Compositions and methods for improving intestinal permeability

Abstract

Disclosed herein are compositions and methods for treating, improving, or ameliorating a disease or condition associated with intestinal permeability, improving intestinal permeability, and improving intestinal barrier function in a subject. Some embodiments include, for example, providing or administering one or more compounds of Formula (I) or one or more compounds of Formula (II). Some embodiments provide compositions formulated as a dietary supplement, food ingredient or additive, food, medical food, dietary supplement, or pharmaceutical composition.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 407,950, filed September 19, 2022, which is incorporated herein by reference in its entirety for all purposes.

[0002] Area of ​​activity The present disclosure relates generally to the field of food and beverage dietary supplements, food ingredients or additives, medical foods, nutraceuticals, or pharmaceutical compositions. More specifically, the present disclosure relates to methods and compositions for improving, maintaining, and / or promoting favorable metabolic, immunomodulatory responses, digestive, and gut health. [Background technology]

[0003] Obesity is associated with increased intestinal permeability, a condition in which hepatocyte nuclear factor 4 alpha (HNF4α), a nuclear transcription factor found in the intestinal lumen, has been shown to play a pivotal role. It influences mucin production, a key component of the intestinal barrier, and regulates tight junction protein expression and Paneth cell differentiation. Summary of the Invention

[0004] Some aspects of the present disclosure relate to compositions and methods for treating, improving, or ameliorating a disease or condition associated with intestinal permeability, improving intestinal permeability, or improving impaired intestinal barrier function in a subject. In some embodiments, the methods include providing or administering to a subject in need thereof a composition comprising at least one carrier and an effective amount of a compound of Formula (I): [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted —(O)C 1-6 Alkyl C 1-12 heteroaryl, wherein the dashed bond is present or absent; X is CH2 or O, Z is CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted —(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl, which treats, improves or ameliorate a disease or condition associated with intestinal permeability in a subject.

[0005] In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration at 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the compound of Formula (I) is selected from the group consisting of N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, N-trans-chlorogenoyltyramine, N-trans-rosmarinoyltyramine, and 5-hydroxyferuloyltyramine, or pharmaceutically acceptable salts, solvates, and combinations thereof. In some embodiments, the disease or condition associated with intestinal permeability in the subject is associated with gastrointestinal epithelial cell barrier dysfunction. In some embodiments, the gastrointestinal epithelial cell barrier dysfunction is a disorder associated with impaired intestinal epithelial integrity. In some embodiments, the gastrointestinal epithelial cell barrier dysfunction is at least one selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, irritable bowel syndrome, intestinal infection, Clostridium difficile infection, metabolic disease, obesity, type 2 diabetes, metabolic dysfunction-associated steatohepatitis, non-alcoholic fatty liver disease, liver damage, alcoholic steatohepatitis, celiac disease, necrotizing enterocolitis, gastrointestinal disorders, short bowel syndrome, stomatitis, chemotherapy-induced mucositis, radiation-induced mucositis, oral mucositis, interstitial cystitis, neurological disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, chemotherapy-associated steatohepatitis (CASH), and pediatric variants of the disorders. In some embodiments, administration comprises rectal, parenteral, intravenous, topical, oral, dermal, transdermal, or subcutaneous administration. In some embodiments, the subject experiences relief of at least one symptom associated with gastrointestinal epithelial cell barrier dysfunction selected from the group consisting of abdominal pain, bloody stools, pus-filled stools, fever, weight loss, frequent diarrhea, fatigue, decreased appetite, tenesmus, and rectal bleeding.In some embodiments, the method further includes administering at least one second therapeutic agent to the subject, the second therapeutic agent including an anti-diarrheal agent, a 5-aminosalicylic acid compound, an anti-inflammatory agent, an antibiotic, an antibody, an anti-cytokine agent, an anti-inflammatory cytokine agent, a steroid, a corticosteroid, and an immunosuppressant. In some embodiments, treating or ameliorating a disease or condition associated with intestinal permeability in a subject improves digestive health in the subject by at least 10%. In some embodiments, treating or ameliorating a disease or condition associated with intestinal permeability in a subject reduces the disease or condition in the subject by at least 10%. In some embodiments, the compound of Formula I is a plant extract. In some embodiments, the plant extract is selected from the group including Allium, Amoracia, Chenopodium, Canabus, Spinacia, Fagopyrum, Annona, Jatropha, Piper, Eragrostis, Zea, Nelumbo, Ipomoea, Capsicum, Lycium, Solanum, and Tribulus. In some embodiments, the plant extract is hemp husk or black seed.

[0006] Some embodiments relate to consumable compositions for treating diseases or conditions associated with intestinal permeability or for ameliorating impaired intestinal barrier function, the compositions comprising at least one carrier and an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt: [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted —(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted —(O)C 1-6 Alkyl C 1-12 heteroaryl, wherein the dashed bond is present or absent; X is CH2 or O, Z is CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted —(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl.

[0007] In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration at 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per administration. In some embodiments, the compound of Formula (I) is selected from the group consisting of N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, N-trans-chlorogenoyltyramine, N-trans-rosmarinoyltyramine, and 5-hydroxyferuloyltyramine, or pharmaceutically acceptable salts, solvates, and combinations thereof. In some embodiments, the compound of Formula (I) is N-trans-caffeoyltyramine and further comprises N-trans-feruloyltyramine. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 10:1 to about 1:10. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 5:1 to about 1:5. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 5:1 to about 1:1. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 2.5:1 to about 2:1. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 2.2:1. In some embodiments, the food product is a food bar. In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-caffeoyltyramine. In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-feruloyltyramine. In some embodiments, the food product comprises at least 10% fiber. In some embodiments, the food product is crispy.In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-caffeoyltyramine. In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-feruloyltyramine. In some embodiments, the food product comprises at least 10% fiber.

