Compositions and methods for enhancing the growth of Faecalibacterium prausnitzii using at least one of inositol, erythritol, or sorbitol - Patents.com

Abstract

One embodiment is a composition containing at least one of inositol, erythritol, or sorbitol and formulated for administration to a subject, wherein the at least one of inositol, erythritol, or sorbitol enhances the growth of Faecalibacterium prausnitzii in the microbiome of the subject. Another embodiment is a method of treating, preventing, reducing the severity, and / or reducing the incidence of a condition in a subject, comprising enhancing the growth of Faecalibacterium prausnitzii in the microbiome of the subject by administering at least one of inositol, erythritol, or sorbitol to the subject. Yet another embodiment is a method for achieving at least one of a metabolic effect, an anti-aging effect, or an anti-inflammatory effect in a subject, comprising enhancing the growth of Faecalibacterium prausnitzii in the microbiome of the subject by administering at least one of inositol, erythritol, or sorbitol to the subject.

Description

[Technical field]

[0001] The present invention relates to compositions and methods for enhancing the growth of Faecalibacterium prausnitzii using at least one of inositol, erythritol, or sorbitol. [Background technology]

[0002]

[0001] The present disclosure generally relates to compositions comprising at least one of inositol, erythritol, or sorbitol in an amount effective to enhance the growth of Faecalibacterium prausnitzii. The present disclosure further relates to methods of making such compositions. The present disclosure also relates to methods of using such compositions therapeutically or prophylactically, for example, for health benefits associated with improved status of Faecalibacterium prausnitzii.

[0003]

[0002] There is increasing scientific evidence showing the importance of gut microbiota in human health. It is well known that diet plays an important role in shaping the function and composition of gut microbiota, but the optimal nutritional composition for maximizing the benefits of gut microbiota remains unknown. Summary of the Invention

[0004]

[0003] Butyrate-producing bacteria are one of the beneficial bacteria in the microbiome. For example, butyrate-producing bacteria play an important role in human colon health. Despite sharing a common ability to produce butyrate, bacteria that share this function are diverse in phylogenetic groups and use different metabolic pathways to produce butyrate. The major butyrate-producing bacteria isolated from the human colon are Gram-positive anaerobic bacteria, many of which belong to the phylum Firmicutes and the clusters Clostridial IV, XIVa, and XVI [1]. Two of the most important groups in the human gut are F. prausnitzii and Eubacterium rectale / Roseburia spp., while the genus Coprococcus (C. catus, C. eutactus, and C. comes) are also known to produce butyrate.

[0005] Butyrate is one of the main short-chain fatty acids resulting from the fermentation of indigestible carbohydrates by butyrate-producing bacteria. In humans, butyrate is essential for maintaining colonic homeostasis by serving as the main energy source for colonic epithelial cells and being a key regulator of the immune system [2,3]. In addition to producing butyrate, butyrate-producing bacteria are found in abundance in many human conditions. In gut-related diseases, low numbers of F. prausnitzii have been found in Crohn's disease [4]. Similarly, roseburia was low in colorectal cancer [5] and constipation-predominant IBS [6]. Reductions in F. prausnitzii have also been reported in patients with type 2 diabetes and metabolic syndrome [7,8]. Conversely, people with improved insulin sensitivity had bacterial populations enriched in butyrate-producing bacteria [9]. The mechanisms by which butyrate mediates immune system regulation and mitochondrial function in host cells have been shown to affect gut homeostasis and other organs beyond the gastrointestinal tract. In the gut, butyrate-producing bacteria are a functionally unique group of bacteria, and their abundance is a major indicator of disease states in humans.

[0006]

[0005] F. prausnitzii is a butyrate-producing bacterium, but its effects are not limited to butyrate production. For example, F. prausnitzii is an important bacterium in the human gut microbiome ecosystem, which is associated with various conditions such as human health [10, 11], anti-inflammation [12, 13], ulcerative colitis

[14] , Crohn's disease

[15] , pediatric allergies such as asthma

[16] , IBD [17, 18], and frailty

[19] .

[0007]

[0006] Furthermore, F. prausnitzii is affected under multiple stress conditions on the gut microbiome ecosystem, such as drastic dietary changes or antibiotic use. For example, Mardinoglu et al. (Cell Metabolism 2018) showed a decrease in F. prausnitzii under ketogenic diet loading. Similarly, Palleja et al. (Nature Microbiology 2018) showed a decrease in F. prausnitzii under antibiotic loading. Furthermore, David et al. (Nature 2014) showed evidence of a decrease in F. prausnitzii abundance under high-fat diet loading.

[0008] As shown in the experimental examples disclosed later in this specification, a study was conducted to discover nutritional features that cause differences in the abundance of F. prausnitzii. In model organisms, the effects of inositol, erythritol, and sorbitol as energy substrates for F. prausnitzii were confirmed. Furthermore, the combination of coumestrol with sorbitol or inositol enhanced the growth of F. prausnitzii more than either component alone, and the addition of quercetin to sorbitol enhanced the growth of F. prausnitzii strain A2-165.

