various exogenous substances by microbial taxa (e.g., those present in the digestive tract of a human subject) can be regulated by administering a glycan composition (as described herein) to a subject in an amount effective to regulate (increase or decrease) the level of the exogenous substance in the subject.

[0359] Example 5: Modulation of beta-glucuronidase levels in the gastrointestinal tract of human subjects and mouse models by glycans to reduce / prevent irinotecan toxicity Patients with histologically or cytologically confirmed colorectal adenocarcinoma were treated with FOLFIRI [folinic acid (leucovorin) 400 mg / m 2 IV on day 1; 5-FU 400 mg / m 2 , IV injection, day 1, followed by 2.4 g / m 2 IV over 46 hours on days 1 through 3; irinotecan 180 mg / m 2Patients will be randomly assigned to receive glycan treatment or placebo for one week prior to administration of a chemotherapy regimen consisting of [false stearate, 100 mg / kg / day, IV]. The primary treatment outcome will be the proportion of patients receiving glycan or placebo who develop grade 2 or greater diarrhea in the week following the FOLFIRI regimen. The first secondary outcome will be the proportion of patients receiving glycan or placebo who develop grade 3 or greater diarrhea in the week following the FOLFIRI regimen. The second secondary outcome will be the proportion of patients receiving glycan or placebo who require antidiarrheal treatment (e.g., loperamide) in the week following the FOLFIRI regimen. Glycan treatment is expected to increase the proliferation of bacteria that do not express β-glucuronidase in the patient's gastrointestinal tract compared with bacteria that do express β-glucuronidase, thus resulting in a relative decrease in the concentration of β-glucuronidase enzymes in the gastrointestinal tract that can activate toxic metabolites of irinotecan (SN38). For example, glycan 1 is expected to increase the growth of the gut commensal bacterial strains BTH.8, BVU.10, and DFO.36, but not LGA.44, ROB.74, BLO.16, and BLO.83 (see Example 2 and Table 8).

[0360] A proof-of-concept experiment was performed to elucidate the effect of glycans on chemotherapy-induced toxicity in a mouse model using irinotecan chemotherapy.

[0361] In this study, 150 male BALB / c mice (Charles River Laboratories) were randomly selected and housed in seven groups of 13 mice per group, three groups of 18 mice per group, and one group of five mice per group. Mice were allowed to acclimate for five days after arrival. One group of five mice was administered irinotecan. All mice were fed a special diet, and their weights were monitored daily from day -7.

[0362] Mice were gavaged with deionized water or the glycan composition for 14 days. Starting on day -6, animals in the glycan treatment group began treatment with 6 g / kg / day of the glycan composition or FOS by gavage, and glycan treatment continued until day 7. During this same period, animals in the control group received water. All groups (except the control group that did not receive irinotecan) received a single intraperitoneal injection of irinotecan at a dose of 250 mg / kg on day 0. To prevent transient diarrhea, atropine was injected subcutaneously at 0.03 mg / kg during irinotecan administration.

[0363] Mice were weighed daily and monitored for survival. On day -1, five mice from each of the four groups were euthanized, and cecal and colonic contents were collected for 16S sequencing and short-chain fatty acid evaluation. Feces were collected on days -6, -1, 1, 3, 5, and 7 and stored at -80°C. On day 7, the remaining animals were euthanized, and blood and tissues were collected. Figures 18A and 18B show that mice fed FOS, Glu50Gal50, or Gal100 lost less weight over the experimental period than mice fed no glycan composition. Reduced weight loss is evidence that the animals were healthier and suffered less toxicity from irinotecan metabolism. These data suggest that glycans may shift the microbial community in animals in a way that limits the production of toxic irinotecan products / intermediates (as described above) resulting from microbial processing of exogenous substances in animals, thereby limiting the overall toxicity of the drug.