[0008] Some aspects relate to methods for improving transepithelial electrical resistance in cells, in some embodiments, comprising contacting the cells with a composition comprising at least one carrier and an effective amount of a compound of Formula (I), [ka] During the ceremony, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted —(O)C 1-6 Alkyl C 1-12 heteroaryl, wherein the dashed bond is present or absent; X is CH2 or O, Z is CHR a , N.R. a , or O, and R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl, thereby treating, improving or ameliorating a disease or condition associated with intestinal permeability in a subject.

[0009] In some embodiments, the compound of formula (I) is selected from the group consisting of N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, N-trans-chlorogenoyltyramine, N-trans-rosmarinoyltyramine, and 5-hydroxyferuloyltyramine, or a pharmaceutically acceptable salt, solvate, or combination of the foregoing.

[0010] The advantages and features of the compositions and methods described herein will become more apparent from the following description taken in conjunction with the drawings. These drawings depict certain aspects of the compositions and methods described in this application and therefore should not be considered limiting. In the drawings, like reference numbers or symbols generally identify like components unless the context dictates otherwise. The drawings may not be drawn to scale. [Brief explanation of the drawings]

[0011] [Figure 1] A shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 1.0 μm plates. B shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 1.0 μm plates. C shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 1.0 μm plates. D shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 1.0 μm plates. [Figure 2] A shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 1.0 μm plates. B shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 1.0 μm plates. C shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 1.0 μm plates. D shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 1.0 μm plates. [Figure 3]A shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. B shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. C shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. D shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. [Figure 4] A shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 0.4 μm plates. B shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 0.4 μm plates. C shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 0.4 μm plates. D shows four scatter plots of TEER transverse colon monolayers in response to Compound 1 on 0.4 μm plates. [Figure 5] A shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 0.4 μm plates. B shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 0.4 μm plates. C shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 0.4 μm plates. D shows four scatter plots of TEER transverse colon monolayers in response to Compound 2 on 0.4 μm plates. [Figure 6] A shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. B shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. C shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. D shows four scatter plots of TEER of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. [Figure 7]A shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 1.0 μm plates. B shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 1.0 μm plates. C shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 1.0 μm plates. D shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 1.0 μm plates. [Figure 8] A shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2 on 1.0 μm plates. B shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2 on 1.0 μm plates. C shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2 on 1.0 μm plates. D shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2 on 1.0 μm plates. [Figure 9] A shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. B shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. C shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. D shows four scatter plots showing the permeability of transverse colon monolayers in response to compound 2-1 on 1.0 μm plates. [Figure 10] A shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 0.4 μm plates. B shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 0.4 μm plates. C shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 0.4 μm plates. D shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 1 on 0.4 μm plates. [Figure 11]A shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 2 on 0.4 μm plates. B shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 2 on 0.4 μm plates. C shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 2 on 0.4 μm plates. D shows four bar graphs depicting the permeability of transverse colon monolayers in response to Compound 2 on 0.4 μm plates. [Figure 12] A shows four bar graphs depicting the permeability of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. B shows four bar graphs depicting the permeability of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. C shows four bar graphs depicting the permeability of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. D shows four bar graphs depicting the permeability of transverse colon monolayers in response to compound 2-1 on 0.4 μm plates. [Figure 13] Two bar graphs are shown showing (a) the reduction in TEER and (b) the protection from administration of NCT against the increase in permeability associated with TNF-induced inflammation. Compound 1 refers to NCT. [Figure 14] Two bar graphs are shown showing (a) the reduction in TEER and (b) protection from the increase in permeability associated with TNF-induced inflammation from administration of NFT. Compound 2 refers to NFT. [Figure 15] Figure 2 shows administration of NCT:NFT (a) modulated TEER and (b) reduced permeability in TNF-induced inflammation. Compound 2-1 refers to the combination of NCT and NFT.

[0012] The present disclosure provides, inter alia, the discovery of a potent HNF4α expression enhancer, as well as methods for improving intestinal permeability and improving impaired intestinal barrier function. In certain aspects, provided herein are formulations and compositions containing one or more tyramine-containing hydroxycinnamic acid amides. Some embodiments provided herein provide compositions for use in methods for treating, improving, or ameliorating diseases or conditions associated with intestinal permeability or improved intestinal barrier function in a subject. Some embodiments provided herein provide compositions for use in methods for improving transepithelial electrical resistance in cells.

[0013] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless stated otherwise.

[0014] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to some extent, or to alleviate, and may include curing, one or more of the symptoms of a disease or condition.

[0015] An "extract" refers to a composition containing one or more compounds described herein, separated from other unwanted substances present in the natural source from which the extract is obtained. In some embodiments, the natural source is a plant. Plant extracts can be obtained from any plant tissue, including the entire plant. Plant parts include vegetative organs / structures of the shoot (e.g., leaves, stems, and tubers), roots, flowers and floral organs / structures (e.g., involucre, sepals, petals, cone, carpels, anthers, and ovules), seeds (including embryos, endosperm, and seed coats) or fruits (mature ovaries), plant tissues (e.g., vascular tissue, ground tissue, etc.), cells (e.g., guard cells, egg cells, etc.), or explants, as well as progeny and their cultures or cell lines. Preferably, the extract contains compounds that are generally recognized as safe for human consumption (GRAS). Thus, in certain embodiments, the extract is derived from an edible source. In this regard, the extract is an edible extract.

[0016] As used herein, "immunomodulatory," "immunomodulatory," and "immunostimulatory" mean causing or having the capacity to cause a detectable change in the immune response and having the capacity to cause a detectable change in the immune response. As used herein, the terms "immunomodulatory," "immunomodulatory," and "immunostimulatory" include immunostimulatory and immunosuppressive effects. Immunomodulation is primarily a qualitative change in the overall immune response, although quantitative changes may also occur in association with immunomodulation.