[0009]

[0008] Accordingly, embodiments provided by the present disclosure include compositions comprising: (i) at least one of inositol, erythritol, or sorbitol; (ii) optionally, a polyphenol, such as coumestrol and / or quercetin; and (iii) optionally, a vitamin, such as one or more of vitamin B5, vitamin B6, vitamin B12, vitamin A, or vitamin D. In some embodiments, a unit dosage form comprises an amount of the composition effective to enhance growth of F. prausnitzii in a subject to whom the composition is administered, preferably orally. In some embodiments, the composition is administered to a subject to treat, prevent, reduce the severity of, and / or reduce the incidence of a condition from enhanced growth of F. prausnitzii, for example, by exerting one or more metabolic, anti-aging, or anti-inflammatory effects.

[0010]

[0009] Additional features and advantages are described herein, and will be apparent from the drawings and detailed description that follow. [Brief description of the drawings]

[0011] [Figure 1A] 1 is a training ROC curve obtained in the experimental examples disclosed herein, showing model performance based on nutritional features alone. [Figure 1B] 1 shows holdout / test curves obtained in the experimental examples disclosed herein, illustrating model performance based on nutritional characteristics alone. [Figure 2A] 1 shows the top 30 nutritional traits in the model obtained in the experimental examples disclosed herein. [Figure 2B] 1 shows the top 30 nutritional traits in the model obtained in the experimental examples disclosed herein. [Figure 3A] 1 shows the results obtained with sugar alcohols in the experimental examples disclosed herein. [Figure 3B] 1 shows the results obtained with sugar alcohols in the experimental examples disclosed herein. [Figure 3C]1 shows the results obtained with sugar alcohols in the experimental examples disclosed herein. [Figure 3D] 1 shows the results obtained with sugar alcohols in the experimental examples disclosed herein. [Figure 4A] The results obtained in the experimental examples disclosed herein are presented and support the effectiveness of inositol and sorbitol as energy substrates for F. prausnitzii. [Figure 4B] The results obtained in the experimental examples disclosed herein are presented and support the effectiveness of inositol and sorbitol as energy substrates for F. prausnitzii. [Figure 5A] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5B] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5C] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5D] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5E] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5F] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5G] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5H] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5I] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5J]The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5K] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 5L] The results for the polyphenols coumestrol and quercetin obtained in the experimental examples disclosed in this specification are shown. [Figure 6A] The results for B vitamins obtained in the experimental examples disclosed in this specification are shown below. [Figure 6B] The results for B vitamins obtained in the experimental examples disclosed in this specification are shown below. [Figure 6C] The results for B vitamins obtained in the experimental examples disclosed in this specification are shown below. [Figure 6D] The results for B vitamins obtained in the experimental examples disclosed in this specification are shown below. [Figure 7A] 1 shows the results for Vitamin A obtained in the experimental examples disclosed herein. [Figure 7B] 1 shows the results for Vitamin A obtained in the experimental examples disclosed herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012]

[0017] definition

[0018] Some definitions are provided below. However, definitions may be found in the "Embodiments" section below, and the heading "Definitions" above does not imply that such disclosure in the "Embodiments" section is not a definition.

[0013]

[0019] All percentages stated herein are by total weight of the composition unless otherwise indicated. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a certain range of numerical values, for example, within the range of -10% to +10% of the referenced number, preferably within the range of -5% to +5% of the referenced number, more preferably within the range of -1% to +1% of the referenced number, and most preferably within the range of -0.1% to +0.1% of the referenced number. All numerical ranges herein should be understood to include all integers or fractions within the range. Furthermore, these numerical ranges should be interpreted as supporting claims directed to any number or subset of numbers within the range. For example, a disclosure of 1 to 10 should be interpreted as supporting ranges such as 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0014]

[0020] As used in this disclosure and the appended claims, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. Thus, for example, a reference to "a vitamin" or "the vitamin" includes both embodiments having a single vitamin and embodiments having two or more vitamins.

[0015]

[0021] The terms "comprise", "comprises", and "comprising" should be interpreted as inclusive rather than exclusive. Similarly, the terms "include", "including", and "or" should all be interpreted as inclusive unless such interpretation is clearly prevented by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of an embodiment "consisting essentially of" the specified components, and an embodiment "consisting of" the specified components.

[0016]

[0022] The terms "at least one of" and "and / or" used in the context of "at least one of X or Y" and "X and / or Y", respectively, should be interpreted as "X" or "Y" or "X and Y". For example, "at least one of inositol or sorbitol" and "inositol and / or sorbitol" should be interpreted as "inositol without sorbitol" or "sorbitol without inositol", or "both inositol and sorbitol".

[0017]

[0023] As used herein, the terms "examples" and "such as," especially when followed by a list of terms, are merely exemplary and illustrative and should not be considered as exclusive or inclusive. As used herein, a condition "associated with" or "linked with" another condition means that the conditions occur simultaneously, preferably that the conditions are caused by the same underlying condition, and most preferably that one of the specified conditions is caused by the other specified condition.