[0364] Example 6: Modulation of phytoestrogen metabolism-related bacteria by glycans for the treatment of breast cancer Metabolism of phytoestrogens, such as plant lignans and isoflavones, into molecules that bind to estrogen receptors by gut bacteria may have a preventive effect against breast cancer (Mabrook, HB et al. Lignin transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Carcinogenesis 33, 203-208 (2012)). Administration of glycans increases the relative proliferation of phytoestrogen metabolism-related bacteria, such as BPR.22 and EFM.66 (see Example 3 and Table 11), thus increasing phytoestrogen concentrations in humans and inducing protective effects against breast cancer and / or other types of cancer. Women at high risk of breast cancer are randomly assigned to receive glycan treatment or a placebo for 12 months. Inclusion criteria were either i) 5-year Gail risk >1.7%, ii) known BRCA1 / BRCA2 gene mutation carrier, iii) family history consistent with hereditary breast cancer, iv) prior biopsy showing atypical hyperplasia or lobular carcinoma in situ (LCIS), or v) personal history of invasive breast cancer or ductal carcinoma in situ (DCIS) who had completed standard therapy including tamoxifen / aromatase inhibitors or would not be treated with tamoxifen / aromatase inhibitors. After one year of glycan or placebo treatment, patients will be evaluated for: i) reduction in magnetic resonance imaging (MRI) volume (equivalent to 3-dimensional mammographic density) in high-risk women or women with invasive breast cancer or DCIS who received daily supplementation with glycan compared to placebo (microcrystalline cellulose); ii) reduction in cell proliferation and apoptosis, as measured by Ki67 and caspase 3 staining, respectively, in breast epithelial cells treated with glycan compared to placebo; and iii) reduction in expression of intermediate molecular markers, estrogen receptor alpha (ER alpha) and ER beta, in women treated with glycan compared to placebo.

[0365] Example 7: Modulation of phytoestrogen metabolism-related bacteria by glycans for the treatment of type 2 diabetes The microbiome influences the onset and progression of type 2 diabetes. Patients with type 2 diabetes have been shown to have altered levels of circulating microbial metabolites, as measured in urine. For example, concentrations of the microbially produced lignan enterolactone are inversely correlated with the risk of type 2 diabetes (Sun et al. Diabetes Care 37.5(2014):1287-95). Increasing concentrations of molecules such as enterolactone can improve outcomes in patients with type 2 diabetes. As shown in Figure 6, glycans can increase dietary enterolactone production in mice.

[0366] Treatment of patients with type 2 diabetes with glycan can increase circulating enterolactone levels compared to placebo-controlled treatment. Patients are included based on at least one of the following criteria: 1) elevated glucose levels (fasting glucose levels ≥ 7.0 mmol / L, random glucose levels ≥ 11.1 mmol / L, or glucose levels after an oral glucose load ≥ 11.1 mmol / L) and at least one symptom associated with diabetes; 2) the absence of symptoms but elevated glucose levels on two separate occasions; or 3) treatment with insulin or oral hypoglycemic agents. Patients are treated with glycan or placebo-controlled treatment for six months. At the end of six months, glycan treatment is expected to increase enterolactone levels in patients' urine compared to placebo, as assessed by electrospray ionization Orbirap liquid chromatography-mass spectrometry. Furthermore, at the end of six months, glycan treatment is expected to decrease fasting glucose levels or glucose levels after an oral load compared to placebo-treated patients.