[0017] As used herein, the phrase "pharmaceutically acceptable" is a broad term and is to be given its ordinary and accustomed meaning to those of ordinary skill in the art (and is not limited to any special or customized meaning), and refers without limitation to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of and / or ingestion by humans and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable risk / benefit ratio.

[0018] As used herein, the terms "pharmaceutically acceptable salt" and "a pharmaceutically acceptable salt thereof" are broad terms and are intended to have the ordinary and customary meaning accorded to those skilled in the art (without being limited to any particular or particular meaning), and refer to, but are not limited to, salts prepared from pharmaceutically acceptable, non-toxic acids or bases. Suitable pharmaceutically acceptable salts include metal salts, such as aluminum salts, zinc salts, alkali metal salts, such as lithium salts, sodium salts, and potassium salts, alkaline earth metal salts, such as calcium salts and magnesium salts; organic salts, such as salts of lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and Tris; salts of free acids and free bases; inorganic salts, such as sulfates, hydrochlorides, and hydrobromides; and other salts currently in widespread pharmaceutical use and listed in sources well known to those skilled in the art, such as The Merck Index. Any suitable component can be selected to prepare salts of the therapeutic agents discussed herein, as long as it is non-toxic and does not substantially interfere with the desired activity. In addition to salts, pharmaceutically acceptable precursors and derivatives of the compounds can be used. Pharmaceutically acceptable amides, lower alkyl derivatives, and protected derivatives may also be suitable for use in the compositions and methods of preferred embodiments. Although it may be possible to administer the compounds of preferred embodiments in the form of pharmaceutically acceptable salts, it is generally preferred to administer the compounds in neutral form.

[0019] The term "pharmaceutical composition," as used herein, is a broad term, given its ordinary and customary meaning to those skilled in the art (and is not limited to any special or particular meaning), and refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. Pharmaceutical compositions facilitate the administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid or base. Pharmaceutical compositions are generally tailored for a specific intended route of administration.

[0020] As used herein, "carrier," as used herein, is a broad term and is intended to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to any special or individualized meaning), and refers to, but is not limited to, a compound that facilitates the introduction of a compound into cells or tissues. "Carrier" refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium, or zinc steric acid), or solvent encapsulating material that is involved in carrying or transporting a compound of interest from one organ or body part to another. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of interest. Water, saline, ethanol, and mineral oil are also carriers used in certain pharmaceutical compositions.

[0021] As used herein, the term "diluent" is a broad term and is intended to be given its ordinary and customary meaning to those of skill in the art (not limited to any special or individualized meaning), and refers, but is not limited to, an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small to manufacture and / or administer. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, but not limited to, phosphate-buffered saline, which mimics the composition of human blood.

[0022] As used herein, the term "food" refers to any food, feed, snack, dietary supplement, therapeutic, meal replacement, or meal substitute, whether intended for humans or animals. Animal food includes foods or feeds intended for any domestic or wild species. In preferred embodiments, animal food refers to a nutritionally complete food or dietary composition. Examples of such animal foods include extruded pet foods, such as dog and cat foods.

[0023] As used herein, "isomer" particularly includes, but is not limited to, optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers, and mixtures thereof), as well as conformational isomers (i.e., isomers that differ only in the angle of at least one chemical bond), positional isomers (especially tautomers), and geometric isomers (e.g., cis-trans isomers).

[0024] As used herein, "excipient," as used herein, is a broad term and is intended to be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to any special or particular meaning), and refers to a substance added to a pharmaceutical composition to impart to the composition, without limitation, bulk, uniformity, stability, binding ability, lubricity, disintegration ability, etc. A "diluent" is a type of excipient.

[0025] As used herein, the term "subject" is a broad term and is to be given its ordinary and customary meaning to those skilled in the art (not limited to any special or individualized meaning), and refers, without limitation, to an animal that is the object of treatment, observation, or experiment. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, and reptiles, particularly mammals. "Mammals" include, but are not limited to, dolphins, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and particularly humans. In some embodiments, the subject is a human.

[0026] As used herein, the terms "treating," "treatment," "therapeutic," or "therapy" are broad terms and should be given their ordinary and customary meaning (and not limited by any particular meaning or context), and do not necessarily imply, without limitation, the complete cure or elimination of a disease or condition. Any degree of alleviation of any undesirable markers, signs, or symptoms of a disease or condition may be considered, to some extent, treatment and / or therapy. Additionally, treatment may include actions that may worsen a patient's overall sense of health or appearance.

[0027] As used herein, the term "remission" refers to any reduction in the degree, severity, frequency, and / or likelihood of symptoms or clinical signs characteristic of a particular condition.

[0028] As used herein, the terms "therapeutically effective amount" and "effective amount" are broad terms and should be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to any particular or individualized meaning), and are used without limitation to refer to the amount of an active compound or pharmaceutical agent that elicits the indicated biological or medical response. For example, a therapeutically effective amount of a compound may be the amount necessary to prevent, reduce, or ameliorate a marker or symptom of a condition or prolong survival in a subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease being treated. Determining a therapeutically effective amount is well within the capabilities of one of ordinary skill in the art in light of the disclosure provided herein. The therapeutically effective amount of a compound disclosed herein required as a dose depends on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, depending on factors such as body weight, diet, concomitant medications, and other factors recognized by those skilled in the medical field.

[0029] The term "solvent" as used herein is a broad term and is intended to be given its ordinary and customary meaning to one of ordinary skill in the art (not limited to any special or particular meaning) and refers to compounds that may be polar or non-polar, straight-chain or branched, cyclic or aliphatic, aromatic, naphthenic, and have some solubilizing properties for other compounds or means, including, but not limited to, alcohols, derivatives, diesters, ketones, acetates, terpenes, sulfoxides, glycols, paraffins, hydrocarbons, anhydrides, heterocycles, among others.