[0018]

[0024] "Prevention" includes reducing the risk, incidence and / or severity of a condition or disorder. The terms "treatment" and "treating" include both preventative or suppressive treatment (treatment that prevents and / or delays the onset of the pathological condition or disorder of interest) and curative, therapeutic or disease-modifying treatment, including, for example, therapeutic measures to cure, delay, reduce symptoms and / or halt the progression of a diagnosed pathological condition or disorder, as well as treatment of patients at risk of or suspected of having a disease, and patients who are unwell or diagnosed with a disease or medical condition. The terms "treatment" and "treating" do not necessarily mean that the subject is treated until fully cured. The terms "treatment" and "treating" also refer to maintaining and / or promoting the health of individuals who are not suffering from a disease but who may be susceptible to an unhealthy condition. The terms "treatment" and "treating" are also intended to include the synergism or otherwise potentiation of one or more primary preventative or therapeutic measures. By way of non-limiting example, treatment can be performed by the patient, a caregiver, a doctor, a nurse, or another medical professional.

[0019]

[0025] As used herein, a prophylactically or therapeutically "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or, more generally, reduces symptoms, manages disease progression, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms "promote," "improve," "increase / enhance," "promote," and the like refer to an enhanced state of F. prausnitzii in the microbiome of a subject following administration of a composition disclosed herein (containing sorbitol, erythritol, and / or inositol) compared to the state of F. prausnitzii in the microbiome of the subject obtained by administration of an identically formulated composition, except that it does not contain sorbitol, erythritol, and inositol. As used herein, "promoted growth" of F. prausnitzii is used interchangeably with "promoted state" of F. prausnitzii.

[0020]

[0026] This enhanced state of F. prausnitzii in the subject's microbiome can be characterized by (i) a high total amount of F. prausnitzii in the subject's microbiome (i.e., total cfu of Faecalibacterium prausnitzii) or (ii) a high relative proportion of Faecalibacterium prausnitzii compared to other bacteria in the subject's microbiome (i.e., cfu of Faecalibacterium prausnitzii / cfu of other bacteria).

[0021]

[0027] As used herein, the terms "food," "food product," and "food composition" refer to a product or composition intended for oral ingestion by humans or other mammals and containing at least one nutrient for humans or other mammals.

[0022]

[0028] As used herein, "nutritional composition" and "nutritional product" include any number of food ingredients and possibly optional additional ingredients based on the functional needs of the product and in full compliance with all applicable regulations. Optional ingredients may include, but are not limited to, conventional food additives such as one or more acidulants, additional thickeners, pH adjusting buffers or pH adjusting agents, chelating agents, colorants, emulsifiers, excipients, flavorings, minerals, osmotic agents, pharma-ceutically acceptable carriers, preservatives, stabilizers, sugars, sweeteners, modifiers and / or vitamins. Optional ingredients may be added in any suitable amount.

[0023]

[0029] "Probiotic" means a microbial cell preparation or microbial cell component that has a beneficial effect on the health or well-being of the host. (Salminen S, Ouwehand A. Benno Y. et al., "Probiotics: how should they be defined", Trends Food Sci. Technol., 1999:10 107-10).

[0024]

[0030] The term "metabolic condition" as used herein refers to metabolic abnormalities that result in negative changes in the body's processing and distribution of macronutrients such as proteins, fats, and carbohydrates. Metabolic abnormalities can occur when abnormal chemical reactions in the body alter normal metabolic processes. Metabolic abnormalities can include diabetes (type 1 and type 2), Gaucher disease, glucose galactose malabsorption, hereditary hemochromatosis, maple syrup urine disease, phenylketonuria, Hunter syndrome, and others. Metabolic abnormalities are also associated with metabolic syndrome, which is associated with the risk of developing cardiovascular disease as well as type 2 diabetes. Metabolic syndrome is the occurrence of at least three of the following five medical conditions together: abdominal obesity, high blood pressure, hyperglycemia, high serum triglycerides, and low high density lipoprotein (HDL).

[0025]

[0031] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a dosage unit for human and animal subjects, each unit containing a predetermined amount of a composition disclosed herein, in an amount sufficient to produce the desired effect, together with a pharma- ceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage form depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0026]

[0032] A "subject" or "individual" is a mammal, preferably a human.

[0027]

[0033] Embodiment

[0034] An embodiment provided by the present disclosure is a composition formulated for administration to a subject comprising at least one of inositol, erythritol, or sorbitol, wherein the at least one of inositol, erythritol, or sorbitol enhances the growth of Faecalibacterium prausnitzii in the microbiome of the subject.

[0028]

[0035] Another aspect is a method of treating, preventing, reducing the severity of, and / or reducing the incidence of a condition in a subject, comprising enhancing the growth of Faecalibacterium prausnitzii in the microbiome of the subject by administering to the subject at least one of inositol, erythritol, or sorbitol.

[0029]

[0036] Yet another aspect is a method for achieving at least one of a metabolic effect, an anti-aging effect, or an anti-inflammatory effect in a subject, comprising enhancing the growth of Faecalibacterium prausnitzii in the subject's microbiome by administering to the subject at least one of inositol, erythritol, or sorbitol.