[0367] Example 8: Protocols for Examples 9-21 Examples 9-21 were carried out according to the following protocol: The ex vivo assay was designed to determine whether glycans could be used to modulate complex microbial communities and whether the glycans produced consistent effects across communities obtained from multiple (12) subjects. Fecal samples and slurries were handled in an anaerobic chamber (AS-580, Anaerobe Systems) featuring a palladium catalyst. The glycans ara100, gal100, glu60man40, glu100, glu50gal50, gal33man33ara33, man75gal25, glu33gal33man34, glu33gal33Ara33, man100, man52glu29gal19, and the commercially available glycans lactulose (Alfa Aesar) and FOS (Nutraflora FOS; NOW Foods, Bloomingdale, IL) were included in the study. Fecal sample donations from 12 subjects were stored at -80°C. To prepare working stocks, fecal samples were transferred to an anaerobic chamber and thawed. The fecal samples were adjusted to 20% w / v in phosphate-buffered saline (PBS) pH 7.4 (P0261, Teknova Inc., Hollister, CA) with 15% glycerol and stored at -80°C. The 20% w / v fecal slurry + 15% glycerol was centrifuged at 2,000 × g, the supernatant removed, and the pellet suspended in PBS pH 7.4 to prepare a 1% w / v fecal slurry. The prepared 1% w / v fecal slurry was anaerobically exposed to the tested glycans at a final concentration of 0.5% w / v in a final volume of 500 μL per well in a 96-well deep-well microplate at 37°C for 18 hours. Genomic DNA was extracted from fecal samples and the variable region 4 of the 16S rRNA gene was amplified and sequenced (Earth Microbiome Project protocol www.earthmicrobiome.org / emp-standard-protocols / 16s / and Caporaso JG et al. 2012. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. ISME J.).Operational taxonomic units (OTUs) were formed by aligning 16S rRNA sequences at 97% identity. Microbial communities were compared to each other using the UniFrac distance metric (Lozupone C. et al., Appl. Environ. Microbiol. December 2005 vol. 71 no. 12 8228-8235).

[0368] Example 9: Regulation of cardiac glycoside (e.g., digoxin) metabolism-related bacteria by glycans The gut actinomycete Eggerthella lenta has previously been shown to inactivate the cardiac drug digoxin (see, e.g., Haiser et al. 2014. Gut Microbes: 5(2): 233-238). Although its association with digoxin inactivation is limited to Eggerthella lenta strains harboring the cardiac glycoside reductase (cgr) operon, suppression of Eggerthella lenta levels in patients on digoxin treatment may prevent or reduce digoxin inactivation.

[0369] Ex vivo assays demonstrated that several glycans significantly reduced Eggerthella lenta levels (Figure 9). All samples containing the glycan preparations showed a statistically significant (Wilcoxon rank sum test - p value < 0.05) reduction in the relative composition of Eggerthella lenta when compared to the control at 45 h postinoculation. Four glycans also showed a greater reduction than naturally occurring fructose oligosaccharides (FOS).

[0370] Example 10: Regulation of sulfonamide (e.g., sulfasalazine) metabolism-related bacteria by glycans Microbial azoreductases, found in Bacteroides species, Enterococcus faecalis, and Lactobacillus species, are known to convert sulfasalazine, used in the treatment of rheumatoid arthritis, to its active form. Increasing the level or activity of microorganisms expressing microbial azoreductases may enhance the efficacy of sulfasalazine treatment.

[0371] Ex vivo assays showed that several glycans significantly increased the levels of Bacteroides species and Enteroccaceae / Enterococcus species (Figures 2 and 3).

[0372] In this assay, man100, glu100, man75gal25, man52glu29gal19, glu50gal50, ara100, FOS, gal100, and glu60man40 appeared to increase levels of Bacteroides species and / or Enteroccaceae / Enterococcus species. Additionally, man100 increased levels of Lactobacillus species.

[0373] Example 11: Regulation of SN-38 glucuronide metabolism-related bacteria by glycans Microbial beta-glucuronidases, found in the Proteobacteria, Firmicutes, and Actinobacteria phyla, are known to modify SN-38 glucuronide, which is used to treat cancer (e.g., colorectal cancer) and has diarrheal side effects, by removing the sugar moiety to produce a compound that is toxic to intestinal epithelial cells. Reducing the level or activity of microorganisms expressing microbial beta-glucuronidase may increase the efficacy of SN-38 glucuronidine treatment and / or reduce / prevent side effects.

[0374] Ex vivo assays showed that several glycans significantly reduced the levels of Firmicutes, Proteobacteria, and Actinobacteria (Figures 4-6).

[0375] In this assay, man100, gal100, man52glu29gal19, man75gal25, glu33gal33man34, glu100, glu50gal50, lactulose, glu33gal33ara33, FOS, glu60man40, and ara100 appeared to reduce levels of Firmicutes, Proteobacteria, and / or Actinobacteria.