[0030] As used herein, "nutraceuticals" generally refer to natural bioactive compounds that can be used to supplement dietary therapy and provide physiological benefits, including disease prevention and health promotion. Nutritional supplements can be purified or concentrated using bioengineering methods and can be enhanced by genetic methods, containing high levels of natural substances. Examples of nutritional supplements include isolated nutrients and herbal products, which generally contain at least one of the following ingredients: vitamins, minerals, herbs or other botanicals, amino acids, metabolites, constituents, extracts, or combinations of these ingredients. Common examples of nutritional supplements include beta-carotene, ephedra, ginkgo biloba, goldenseal, valeric acid, ginseng, green tea extract, and echinacea. The nutritional supplements described herein can be useful, for example, for maintaining and supporting healthy joints, skin, eye and brain function, heart and circulatory system, and overall health.

[0031] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain containing a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms. (Whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range. For example, "1 to 20 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. (up to 20 carbon atoms), but this definition also encompasses the occurrence of the term "alkyl" without a specified numerical range.) The alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted.

[0032] As used herein, the term "halogen atom" or "halogen" refers to any one of the radioactive stable atoms in column 7 of the periodic table of the elements, such as chloro (Cl), fluoro (F), bromo (Br) and iodo (I) groups.

[0033] In any of the groups described herein, an available hydrogen can be selected from, but is not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkoxy, alkoxycarbonyl, acyl, halo, nitro, aryloxycarbonyl, cyano, carboxy, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, or heterocyclyl.

[0034] Any undefined valency on an atom of the structures depicted in this application implicitly represents a hydrogen atom bonded to the atom.

[0035] As used herein, "alkenyl" refers to an alkyl group, as defined herein, containing one or more double bonds in the straight or branched hydrocarbon chain. An alkenyl group can be unsubstituted or substituted.

[0036] As used herein, "alkynyl" refers to an alkyl group, as defined herein, containing one or more triple bonds in the straight or branched hydrocarbon chain. An alkynyl group can be unsubstituted or substituted.

[0037] As used herein, "cycloalkyl" refers to a monocyclic or polycyclic hydrocarbon ring system that is fully saturated (no double or triple bonds). When composed of more than one ring, the rings may be joined together in a fused manner. A cycloalkyl group may contain 3 to 10 atoms in the ring(s), or 3 to 8 atoms in the ring(s). A cycloalkyl group may be substituted or unsubstituted. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0038] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (e.g., containing one or more aryl rings containing one or more aryl or non-aryl rings, including, for example, fused, bridged, or spiro ring systems in which two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout at least one of the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be C6 to C8. 14 Aryl groups, C6-C 10 The aryl group may be a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted or unsubstituted.

[0039] As used herein, "heterocyclyl" refers to a monocyclic or polycyclic ring system containing at least one heteroatom (e.g., O, N, S). Such systems can be unsaturated, contain some unsaturation, or contain some aromatic moieties, or can be entirely aromatic. Heterocyclyl groups can contain from 3 to 30 atoms. Heterocyclyl groups can be substituted or unsubstituted.

[0040] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having at least one ring with a fully delocalized π-electron system) containing one or more heteroatoms, i.e., elements other than carbon (including, but not limited to, nitrogen, oxygen, and sulfur), and at least one aromatic ring. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, a heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems in which two rings, e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl groups can be substituted or unsubstituted.

[0041] As used herein, the term "amino" refers to the group --NH.sub.2.

[0042] As used herein, the term "hydroxy" refers to an --OH group.

[0043] A "cyano" group refers to a "-CN" group.

[0044] A "carbonyl" group refers to a C=O group.

[0045] A "C-amido" group is defined as "-C(=O)N(R A R B ) group, where R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. The C-amide can be substituted or unsubstituted.

[0046] The "N-amide" group is defined as "RC(=O)N(R A )-" group, where R and R A can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. N-amides can be substituted or unsubstituted.

[0047] The "urea" group is defined as "-N(R A R B )-C(=O)-N(R A R B )-" group, R A and R B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. The urea group can be substituted or unsubstituted.

[0048] With respect to groups herein, the parenthetical subscript below further defines the group as follows: "(C n ) defines the exact number (n) of carbon atoms in the group. For example, "C1-C6-alkyl" refers to an alkyl group having from 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, or 6, or any range derivable therein, e.g., 3 to 6 carbon atoms).

[0049] The term "about" or "approximately" can mean within an acceptable error range for a particular value as determined by one of ordinary skill in the art, and will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean one or more standard deviations. Alternatively, "about" can mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within five or two orders of magnitude of a value. Unless otherwise stated, when a particular value is described in this application and claims, the term "about" is deemed to mean within an acceptable error range for the particular value.

[0050] As used herein, the term "weight percent" when referring to an ingredient is the weight of the ingredient divided by the weight of the composition containing that ingredient multiplied by 100%. For example, if 5 grams of ingredient A is added to 95 grams of ingredient B, the weight percent of ingredient A is 5% (e.g., 5gA / (5gA+95gB)×100%).

[0051] Any percentages, ratios, or other amounts referred to herein are by weight unless otherwise indicated.

[0052] composition In some aspects, the present specification discloses compositions comprising one or more tyramine-containing hydroxycinnamic acid amides and their use in treating gastrointestinal disorders or improving digestive function. In some embodiments, the one or more tyramine-containing hydroxycinnamic acid amides are plant-derived aromatic metabolites having one or more acidic hydroxyl groups attached to an aromatic arene. In some embodiments, the one or more tyramine-containing hydroxycinnamic acid amides are derived from cells. In some embodiments, the one or more tyramine-containing hydroxycinnamic acid amides are synthetically produced.

[0053] In particular, the present disclosure encompasses compounds of formula (I), or an isomer, salt, homodimer, heterodimer, or conjugate thereof: [ka]

[0054] In some embodiments, the composition comprises a compound of formula (II), or an isomer, salt, homodimer, heterodimer, or conjugate thereof: [ka]

[0055] In some embodiments of the compounds of Formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl.