[0030]

[0037] Another aspect is a unit dosage form of a composition comprising at least one of inositol, erythritol, or sorbitol, the unit dosage form comprising an amount of at least one of inositol, erythritol, or sorbitol effective to enhance the growth of Faecalibacterium prausnitzii in the microbiome of a subject to which the unit dosage form is administered.

[0031]

[0038] Yet another aspect is a method of producing a composition for enhancing the growth of Faecalibacterium prausnitzii in the microbiome of a subject to which the composition is administered, comprising adding at least one of inositol, erythritol, or sorbitol to at least one additional component.

[0032]

[0039] The inositol, erythritol, and / or sorbitol are preferably administered orally in a composition, such as a food composition. The inositol, erythritol, and / or sorbitol may be the only sugar alcohol in the composition, or the composition may include one or more additional sugar alcohols.

[0033]

[0040] In some embodiments, inositol, erythritol, and / or sorbitol comprise a combined amount of at least 50% by weight of all sugar alcohols in the composition, preferably at least 60% by weight of all sugar alcohols in the composition, more preferably at least 70% by weight of all sugar alcohols in the composition, even more preferably at least 80% by weight of all sugar alcohols in the composition, and most preferably at least 90% by weight of all sugar alcohols in the composition.

[0034]

[0041] Inositol, erythritol, and / or sorbitol are preferably administered in a composition further comprising a polyphenol. The polyphenol may comprise at least one of coumestrol or quercetin, for example, as the only polyphenol in the composition or in combination with one or more other polyphenols. In some embodiments, at least one of coumestrol or quercetin is present in a total amount of at least 50% by weight of the total polyphenols in the composition, preferably at least 60% by weight of the total polyphenols in the composition, more preferably at least 70% by weight of the total polyphenols in the composition, even more preferably at least 80% by weight of the total polyphenols in the composition, and most preferably at least 90% by weight of the total polyphenols in the composition.

[0035]

[0042] Inositol, erythritol, and / or sorbitol are preferably administered in a composition further comprising vitamins. The vitamins can include at least one of vitamin B5, vitamin B6, vitamin B12, vitamin A, or vitamin D, for example, as the only vitamin in the composition or in combination with one or more other vitamins. In some embodiments, at least one of vitamin B5, vitamin B6, vitamin B12, vitamin A, or vitamin D is present in a total amount of at least 50% by weight of all vitamins in the composition, preferably at least 60% by weight of all vitamins in the composition, more preferably at least 70% by weight of all vitamins in the composition, even more preferably at least 80% by weight of all vitamins in the composition, and most preferably at least 90% by weight of all vitamins in the composition.

[0036]

[0043] Administration of inositol, erythritol, and / or sorbitol can treat, prevent, reduce the severity, and / or reduce the incidence of a condition in a subject. For example, the condition can include at least one of a metabolic condition, an inflammatory condition, an inflammatory bowel disease such as ulcerative colitis or Crohn's disease, a childhood allergy such as asthma, multiple sclerosis, aging, or frailty. In some embodiments, inositol, erythritol, and / or sorbitol promote the growth of Faecalibacterium prausnitzii in the microbiome of the subject to exert at least one of a metabolic effect, an anti-aging effect, or an anti-inflammatory effect in the subject.

[0037]

[0044] The subject to which inositol, erythritol, and / or sorbitol is administered can be selected from the group consisting of a human infant, a human child, a human adolescent, a human adult, and a human geriatric.

[0038]

[0045] In some embodiments, inositol, erythritol, and / or sorbitol are administered in a composition that further comprises one or more probiotics. Alternatively, inositol, erythritol, and / or sorbitol can be administered in a composition that does not contain any probiotics in the composition.

[0039]

[0046] The inositol, erythritol, and / or sorbitol may be administered to an individual by at least one route selected from the group consisting of oral, topical, enteral, and parenteral. For example, the inositol, erythritol, and / or sorbitol may be administered in a composition selected from the group consisting of a complete nutritional product, a beverage, a dietary supplement, a meal replacement, a food additive, a supplement to a food product, a dissolving powder, an enteral nutritional product, an infant formula, and combinations thereof.

[0040]

[0047] In some embodiments, inositol, erythritol, and / or sorbitol can be administered in an amount effective to treat, prevent, reduce the incidence of, and / or reduce the severity of inflammation. Non-limiting examples of such inflammation include acute inflammation, skin inflammation, inflammatory bowel disease (IBD) including Crohn's disease and / or ulcerative colitis, irritable bowel syndrome, hepatitis (NASH, NAFLD, alcohol-induced liver injury), allergies, atopy, bone inflammation, rheumatoid arthritis, systemic lupus, Gougerot-Sjogren's syndrome, Reiter's syndrome, poliomyelitis, dermatomyositis, thyroiditis, Graves', Hashimoto's disease, type I diabetes, Addison's disease, autoimmune hepatitis, celiac disease, Biermer's disease, multiple sclerosis, myasthenia gravis, ophthalmia, obesity-associated inflammation, age-related low-grade inflammation, and the like. inflammation), Blau syndrome, Alzheimer's disease, cardiovascular disease, atherosclerosis, metabolic syndrome, type II diabetes, gingivitis, paronditis, food sensitivities, celiac disease, and combinations thereof.