[0376] Example 12: Regulation of NSAID (e.g., tyrosine and phenylalanine) metabolism-related bacteria by glycans Microbial enzymes found in the phyla Firmicutes (e.g., Clostridium difficile), Bacteroidetes, Actinobacteria, and / or Fusobacteria are known to convert tyrosine and / or phenylalanine to p-cresol, which competes with acetaminophen for SULT1A1. Reducing the levels or activity of microorganisms expressing these microbial enzymes may increase the efficacy of acetaminophen and / or reduce drug-induced toxicity.

[0377] Ex vivo assays showed that some glycans significantly reduced the levels of Firmicutes and Actinobacteria (Figures 4 and 6).

[0378] In this assay, man100, gal100, man52glu29gal19, man75gal25, glu33gal33man34, glu33gal33ara33, and gal33man33ara33 appeared to reduce levels of Firmicutes and / or Actinobacteria.

[0379] Example 13: Regulation of polyphenol (e.g., ellagitannin) metabolism-related bacteria by glycans Microbial enzymes found in the phylum Actinobacteria and family Coriobacteriaceae / genus Gordonibacter are known to hydrolyze ellagitannins to ellagic acid.

[0380] Ex vivo assays showed that several glycans significantly reduced the levels of Actinobacteria and Coriobacteriaceae / Gordonibacter (Figures 6 and 8). In this assay, man100, gal100, man75gal25, man52glu29gal19, glu33gal33man34, glu33gal33ara33, glu50gal50, glu100, lactulose, glu60man40, FOS, and ara100 appeared to reduce the levels of Actinobacteria and / or Coriobacteriaceae / Gordonibacter.

[0381] Example 14: Regulation of phytoestrogen metabolism-related bacteria by glycans Microbial enzymes found in the Actinobacteria, Bacteroidetes, and Firmicutes phyla are known to metabolize phytoestrogens into molecules that bind to estrogen receptors and may have a preventive effect against breast cancer. Increasing the level or activity of microorganisms that express these microbial enzymes may have a preventive effect against cancer, such as breast cancer, or may treat cancer, such as breast cancer.

[0382] Ex vivo assays showed that several glycans significantly increased the levels of Bacteroidetes (Figure 9).

[0383] In this assay, gal100, man75gal25, man100, glu33gal33man34, man52glu29gal19, glu100, glu50gal50, glu33gal33ara33, glu60man40, and gal33man33ara33 appeared to increase levels of Bacteroidetes.

[0384] Example 15: Regulation of polyphenol / isoflavones (e.g., daidzein) metabolism-related bacteria by glycans Microbial enzymes found in Enterococcus faecium, Lactobacillus mucosae, Bifidobacterium species, and Eggerthella species are known to metabolize daidzin into equol, which binds to estrogen receptor-beta and may be associated with a reduced risk / occurrence of breast cancer. Increasing the level or activity of microorganisms expressing these microbial enzymes may enhance the preventive effect against cancer, e.g., breast cancer, or may treat cancer, e.g., breast cancer.

[0385] Ex vivo assays showed that several glycans significantly increased the levels of Enterococcaceae / Enterococcus and Bifidobacteriaceae / Bifidobacterium (Figures 3 and 10).

[0386] In this assay, glu60man40, gal33man33ara33, man75gal25, glu50gal50, man100, FOS, and lactulose appeared to increase levels of Enterococcaceae / Enterococcus and / or Bifidobacteriaceae / Bifidobacterium.

[0387] Example 16: Regulation of phytoestrogen / polyphenol (e.g., lignan) metabolism-related bacteria by glycans Microbial enzymes found in E. faecalis, E. lenta, Blautia producta, Eubacterium limosum, Clostridium scindens, Lactonifactor longoviformis, Clostridium saccharogumia, and P. producta are known to metabolize lignans, such as pinoresinol and secoisolariciresinol, into enterodiol and enterolactone, which may prevent breast cancer. Increasing the level or activity of microorganisms expressing these microbial enzymes may enhance the preventive effect against cancer, such as breast cancer, or may treat cancer, such as breast cancer.