[0056] In some embodiments of the compounds of Formula (I), R 1 , R 2 , R 3 , and R 8 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted —(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted alkyl-(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 Heteroaryl, and R 4 , R 5 , R 6 , R 7 is selected from R 9 are each independently hydrogen, deuterium, hydroxyl, or halogen;

[0057] In some embodiments of Formula (I), R 1 , R2 , and R 8 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted —(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 Heteroaryl, and R 3 , R 4 , R 5 , R 6 , R 7 , and R 9 are each independently selected from hydrogen, deuterium, hydroxyl, or halogen.

[0058] In some embodiments of the compound of Formula (II), R 1 , R 2 , R 3 , R 4 are each independently hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C1-6 Alkyl, optionally substituted -(O)C 1-6 Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl.

[0059] In some embodiments of the compounds of Formula (I) or Formula (II), the dashed bond is present or absent.

[0060] In some embodiments of the compounds of Formula (I), X is CH 2 or O.

[0061] In some embodiments of the compounds of Formula (I) or Formula (II), Z is CHR a , N.R. a , or O.

[0062] In some embodiments of the compounds of Formula (I) or Formula (II), R a is hydrogen, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted -C 1-6 Alkyl, optionally substituted -(O)C 1-6 Alkyl, optionally substituted -(O)C 1-6Alkenyl, optionally substituted -(O)C 1-6 Alkynyl, optionally substituted -(O)C 4-12 Cycloalkyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Cycloalkyl, optionally substituted -(O)C 4-12 Heterocyclyl, optionally substituted -(O)C 1-6 Alkyl C 4-12 Heterocyclyl, optionally substituted -(O)C 4-12 Aryl, optionally substituted -(O)C 1-6 Alkyl C 5-12 Aryl, optionally substituted -(O)C 1-12 Heteroaryl and optionally substituted -(O)C 1-6 Alkyl C 1-12 heteroaryl.

[0063] In some embodiments, the compound of Formula (I) or Formula (II) is provided as a pharmaceutically acceptable salt or solvate thereof.

[0064] In some embodiments, the compound of Formula (I) or Formula (II) is (E)-3-(3,4-dihydroxyphenyl)-N-(4-ethoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-methoxyethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(methylsulfonyl)ethoxy)phenethyl)acrylamide, (E)-2-(4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetic acid, (E)-2- Ethyl (4-(2-(3-(3,4-dihydroxyphenyl)acrylamido)ethyl)phenoxy)acetate, (E)-N-(4-(cyclopropylmethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3,3-trifluoropropoxy)phenethyl)acrylamide, (E)-3-(3,-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-4-yl)methoxy)phenethyl)acrylamide (E)-N-(4-((4-fluorobenzyl)oxy)phenethyl)acrylamide, (E)-N-(4-(cyanomethoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-2-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-(dimethylamino)ethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-isobutoxyphenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(pyridin-4-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((4-methoxybenzyl)oxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(oxetan-3-ylmethoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydro-2H-pyran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-((tetrahydrofuran-2-yl)methoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(thiophen-2-yloxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(3,3-dimethylbutoxy)phenethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-(2-hydroxyethoxy)phenethyl)acrylamide, (E)-N-(4-((1H-tetrazol-5-yl)methoxy)phenethyl)-3-(3,4-dihydroxyphenyl)acrylamide, (E)-3-(3,4-Dihydroxyphenyl)-N-(4-((1-methylpyrrolidin-2-yl)methoxy)phenethyl)acrylamide, (E)-2-hydroxy-5-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenyl hydrogencarbonate, (E)-3-(4-hydroxy-3-(pyridin-4-yloxy)phenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-hydroxy-3-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide amide, (E)-3-(3-(4-fluorophenoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-(cyanomethoxy)-4-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-2-(2-hydroxy-4-(3-((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)phenoxy)acetic acid, (E)-3-(3-hydroxy-4-(pyridin-4-ylmethoxy)phenyl)-N-(4-hydroxyphenyl)- (E)-3-(4-((4-fluorobenzyl)oxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(3-hydroxy-4-isobutoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-3-(4-(cyanomethoxy)-3-hydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, (E)-N-(3-(3,4-dihydroxyphenyl)acryloyl)-N-(4-hydroxyphenethyl)acrylamide (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-(pyridin-4-ylmethyl)acrylamide, (E)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)-N-isobutylacrylamide, (E)-N-(cyanomethyl)-3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)acrylamide, 3-(3,4-dihydroxyphenyl)-N-(4-hydroxyphenethyl)propanamide, 3-(3,4-dihydroxyphenyl)-N-(4-(methylsulfonamido)phenethyl)propanamide, or pharmaceutical salts, solvates, and combinations thereof.

[0065] In certain embodiments, the compound of Formula (I) or Formula (II) is selected from: [ka]

[0066] Salts of the compounds of the present disclosure refer to compounds that possess the desired pharmacological activity of the parent compound, and include the following: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or those formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid. , benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, camphorsulfonic acid, 4-toluenesulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) a salt formed by substitution of an acidic proton present in the parent compound.

[0067] As known in the art, a homodimer is a molecule composed of two identical tyramine-containing hydroxycinnamic acid amide subunits. In comparison, a heterodimer is a molecule composed of two different tyramine-containing hydroxycinnamic acid amide subunits. Examples of homodimers of the present disclosure include, but are not limited to, cross-linked N-trans-feruloyltyramine dimers, cross-linked N-trans-caffeoyltyramine dimers, and cross-linked p-coumaroyltyramine dimers. See, for example, King & Calhoun (2005) Phytochemistry 66(20):2468-73, which teaches the isolation of cross-linked N-transferuloyltyramine dimers from potato scab lesions.

[0068] Conjugates of tyramine monomers containing hydroxycinnamic acid amide with other compounds such as lignanamides. Examples of conjugates include, but are not limited to, cannabidiin A, cannabidiin B, cannabidiin C, cannabidiin D, cannabidiin E, cannabidiin F, and glossamide.