[0041]

[0048] The inflammation treated or prevented by inositol, erythritol, and / or sorbitol can be IBD, such as Crohn's disease or ulcerative colitis.

[0042]

[0049] In some embodiments, the subject to which inositol, erythritol, and / or sorbitol is administered is selected from the group consisting of infants, children, adolescents, adults, and the elderly.

[0043]

[0050] Optionally, the inositol, erythritol, and / or sorbitol are administered in a composition further comprising at least one component selected from the group consisting of prebiotics, amino acids, proteins, nucleotides, fish oil, non-marine sources of omega-3 fatty acids, phytonutrients, antioxidants, and mixtures thereof.

[0044]

[0051] "Prebiotics" are foods that promote the growth of beneficial bacteria in the intestine. Prebiotics are not degraded in the stomach of the individual who ingests them, or absorbed in the GI tract, but are fermented by the gastrointestinal microflora and / or probiotics. Prebiotics that can be used with at least one of inositol, erythritol, or sorbitol are not particularly limited and include all food substances that promote the growth of probiotics in the intestine. Preferably, the prebiotics can be selected from the group consisting of oligosaccharides, optionally containing fructose, galactose, mannose; dietary fiber, especially soluble fiber, soy fiber; inulin; or mixtures thereof. Preferred prebiotics are fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), isomaltooligosaccharides, xylooligosaccharides, soybean oligosaccharides, glycosylsucrose (GS), lactosucrose (LS), lactulose (LA), palatinose-oligosaccharides (PAO), maltooligosaccharides, hemicellulosic polysaccharides (e.g., arabinoxylan), pectin, and / or hydrolysates thereof.

[0045]

[0052] The composition comprising inositol, erythritol, and / or sorbitol can be a food product, an animal food product, or a pharmaceutical composition. For example, the product can be a nutritional composition, a nutraceutical, a beverage, a food additive, or a pharmaceutical. The food additive or pharmaceutical can be, for example, in the form of a tablet, capsule, lozenge, liquid, or powder in a sachet.

[0046]

[0053] The composition comprising inositol, erythritol and / or sorbitol is preferably selected from the group consisting of: milk powder based products; instant beverages; ready-to-drink formulations; nutritional powders; nutritional liquids; milk based products, in particular yoghurt or ice cream; cereal products; beverages; water; coffee; cappuccino; malt beverages; chocolate flavoured beverages; cooked products; soups; tablets; and / or syrups.

[0047]

[0054] The composition may optionally comprise any milk obtained from an animal or vegetable source, such as, for example, one or more of cow's milk, human milk, sheep's milk, goat's milk, horse's milk, camel's milk, rice milk, or soy milk. Additionally or alternatively, a milk-derived protein fraction or colostrum may be used.

[0048]

[0055] Compositions comprising inositol, erythritol, and / or sorbitol may further contain protective hydrocolloids (gums, proteins, modified starches, etc.), binders, film formers, encapsulants / encapsulants, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, flavoring agents, bulking agents, jellifying agents, gel forming agents, antioxidants, and antimicrobial agents. Compositions comprising inositol, erythritol, and / or sorbitol may also contain conventional pharmaceutical additives and adjuvants, excipients and diluents, including, but not limited to, water, gelatin from any source, vegetable gums, lignin sulfonates, talc, sugars, starches, gum arabic, vegetable oils, polyalkylene glycols, flavorings, preservatives, stabilizers, emulsifiers, buffers, lubricants, colorants, humectants, fillers, etc. Additionally, compositions comprising inositol, erythritol, and / or sorbitol may also contain vitamins, minerals, trace elements and other micronutrients in accordance with recommendations of government agencies such as the USRDA, in addition to organic or inorganic carrier materials suitable for oral or enteral administration.

[0049]

[0056] Compositions comprising inositol, erythritol, and / or sorbitol may optionally contain one or more amino acids, a protein source, a carbohydrate source, and / or a lipid source, particularly in embodiments of the composition that are food products.

[0050]

[0057] Any suitable food-derived protein may be used, such as animal proteins (such as milk proteins, meat proteins, and egg proteins); vegetable proteins (such as soybean proteins, wheat proteins, rice proteins, and pea proteins); mixtures of free amino acids; or combinations thereof. Milk proteins such as casein and whey proteins, and soybean proteins are particularly preferred.

[0051]

[0058] The composition comprising inositol, erythritol, and / or sorbitol can be administered to humans or animals, particularly companion animals, pets, or livestock. The composition has beneficial effects on all age groups. Preferably, the composition is formulated for administration to infants, juveniles, adults, or the elderly. In some embodiments, the composition can be administered to pregnant and lactating mothers to treat their infants.