[0388] Ex vivo assays showed that some glycans significantly increased the levels of Lachnospiraceae / Blautia, Eryspelotrichaceae / Clostridium_XVIII, and / or Lactonifactor / longoviformis (Figures 11-13).

[0389] In this assay, glu100, glu60man40, ara100, gal33man33ara33, glu33gal33ara33, glu50gal50, man75gal25, man52glu29gal19, and glu33gal33man34 appeared to increase levels of Lachnospiraceae / Blautia, Eryspelotrichaceae / Clostridium XVIII, and / or Lactonifactor / longoviformis.

[0390] Example 17: Regulation of heterocyclic amine (HCA) / polycyclic aromatic hydrocarbon (PAH) metabolism-related bacteria by glycans Microbial beta-glucuronidase, found in bacteria (e.g., Escherichia coli) that harbor the uidA gene, is known to activate glucuronidated substrates, such as heterocyclic amines (which are detoxified by glucuronidation in the liver), by removing the conjugate to produce toxic compounds. Reducing the level or activity of microorganisms that express microbial beta-glucuronidase can reduce the production of toxic, e.g., carcinogenic, compounds, which can have a preventative effect on cancer.

[0391] Ex vivo assays showed that several glycans significantly reduced the levels of Enterobacteriaceae / Escherichia / Shigella microorganisms (FIG. 14).

[0392] In this assay, ara100, gal33man33ara33, glu33gal33ara33, glu60man40, man75gal25, man100, FOS, glu33gal33man34, man52glu29gal19, gal100, lactulose, glu100, and glu50gal50 appeared to reduce levels of Enterobacteriaceae / Escherichia / Shigella organisms.

[0393] Example 18: Regulation of bacteria related to non-caloric artificial sweetener metabolism by glycans Microbial enzymes found in the genera Enterococcus, Clostridium, Corynebacterium, Campylobacter, and Escherichia are known to convert sweeteners into potentially toxic compounds, for example, converting cyclamate to the potentially toxic cyclohexylamine. Reducing the level or activity of microorganisms expressing said microbial enzymes can reduce the production of toxic compounds.

[0394] Ex vivo assays showed that several glycans significantly reduced the levels of Enterococcaceae / Enterococcus and Enterobacteriaceae / Escherichia / Shigella organisms (Figures 3 and 14).

[0395] In this assay, ara100, gal33man33ara33, glu33gal33ara33, glu60man40, man75gal25, man100, FOS, glu33gal33man34, man52glu29gal19, gal100, lactulose, glu100, and glu50gal50 appeared to reduce levels of Enterococcaceae / Enterococcus and / or Enterobacteriaceae / Escherichia / Shigella organisms.

[0396] Example 19: Regulation of nucleoside analog (e.g., sorivudine) metabolism-related bacteria by glycans Microbial phosphorylases (such as thymidine phosphorylase or uridine phosphorylase) found in enterobacteria, such as K. pneumoniae, are known to deglycosylate and inactivate sorivudine. Sorivudine is used to treat viral infections (such as herpes simplex virus type 1 and varicella-zoster virus). Reducing the level or activity of microorganisms expressing the microbial phosphorylase can reduce the inactivation of sorivudine and increase the effectiveness of sorivudine treatment against viral infections.

[0397] Ex vivo assays showed that several glycans significantly reduced the levels of Enterobacteriales / Enterobacteriaceae microorganisms (Figure 15).

[0398] In this assay, ara100, gal33man33ara33, glu60man40, FOS, man75gal25, glu33gal33man34, glu33gal33ara33, man52glu29gal19, man100, gal100, glu100, lactulose, and glu50gal50 appeared to reduce levels of Enterobacteriales / Enterobacteriaceae organisms.

[0399] Example 20: Modulation of immunotherapy antigen (e.g., CTLA4 inhibitor) metabolism-associated bacteria by glycans Bacteroides, such as Bacteroides thetaiotaomicron and / or Bacteroides fragilis, are known to modify immunotherapy antigens, and increasing the level or activity of microorganisms expressing these microbial enzymes may increase the effectiveness of CTLA4 inhibitors, for example, in cancer therapy.