[0069] Whenever a group is described as "optionally substituted," the group can be unsubstituted or substituted with one or more of the indicated substituents. Similarly, when a group is described as "unsubstituted or substituted" when it is substituted, the substituents can be selected from one or more of the indicated substituents. When no substituents are specified, the indicated "optionally substituted" or "substituted" group can be any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and the like. "C" means that the amino group can be individually and independently substituted with one or more group(s) individually and independently selected from aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino, and disubstituted amino groups, and protected derivatives thereof.

[0070] In addition to isomers, salts, homodimers, heterodimers, and conjugates, the tyramine-containing hydroxycinnamic acid amides may also be glycosylated. Glycosylated tyramine-containing hydroxycinnamic acid amides can be produced by transglycosylating a tyramine-containing hydroxycinnamic acid amide to add glucose units, e.g., 1, 2, 3, 4, 5, or more than 5 glucose units, to the tyramine-containing hydroxycinnamic acid amide. Transglycosylation can be carried out using any suitable enzyme, including, but not limited to, pullulanase and isomaltase (Lobov, et al. (1991) Agric. Biol. Chem. 55:2959-2965), -galactosidase (Kitahata, et al. (1989) Agric. Biol. Chem. 53:2923-2928), dextrin saccharase (Yamamoto, et al. (1994) Biosci. Biotech. Biochem. 58:1657-1661), or cyclodextrin gluconotransferase, with pullulan, maltose, lactose, partially hydrolyzed starch, and maltodextrin as donors.

[0071] Furthermore, in any compound described herein having one or more chiral centers, unless the absolute stereochemistry is explicitly indicated, it is understood that each center may independently be in the R or S configuration, or a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, or stereoisomeric mixtures, including all diastereomeric and enantiomeric forms. Furthermore, in any compound described herein having one or more double bond(s) that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof. Stereoisomers may be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns.

[0072] Likewise, it is understood that all tautomeric forms of any compounds described are intended to be included.

[0073] It is understood that the compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorophores, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen 1 (protium), hydrogen 2 (deuterium), and hydrogen 3 (tritium). Therefore, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0074] It is understood that the compounds described herein may be labeled by other means, including, but not limited to, the use of chromophores or fluorophores, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may confer certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in a compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen 1 (protium), hydrogen 2 (deuterium), and hydrogen 3 (tritium). Therefore, reference to a compound herein encompasses all possible isotopic forms unless the context clearly indicates otherwise.

[0075] It is understood that the methods and formulations described herein include the use of crystalline forms, amorphous phases, and / or pharmaceutically acceptable salts, solvates, hydrates, and conformers of the compounds of some embodiments, as well as metabolites and active metabolites of these compounds with the same type of activity. Conformers are structures that are conformational isomers. Conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (conformers) in terms of the arrangement of atoms around a rotatable bond. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms. Solvates contain either stoichiometric or non-stoichiometric solvents and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Other forms in which the compounds of some embodiments may be provided may include amorphous, milled, and nanoparticulate forms.

[0076] Similarly, it is understood that the compounds described herein, e.g., compounds of some embodiments, are compounds in any of the forms described herein (e.g., pharmaceutically acceptable salts, prodrugs, crystalline forms, amorphous forms, solvated forms, enantiomeric forms, tautomeric forms, etc.).

[0077] In some embodiments, the compositions described herein may include one or more compounds of Formula (I) or Formula (II). In some embodiments, the one or more compounds described herein may be in a ratio of about 10:1 to about 1:10, or may be in a range including and / or spanning the aforementioned values. In some embodiments, one or more compounds described herein can be about 10:1, 9.5:1, 8.5:1, 8.0:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3.0:1, 2.5:1, 2.0:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine and N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5.

[0078] In some embodiments, the one or more compounds are derived from a plant or plant extract. In some embodiments, the extract comprises one or more compounds described herein. In some embodiments, the plant extract is selected from the group consisting of Allium, Amoracia, Chenopodium, Cannabis, Spinacia, Fagopyrum, Annona, Jatropha, Piper, Eragrostis, Zea, Nelumbo, Ipomoea, Capsicum, Lycium, Solanum, and Tribulus. In some embodiments, the plant extract is hemp husk, peppercorns, or black seeds. In some embodiments, the extract is derived from hemp husk.

[0079] formulation Aspects of the present disclosure relate to formulations containing one or more compounds described herein. In some embodiments, a substantially pure compound or extract containing one or more compounds of the present disclosure can be combined with a carrier and provided in any form suitable for consumption by, provision to, or administration to a subject. In some embodiments, one or more compounds or an extract containing one or more compounds is added to a consumable product as an exogenous ingredient or additive. Suitable consumption forms include, but are not limited to, dietary supplements, food ingredients or additives, foods, medical foods, nutritional supplements, or pharmaceutical compositions. In some embodiments, one or more compounds or an extract containing one or more compounds is provided in either liquid, granular, or powder form. In some embodiments, the formulation can be a food product.