[0052]

[0059] The composition comprising inositol, erythritol, and / or sorbitol can be administered at least 1 day per week, preferably at least 2 days per week, more preferably at least 3 or 4 days per week (e.g., every other day), most preferably at least 5 days per week, 6 days per week, or 7 days per week. The administration period can be at least 1 week, preferably at least 1 month, more preferably at least 2 months, most preferably at least 3 months, e.g., at least 4 months. In one embodiment, administration is at least daily, e.g., the subject may receive one or more doses per day. In some embodiments, administration continues for the remainder of the individual's life. In other embodiments, administration is administered until there is no detectable symptom of the medical condition. In a specific embodiment, administration is administered until there is a detectable improvement in at least one symptom, and in further cases, administration is continued to maintain remission. EXAMPLES

[0053]

[0061] The following non-limiting examples generally illustrate the concepts underlying the embodiments disclosed herein.

[0054]

[0062] Example 1: Conversion of food frequency data to nutrients

[0063] Food intake data from participants in a publicly available citizen science project called the American Gut Project (AGP) (McDonald D., et al. mSystems. 2018) were converted to nutrient intakes using a tool called vioscreen and made publicly available by the AGP.

[0055]

[0064] Example 2: Building a model to estimate the relative abundance of Faecalibacterium prausnitzii (Fprau)

[0065] A predictive model was constructed to determine the relative abundance of Faecalibacterium prausnitzii (Fprau) in individual subjects. Specifically, the model predicts the relative abundance of Fprau by several characteristic parameters and determines whether the subject has the above-defined categories of "low" or "non-low"; "high" or "non-high"; "low" or "high" Fprau abundance.

[0056]

[0066] Before binning the Fprau quantities into different categories, a cube root transformation was performed to make them normally distributed. The values ​​for the various definitions of the bins were 1st / lower quartile -0.2819, 3rd / upper quartile -0.4666, mean -std -0.1954, and mean +std -0.5220.

[0057]

[0067] To build the classification model, the data was split into a training set, “train”, and a test set, “holdout / test set”. For optimal model performance, downsampling was used to balance possible imbalanced classes based on the bin definition.

[0058]

[0068] The training set was used by the machine learning algorithm to train the model. The training set included finding the variables (i.e., features) and thresholds (or coefficients) used to classify the groups. Learning from the data was done in a cross-validation fashion, where the training data was split into multiple partitions, some parts were used to train the model and other parts were used for internal testing (k-fold cross-validation, e.g., 3-fold), or this process was repeated several times (repeated k-fold cross-validation, e.g., 10-fold, 10 iterations).

[0059]

[0069] The holdout / test set was only used to check the performance of the final trained model. Therefore, this holdout / test data set was not used in the model training stage. This study evaluated multiple statistical models (different machine learning algorithms) using freely available tools (R software, Python) and identified the best models for "low" vs. "non-low", "high" vs. "non-high", and "low" vs. "high" Fprau quantities.

[0060]

[0070] Evaluation of model performance was important in all stages of modeling. The trained model was applied to hold-out / test data that was not used in the training stage. The model calculated the probability of belonging to each group (e.g., "low", "non-low"). The final decision was made based on this probability. Therefore, the use of a threshold was necessary. This threshold influenced the final classification of the subject, whether it was correctly classified or not. Therefore, the error was evaluated for different choices of threshold. For each given threshold, a confusion matrix was calculated. This confusion matrix essentially enumerated the number of correctly classified and incorrectly classified subjects. By using different thresholds, many confusion matrices were generated, which were then used to derive sensitivity and specificity at different thresholds. These two metrics (sensitivity and specificity) were commonly presented in the form of a receiver operating curve (ROC) to summarize the model performance over several thresholds.

[0061]

[0071] Receiver operating characteristic (ROC) curves were generated for this model. The study defined a group of "low" subjects (and a "non-low" group) and predicted the probability that a subject would fall into this group; or defined subjects in a "high" group (and a "non-high" group) and predicted the probability that a subject would fall into this group; or defined subjects in a "low" group (and a "high" group) and predicted the probability that a subject would fall into this group.

[0062]

[0072] As mentioned above, the dataset used for the predictive model examples comes from the American Gut Project (AGP) database (http: / / americangut.org).

[0063]

[0073] Example 3: Estimation of "low" Fprau amounts from nutrient intake data (I)

[0074] A model of low vs. non-low Fprau amounts was trained using the following parameters: Bin definition: (mean-1 * std) vs. rest; feature cutoff: none; algorithm: random forest; training mode: cv-splits-3, cv-repeats-3; post-training size: 896; and holdout / test size (original / pre-training / test split): 764 (test percentage: 20.0%). The results obtained for training in cross-validation were accuracy -0.58 ± 0.02, sensitivity -0.61 ± 0.05, and specificity -0.58 ± 0.03. The training ROC curve is shown in Figure 1A. The results obtained for the holdout / test set were accuracy -0.64, sensitivity -0.56, and specificity -0.65. The holdout / test ROC curve is shown in Figure 1B.

[0064]

[0075] Example 4: Nutrition to maintain or improve Fprau levels

[0076] The important features and their association with Fprau amount are shown in Figure 2A and Figure 2B. Specifically, for the model presented in Example 3, the top 30 features that make up the model are shown in Figure 2A and Figure 2B, which were obtained by performing SHAP algorithm analysis. Figure 2A shows the average impact per feature on the model output in order of high to low importance. The main / best feature is the top horizontal bar. The next best feature is the second horizontal bar, and so on. Figure 2B shows the impact of the feature per instance / sample on the model output in more detail. The color gradation from gray to black indicates the low to high value of that feature. The vertical line at 0.00 defines the direction of the impact (left side is negative impact on the model output, right side is positive impact on the model output). Here, the SHAP analysis output was for the reference class, which is "low".