[0400] Ex vivo assays showed that some glycans significantly increased the levels of Bacteroides / dorei / fragilis and Bacteroidaceae / Bacteroides microorganisms (Figures 16 and 2).

[0401] In this assay, man72gal25, glu33gal33man34, glu50gal50, man100, glu100, man52glu29gal19, ara100, FOS, gal100, and glu60man40 appeared to increase levels of Bacteroides / dorei / fragilis and Bacteroidaceae / Bacteroides organisms.

[0402] Example 21: Regulation of drug additive (e.g., emulsifier) ​​metabolism-related bacteria by glycans Microbial enzymes found in Bacteroidetes (e.g., Bacteroidales) and mucolytic bacteria such as Ruminococcus gnavus are known to induce metabolic and inflammatory responses to emulsifiers. Reducing the levels or activity of microorganisms expressing these microbial enzymes may increase the effectiveness of emulsifiers, such as carboxymethylcellulose or polysorbate 80, and may reduce the risk / occurrence of, for example, metabolic syndrome and / or inflammation.

[0403] Ex vivo assays showed that several glycans significantly reduced the levels of Ruminococcaceae / Ruminococcus microorganisms (FIG. 17).

[0404] In this assay, ara100, lactulose, gal33man33ara33, glu60man40, man100, glu33gal33ara33, glu33gal33man34, man75gal25, glu50gal50, man52glu29gal19, gal100, and glu100 appeared to reduce levels of Ruminococcaceae / Ruminococcus organisms.