[0080] A food ingredient or additive includes an edible substance intended, directly or indirectly, to be an ingredient or otherwise affect the properties of any food product (including any substance intended for use in the production, manufacture, packaging, processing, preparation, treatment, packaging, transport, or holding of such food products). Food products, particularly functional foods, include foods that have been enriched or fortified during processing to include additional complementary nutrients and / or beneficial ingredients. Food products according to the present disclosure can be, for example, butter, margarine, sweet or savory spreads, condiments, biscuits, food bars, crisps, crackers, granola, health bars, breads, cakes, cereals, candy, confectionery, soups, milk, yogurt or fermented dairy products, cheese, juice-based and plant-based beverages, functional beverages, powdered drink mixes, fermented beverages, shakes, flavored waters, teas, oils, or any other suitable food product. In some embodiments, the food product includes a whole food product in which the concentration of one or more compounds has been enriched to a level that provides an effective amount of the compound through specific post-harvest processing and food production processing methods. In some embodiments, the food product comprises one or more compounds described herein and a fiber source. In some embodiments, the food product comprises a compound selected from the group consisting of N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, N-trans-chlorogenoyltyramine, N-trans-rosmarinoyltyramine, and 5-hydroxyferuloyltyramine, or a pharmaceutically acceptable salt, solvate, or combination thereof. In some embodiments, the food product comprises N-trans-feruloyltyramine. In some embodiments, the food product comprises N-trans-caffeoyltyramine. In some embodiments, the food product comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 10:1 to about 1:10.In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 5:1 to about 1:5. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 5:1 to about 1:1. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 2.5:1 to about 2:1. In some embodiments, the N-trans-caffeoyltyramine and N-trans-feruloyltyramine are in a ratio of about 2.2:1. In some embodiments, the food product is a food bar. In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-caffeoyltyramine. In some embodiments, the food bar comprises about 0.01% to about 20% (w / w) N-trans-feruloyltyramine. In some embodiments, the food product is crispy. In some embodiments, the food bar comprises from about 0.01% to about 20% (w / w) N-trans-caffeoyltyramine, hi some embodiments, the food bar comprises from about 0.01% to about 20% (w / w) N-trans-feruloyltyramine.

[0081] In some embodiments, the food product contains carbohydrates. Various carbohydrates, such as various sugars and starches, are used in foods. Carbohydrates are an important source of energy for the body and include complex carbohydrates (such as whole grains and vegetables) and simple carbohydrates (such as sugars and refined grains). Several common carbohydrates are used in foods, including starch, sugar, fructose, maltodextrin, dextrose, corn syrup, oligosaccharides, cellulose, and complex carbohydrates, such as inulin, which can be added to processed foods as a prebiotic fiber. According to the present disclosure, the concentration of carbohydrates can vary depending on the intended use of the product. In some embodiments, carbohydrates can comprise from about 1% to about 95% by weight of the food product. In some embodiments, carbohydrates can comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or a range therebetween and / or including ranges spanning the aforementioned values.

[0082] In some embodiments, the food product may contain sugar. Sugars, such as high fructose corn syrup, sucrose, glucose syrup, dextrose, and other sweeteners, are often added to processed foods to make them more palatable. Additionally, sugar alcohols or maltodextrins may be added to foods to reduce the calorie content of the product and / or enhance its nutritional profile. In some embodiments, the food product may contain one or more sugars that are slowly or incompletely digestible by humans, if not completely indigestible. These sugars may include isomaltose, panose, and branched oligomers with a degree of polymerization of four or more. Additional non-limiting examples of sugars include sucrose, HFCS, fructose, brown sugar (which may be partially or fully refined), powdered sugar (also known as confectioner's sugar), high fructose corn syrup, honey, molasses, maple syrup, agave nectar, coconut sugar, jujube sugar, fruit juice concentrate, maltodextrin, dextrose, glucose syrup, maple syrup, molasses, and lactose. According to the present disclosure, the concentration of sugars may vary depending on the intended use of the product. In some embodiments, sugars may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the sugar(s) component comprises from about 2% to about 10% by weight of the composition. In some embodiments, sugars may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain sugars in a range of high and low values ​​independently selected from about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or ranges therebetween and / or including ranges spanning the aforementioned values.

[0083] In some embodiments, the food product comprises a fiber source. In some embodiments, the food product comprises about 5% to about 30% (w / w) fiber. In some embodiments, the food product comprises at least 10% fiber. In some embodiments, the food product comprises at least 15% fiber. In some embodiments, the food product comprises at least 20% fiber. In some embodiments, the food product comprises at least 30% fiber.

[0084] In some embodiments, the food product may contain protein. Protein may be present in a range of concentrations depending on the product. Protein sources may include soy protein, soy flour, soy protein isolate, whey protein isolate, casein, gelatin, legume protein isolate, soy protein concentrate, egg albumin or egg white, wheat protein concentrate, legume protein concentrate, and mixtures thereof. In some embodiments, meat products such as jerky, sausage, or meatballs may contain protein as a major ingredient. Protein may be present in concentrations ranging from about 10% to about 25% of the total ingredients. In dairy products such as cheese, yogurt, or milk, proteins such as casein or whey may be the major ingredient. Protein may be present in concentrations ranging from about 3% to about 15% of the total ingredients. In plant-based products such as tofu, tempeh, or seitan, proteins derived from soybeans, peas, legumes, or wheat may be the major ingredient. Protein may be present at a concentration ranging from about 10% to about 25% of the total ingredients. In energy and protein bars, proteins such as whey or soy, or any protein according to the present disclosure, may be added to provide a protein source. Protein may be present at a concentration ranging from about 10% to about 25% of the total ingredients. According to the present disclosure, the protein concentration may vary depending on the intended use of the product. In some embodiments, the protein may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the protein may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may comprise about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% protein or a range of high and low values ​​independently selected from ranges therebetween and / or including ranges spanning the aforementioned values.

[0085] In some embodiments, the food product may include starch. In some embodiments, the food product may further include a starch component(s) in an amount sufficient to provide about 5% to 45%, or about 10% to 30%, or about 15% to 25% starch in the food product. The starch component may include purely added flour or other granules, as well as any starch fraction provided by other ingredients, such as oat bran or soy protein. In some embodiments, the starch may include any conventionally used starch or flour component for use in ready-to-eat cereals. Exemplary suitable starchy grains include flours derived from primary grains, including wheat, rice, corn (maize), oats, barley, rye, or starch fractions isolated from cereal flours, including, for example, corn starch, wheat starch, rice starch, and various processed starches, including gelatinized starch and / or modified starches.