[0065]

[0077] If a feature has a black value toward the right of the 0.00 vertical line, this indicates that higher values ​​of this feature contribute positively to the model output. Vice versa, features with black values ​​toward the left of the 0.00 vertical line indicate that higher values ​​of this feature contribute negatively to the model output. Similarly, features with gray values ​​toward the right of the 0.00 vertical line indicate that lower values ​​of this feature contribute positively to the model output. Vice versa, features with gray values ​​toward the left of the 0.00 vertical line indicate that lower values ​​of this feature contribute negatively to the model output.

[0066]

[0078] As can be seen from Figures 2A and 2B, as an example, a key feature of the model for predicting low vs. non-low Fprau levels had to do with inositol (g inositol).

[0067]

[0079] In Figures 3A-3D, 5A, 6A-6C, 7A and 7B, for each feature, the SHAP dependency plot shows a point for each data instance / sample with the feature value on the x-axis and the corresponding Shapley value on the y-axis. SHAP explained the prediction of each instance by calculating the contribution of each feature to the prediction. The explanation of the Shapley value was expressed as a linear model, as an additive feature imputation method. The reference class here was "low", so a positive coefficient of the SHAP value for the corresponding x-value of a feature indicates how much the model was influenced by this feature in predicting the "low" class.

[0068]

[0080] As can be seen, inositol influenced Fprau levels - Fprau levels were one of the top features used in the model (Figures 2A and 2B). As shown in Figure 3A, the specific intake value of inositol was associated with an impact on the model output, with low inositol intake tending to lower Fprau status, while high inositol intake tending to move Fprau status into the "non-low" class. Thus, Fprau status would benefit from more inositol in the diet, preferably more than 0.2 g inositol per day.

[0069]

[0081] 3B-3D show the SHAP dependence plots for xylitol, erythritol, and sorbitol, respectively.

[0070]

[0082] Example 5:

[0083] Using model organisms, the effects of inositol and sorbitol, but not xylitol, as energy substrates for F. prausnitzii were confirmed (Figures 4A and 4B), and therefore it cannot be assumed that all sugar alcohols have the same effect on F. prausnitzii.

[0071]

[0084] Example 6:

[0085] As shown in Figure 5A, the specific intake value of coumestrol was related to its effect on the model output, suggesting a nonlinear effect of coumestrol.

[0072]

[0086] In vitro testing of coumestrol alone or in combination with sorbitol and inositol is shown in Figures 5B and 5C. The combination of coumestrol with sorbitol or inositol enhances the growth of F. prausnitzii strain DSMZ A2-165 more than each component alone. As shown in Figure 5D, the growth-promoting effect of coumestrol on F. prausnitzii strain DSMZ A2-165 is also observed when combined with glucose. Figure 5E shows the growth-promoting effect of quercetin and sorbitol on F. prausnitzii strain DSMZ A2-165. Figures 5F and 5G show the growth-promoting effect of quercetin and inositol on F. prausnitzii strain DSMZ A2-165 and ATCC 27768, respectively. 5H to 5L show that the growth-promoting effect of the combination of quercetin and glucose is most positive in the DSMZ A2-165 and ATCC 27768 strains of F. prausnitzii.

[0073]

[0087] Example 7

[0088] Figures 6A-C show that the model identified vitamin B as a nutrient that contributes to the growth of F. prausnitzii. Figure 6D shows that the addition of vitamin B12 and a mixture of vitamins B5, B6, and B12 each enhances the growth of F. prausnitzii over the control when glucose is used as a substrate.

[0074]

[0089] Example 8

[0090] As can be seen from Figures 2A and 2B, as an example, features important to the model for predicting low vs. non-low Fprau doses were related to vitamin A (vita_iu-total vitamin A activity in IU, vita_rae-total vitamin A active retinol activity equivalents in mcg, and vita_re-total vitamin A active retinol equivalents in mcg).

[0075]

[0091] Figures 7A and 7B show that increasing the amount of vitamin A has the desired effect on Fprau levels. This effect was captured in the AGP data as vita_rae (total vitamin A active retinol activity equivalents in mcg) and vita_re (total vitamin A active retinol equivalents in mcg). 1 IU of retinol corresponds to approximately 0.3 micrograms (300 nanograms). Figures 7A and 7B show that vita_rae>2000mcg and vita_re>3000mcg had the desired effect on Fprau levels.

[0076]

[0092] It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. Accordingly, such changes and modifications are intended to be encompassed by the appended claims.