[0405] Equivalence and Scope This application refers to various issued patents, published patent applications, journal articles, and other publications, each of which is incorporated herein by reference in its entirety and in the form of all pages, sections, or topics mentioned. In the event of a conflict between any of the incorporated references and this application, this application shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly stated herein, because they are deemed to be known to those of ordinary skill in the art. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0406] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the invention described herein is set forth in the appended claims, but is not intended to be limited to the above detailed description of the invention, drawings, or examples. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims. In one aspect, the present invention provides the following. [Item 1] 1. A method of increasing drug activity in a subject, comprising: a) administering a glycan composition in an amount and for a period of time effective to increase drug activity in the subject; b) administering a glycan composition in an amount and for a time sufficient to increase drug activity in the subject, wherein upon administration of the glycan composition, the subject contains a level of the drug that provides a therapeutic effect in the presence of the administered glycan composition; c) administering a drug, wherein at the time of administration of the drug, the subject has already been administered the glycan composition in an amount and for a sufficient time to increase the activity of the drug in the subject; d) administering a drug in an amount and for a time sufficient to increase the activity of the drug in the subject, the subject being determined to be in need of the glycan composition, for example, to increase the activity of the drug; or e) administering the drug and the glycan composition to the subject in an amount and for a time sufficient to increase the activity of the drug in the subject, wherein the administration of the drug and the glycan composition overlaps. Including, i) the glycan preparation comprises a glycan polymer comprising a glycan unit of glucose, galactose, arabinose, mannose, fructose, xylose, fucose, or rhamnose; ii) the average degree of branching (DB) of the glycan polymers in the glycan preparation is 0, 0.01 to 0.6, 0.05 to 0.5, 0.1 to 0.4, or 0.15 to 0.4; iii) at least 50% (at least 60%, 65%, 70%, 75%, 80%, or 85%, or less than 50%) of the glycan polymers in the glycan preparation have a degree of polymerization (DP) of at least 3 and less than 30 glycan units, at least 3 and less than 10 glycan units, at least 5 and less than 25 glycan units, or at least 10 and less than 35 glycan units; iv) the average DP (average DP) of the glycan preparation is about 5 to 8, about 8 to 13, about 13 to 25, about 5 to 15, about 5 to 20, or about 5 to 15; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan preparation is 0, or about 0.8:1 to about 5:1, about 1:1 to about 5:1, about 1:1 to about 3:1, about 3:2 to about 2:1, or about 3:2 to about 3:1; vi) the glycan preparation contains 15 mol% to 75 mol% (20 mol% to 60 mol%, 25 mol% to 50 mol%, or 30 mol% to 45 mol%) of 1,6 glycosidic bonds; vii) the glycan preparation contains at least one, two, or three of the following 1,2 glycosidic bonds, 1,3 glycosidic bonds, and 1,4 glycosidic bonds in an amount of 1 mol% to 40 mol% (1 mol% to 30 mol%, 5 mol% to 25 mol%, 10 mol% to 20 mol%); viii) the glycan preparation has a pH of at least about 50 (at least about 60, 70, 80, 90, 100, 120, 140, 160, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 300, 310, 320 or having a final solubility limit in water of Brix (0, at least about 75, or less than 50); ix) the glycan preparation has a dietary fiber content of at least 50% (at least 60%, 70%, 80%, or at least 90%, or less than 50%); x) any combination of two, three, four, five, six, seven, eight, or nine of i), ii), iii), iv), v), vi), vii), viii), viii), and ix); and The drug is v) cardiac glycosides; vi) sulfonamides; vii) a nucleoside analog; or viii) aminosalicylates Contains, or The drug is -Nonsteroidal anti-inflammatory (NSAID) drugs; - chemotherapeutic drugs, or generally drugs that have an antiproliferative effect on target cells (e.g. cancer cells); -Antibiotics or antimicrobials; -Antifungal agents; -Antiparasitic agents, e.g., antinematodic drugs; -hormone; - sedatives; -cardiac medications; -hypertension medication; -Colony-stimulating factors; -Dopamine; -Opioid receptor agonists; -Statins; -Central nervous system stimulants; -sensitizers / radiotherapeutic agents; - Narcotic painkillers; -hypnotic drugs; -antacids; - Painkillers; -Uricase inhibitors; - Antipsychotic medication; or -Laxatives; or neurotrophic factors, e.g., anticonvulsants How to be. [Item 2] Item 1. The method according to item 1, comprising: [Item 3] Item 1. The method according to item 1, comprising b. [Item 4] Item 1. The method of item 1, comprising: [Item 5] Item 1, the method according to item 1, comprising: [Item 6] The method of claim 1, comprising: [Item 7] The method of any one of items 1 to 6, wherein the drug activity is increased relative to a reference level, e.g., a reference level, e.g., a preselected level, a baseline level at the time of administration of the glycan composition, or a level that would be observed if the glycan composition were not administered. [Item 8] The method according to any one of items 1 to 7, wherein the drug comprises a cardiac glycoside, such as digoxin, digitoxin, convallatoxin, anthialin, or oleandrin. 8. The method of any one of items 1 to 7, wherein the drug comprises a sulfonamide (sulfa drug), e.g., an antimicrobial agent, such as sulfafurazole, sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole (sulfisoxazole), sulfisomidine (sulfaisodimidine), sulfadoxine, sulfamethoxazole, sulfamoxole, sulfanitran, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxydiazine, sulfadoxine, sulfamethopyrazine, or terephthyl. [Item 10] 8. The method of any one of items 1 to 7, wherein the drug comprises a sulfonamide, e.g., a sulfonylurea, e.g., acetohexamide, carbutamide, chlorprotamide, glibenclamide (glyburide), glibornuride, gliclazide, glyclopyramide, glimepiride, glipizide, gliquidone, glisoxepide, tolazamide, or tolbutamide. [Item 11] 8. The method of any one of items 1 to 7, wherein the drug comprises a sulfonamide, e.g., a diuretic, e.g., acetazolamide, bumetanide, chlorthalidone, clopamide, furosemide, hydrochlorothiazide, indapamide, mefruside, metolazone, or xipamide. [Item 12] 8. The method of any one of items 1 to 7, wherein the drug comprises a sulfonamide, e.g., an antispasmodic, e.g., ethoxzolamide, sulthiame, topiramate, or zonisamide. [Item 13] 8. The method of any one of items 1 to 7, wherein the drug is a sulfonamide, e.g., an antiretroviral drug, e.g., amprenavir (or other HIV protease inhibitors), darunavir, delavirdine (or other non-nucleoside reverse transcriptase inhibitors), fosamprenavir, or tipranavir. [Item 14] 8. The method of any one of items 1 to 7, wherein the drug comprises a sulfonamide, e.g., a hepatitis C antiviral drug, e.g., asunaprevir (or other NS3 / 4A protease inhibitor), beclabuvir (or other NS5B RNA polymerase inhibitor), dasabuvir, grazoprevir, paritaprevir, or simeprevir. [Item 15] The drugs include sulfonamides (sulfa drugs), such as apricoxib (COX-2 inhibitors), bosentan (endothelin receptor antagonists), brinzolamide (carbonic anhydrase inhibitors for glaucoma), c...