[0077] References [1]Louis,P.,Flint,HJ(2009)Diversity,metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine.FEMS Microbiol Lett.294(1):1-8. [2]Nicholson,J.K.,Holmes,E,Kinross,J.,Burcelin,R.,Gibson,G.et al.(2012)The Microbial Metabolites,Short-Chain Fatty Acids,Regulate Colonic Treg Cell Homeostasis Science 336,Issue 6086,pp.1262-1267. [3]Smith,P.M.,Howitt,M.R.,Panikov,N.,Michaud,M.,Gallini,C.M.et al.(2013)Science 341,Issue 6145,pp.569-573. [4]Sokol,H,Pigneur,B.,Watterlot,L.,Lakhdari,O.,Bermudez-Humaran,L.G.,et al.(2008)Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients PNAS,105(43)16731-16736. [5]Wang,T.,Cai,G.,Qiu,Y.,Fei,N.,Zhang,M.,et al.(2012)Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers.ISME J.6(2):320-9. [6]Chassard,C.,Dapoigny,M.,Scott,K.P.,Crouzet,L.,Del’homme,C.,et al(2012).Functional dysbiosis within the gut microbiota of patients with constipated-irritable bowel syndrome.Aliment Pharmacol Ther.35(7):828-38. [7]Qin,J.,Li,Y.,Cai,Z.,Li,S.,Zhu,J.,et al.(2012).A metagenome-wide association study of gut microbiota in type 2 diabetes.Nature.490(7418):55-60. [8] Le Chatelier,E.,Nielsen,T.,Qin,J.,Prifti,E.,Hildebrand,F.,et al.(2013)MetaHIT consortium,Bork P,Wang J,Ehrlich SD,Pedersen O.Richness of human gut microbiome correlates with metabolic markers.Nature.500(7464):541-6.doi:10.1038 / nature12506. [9]Vrieze,A.,Van Nood,E.,Holleman,F.,Salojarvi,J.,Kootte,R.S.et al.(2012).Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.Gastroenterology.143(4):913-6.

[10] Miquel,S.et al.Current opinion in microbiology,2013.

[11] Ferreira-Halder,C.V.et al.Clinical gastroenterology,2017.

[12] Quevrain,E.et al.Gut,2016.

[13] Sokol,H.et al.PNAS,2008.

[14] Machiels,K.et al.Gut,2014.

[15] Takahashi,K.et al.Digestion,2016.

[16] Demirci,M.et al.Allergologia et immunopathologia,2019.

[17] Zhao H.,Xu H.,Chen S.,He J.,Zhou Y.,Nie Y.,2020.J Gastroenterol Hepatol.

[18] Machiels K.et al.,Gut.2014.

[19] Jackson MAet al.Genome Med.2016.

Claims

1. A composition comprising at least one of inositol, erythritol, or sorbitol and formulated for administration to a subject, wherein the at least one of inositol, erythritol, or sorbitol enhances the growth of Faecalibacterium prausnitzii in the microbiome of the subject.

2. The composition of claim 1 further comprising a polyphenol.

3. 3. The composition of claim 2, wherein the polyphenol comprises at least one of coumestrol or quercetin.

4. The composition according to any one of claims 1 to 3, further comprising a vitamin.

5. 5. The composition of claim 4, wherein the vitamins include at least one of vitamin B5, vitamin B6, vitamin B12, vitamin A, or vitamin D.

6. The composition of any one of claims 1 to 3, wherein the composition is formulated for oral administration.

7. 4. The composition of any one of claims 1 to 3 for use in treating, preventing, reducing the severity and / or reducing the incidence of a condition in a subject.

8. 8. The composition of claim 7, wherein the disease state comprises at least one of a metabolic condition, an inflammatory condition, an inflammatory bowel disease such as ulcerative colitis or Crohn's disease, a childhood allergy such as asthma, multiple sclerosis, aging, or frailty.

9. The composition of any one of claims 1 to 3, wherein at least one of inositol, erythritol, or sorbitol enhances the growth of Faecalibacterium prausnitzii in the microbiome of the subject, thereby exerting at least one of a metabolic effect, an anti-aging effect, or an anti-inflammatory effect in the subject.

10. The composition of any one of claims 1 to 3, wherein the subject is selected from the group consisting of a human infant, a human child, a human adolescent, a human adult, and a human geriatric.

11. A unit dosage form of a composition comprising at least one of inositol, erythritol, or sorbitol, the unit dosage form comprising an amount of at least one of inositol, erythritol, or sorbitol effective to enhance the growth of Faecalibacterium prausnitzii in the microbiome of a subject to which the unit dosage form is administered.

12. A method for producing a composition for enhancing the growth of Faecalibacterium prausnitzii in the microbiome of a subject to which the composition is administered, the method comprising adding at least one of inositol, erythritol, or sorbitol to at least one additional component.

13. 13. The method of claim 12, wherein the at least one additional ingredient comprises at least one of a polyphenol or a vitamin.

14. 14. The method of claim 13, wherein the polyphenol comprises at least one of coumestrol or quercetin.

15. 14. The method of claim 13, wherein the vitamins include at least one of vitamin B5, vitamin B6, vitamin B12, vitamin A, or vitamin D.

16. The method of any one of claims 12 to 15, wherein the at least one additional component comprises at least one of an amino acid, a protein, a carbohydrate, or a lipid.

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