Claims

1. A glycan composition for use in increasing drug activity in a human subject, comprising: a) administering a glycan composition in an amount and for a period of time effective to increase drug activity in the subject; b) administering a glycan composition in an amount and for a time sufficient to increase drug activity in the subject, wherein upon administration of the glycan composition, the subject contains a level of the drug that provides a therapeutic effect in the presence of the administered glycan composition; c) administering a drug, wherein at the time of administration of the drug, the subject has already been administered the glycan composition in an amount and for a sufficient time to increase the activity of the drug in the subject; d) administering a drug in an amount and for a time sufficient to increase drug activity in the subject, the subject being determined to be in need of the glycan composition; or e) administering the drug and the glycan composition to the subject in an amount and for a time sufficient to increase the activity of the drug in the subject, wherein the administration of the drug and the glycan composition overlaps; where: i) the glycan composition comprises glycan polymers man100, glu100, man75gal25, man52glu29gal19, glu50gal50, ara100, FOS, gal100, glu60man40, or combinations thereof; ii) the average degree of branching (DB) of the glycan polymers in the glycan composition is 0.01 to 0.6; iii) at least 50% of the glycan polymers in the glycan composition have a degree of polymerization (DP) of at least 3 and less than 30 glycan units; iv) the average DP (average DP) of the glycan polymers in the glycan composition is 5 to 15, 13 to 25, or 5 to 20; v) the ratio of alpha-glycosidic bonds to beta-glycosidic bonds present in the glycan polymers of the glycan composition is 0.8:1 to 5:1; and vi) the glycan polymer in the glycan composition contains at least one of 1,2 glycosidic bond, 1,3 glycosidic bond, and 1,4 glycosidic bond in an amount of 1 mol% to 40 mol%; and the drug is a chemical entity that is converted by metabolism in a human subject to an aminosalicylate; The composition wherein the chemical moiety that is converted into an aminosalicylate by metabolism in a human subject is a derivative of 5-aminosalicylic acid, the derivative being balsalazide, olsalazine or sulfasalazine.

2. The glycan composition for use according to claim 1, wherein the drug activity is increased relative to a reference level, the reference level being a preselected level, a baseline level at the time of administration of the glycan composition, or a level that would be observed if the glycan composition were not administered.

3. The glycan composition for use according to any one of claims 1 to 2, wherein the use comprises changing the abundance of a microbial taxon in the subject's gastrointestinal tract compared to a reference level, wherein the reference level is a baseline level, a level before administration of the glycan composition, or a level when the glycan composition is not administered.

4. The glycan composition for use according to any one of claims 1 to 3, wherein the use comprises altering enzyme activity in the digestive tract of the human subject.

5. The glycan composition for use according to any one of claims 1 to 4, wherein the glycan composition comprises a glycan polymer comprising at least two distinct glycan units selected from the group consisting of glucose, galactose, arabinose, mannose, and fructose.

6. The glycan composition for use according to any one of claims 1 to 5, wherein at least three of the glycosidic bonds independently comprise a 1,2 glycosidic bond, a 1,3 glycosidic bond, a 1,4 glycosidic bond, or a 1,6 glycosidic bond.

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