[0086] In some embodiments, the food product may contain wheat flour. According to the present disclosure, several types of wheat flour may be used. For example, common types of flour used in food products include all-purpose flour (which may contain protein, like most other flours), whole wheat flour, bread flour, cake flour, pastry flour, self-rising flour, and gluten-free flour. According to the present disclosure, the concentration of wheat flour may vary depending on the intended use of the product. For example, in baked products such as bread, cake, and cookies, wheat flour is typically the primary ingredient and may be present at a concentration ranging from 50% to 100% of the total dry ingredients. In soups and sauces, wheat flour is often used as a thickener and may be present at a concentration ranging from 1% to 5% of the total ingredients. Butter and Breadcrumbs: In fried foods such as chicken or fish, wheat flour is often used as part of the batter or breadcrumbs and may be present at a concentration ranging from 20% to 50% of the total dry ingredients. In snack foods such as crackers and chips, wheat flour may be present at a concentration ranging from 30% to 70% of the total ingredients. In some embodiments, the flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the flour may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% flour, or a range of higher and lower values ​​independently selected from ranges therebetween and / or including ranges spanning the aforementioned values.

[0087] In some embodiments, the food product may include a fat. In some embodiments, the food product may include an oil. In some embodiments, the food product may include one or more fats or oils. Several types of fats may be used according to the present disclosure. For example, common types of fats include butter, margarine, vegetable oil, shortening, and lard. According to the present disclosure, the concentration of fat may vary depending on the intended use of the product. In baked goods such as cakes, cookies, and pastries, fats such as butter, shortening, or oil are often used to provide moisture, flavor, and texture. In some embodiments, fats may be included at a concentration ranging from 10% to 30% of the total ingredients. In some embodiments, fats such as olive oil or mayonnaise are often used to provide flavor and texture, as are sauces and dressings. In some embodiments, fats may be included at a concentration ranging from 10% to 30% of the total ingredients. In fried foods such as chicken or French fries, fats such as vegetable oil or lard are used for frying and may be included at a concentration ranging from 30% to 60% of the total ingredients. In snack foods such as chips and crackers, fats such as vegetable oils or palm oil are often used to provide flavor and texture. In some embodiments, fats may be present in concentrations ranging from 10% to 30% of the total ingredients. In some embodiments, fats may comprise from about 1% to about 95% by weight of the food product. In some embodiments, fats may comprise from about 1% to about 95% by weight of the food product. In some embodiments, the food product may contain about 1%, 3%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% fat, or ranges of higher and lower values ​​independently selected from ranges inclusive of those values ​​and / or ranges spanning the aforementioned values.

[0088] In some embodiments, the food product may contain one or more additional ingredients. Optionally, the food products of the present disclosure may further contain various ingredients designed to improve their aesthetic or nutritional qualities. These supplemental ingredients may include vitamin and / or mineral fortification, colorants, flavors, sweetener(s), and mixtures thereof. Exact ingredient concentrations may vary. However, generally, such ingredients may each comprise from about 0.01% to about 5%, or from about 0.1% to 2%, by dry weight of the food product. One particularly useful ingredient is common table salt. In some embodiments, salt comprises from about 0.1% to 5%, or from about 0.5% to 4.0% of the food product.

[0089] In some embodiments, the food product is derived from a plant. In some embodiments, the food product is derived from hemp husk. In some embodiments, the food product is a solid food. In some embodiments, the food product is a semi-solid food. In some embodiments, the food product is a puffed product, a bakery product, a press cake, a ready-to-eat product, a food bar, a cereal, a crispy, or a spread.

[0090] Dietary supplements are orally ingested products containing the compounds or extracts of the present disclosure and intended to supplement the diet. Dietary supplements are products derived from food sources that provide additional health benefits in addition to the basic nutritional value contained in food. Pharmaceutical compositions are defined as any component of a pharmaceutical product intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the human or other animal body. Dietary supplements, nutritional supplements, and pharmaceutical compositions can be found in many forms, such as capsules, tablets, coated tablets, pills, capsules, pellets, granules, softgels, gelcaps, liquids, powders, emulsions, suspensions, elixirs, syrups, and any other form suitable for use.

[0091] The pharmaceutical compositions herein can be manufactured in a manner known per se, such as by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or tabletting processes. Moreover, the active ingredient is present in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts containing pharmaceutically compatible counterions.

[0092] Multiple techniques for administering compounds, salts, and / or compositions exist in the art, including oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery (including, but not limited to, intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection). In some embodiments, the compounds described herein, including compounds of Formula (I), (II), or pharmaceutically acceptable salts thereof, may be administered orally. In some embodiments, the compounds described herein, including compounds of Formula (I), (II), or pharmaceutically acceptable salts thereof, may be provided in a form for oral consumption.

[0093] One or more compounds, salts, and / or compositions may be provided or administered locally rather than systemically, for example, by directly delivering the compound to the affected area, often in a depot or sustained-release formulation. Additionally, the compound may be provided or administered in a targeted drug delivery system, for example, a liposome coated with a tissue-specific antibody. The liposome targets and is selectively taken up by an organ. For example, intranasal or pulmonary delivery may be desirable to target respiratory diseases or conditions.

[0094] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. For example, the pack may comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, with notice associated with the container, which notice reflects the agency's approval of the pharmaceutical dosage form for human or veterinary administration. Such notice may, for example, be labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions containing the compounds and / or salts described herein may also be compounded and formulated in a compatible pharmaceutical excipient, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0095] The compounds, salts, and / or pharmaceutical compositions may be provided to the administering physician or other medical professional in the form of a kit. The kit is a package housing a container containing the compound(s) in a suitable pharmaceutical composition and instructions for administering the pharmaceutical composition to a subject. The kit may also optionally contain one or more additional therapeutic agents. The kit may also include separate doses of the compound(s) or pharmaceutical composition for sequential or sequential administration. The kit may optionally include one or more diagnostic tools and instructions for use. The kit may include a suitable delivery device, such as a syringe, with instructions for administering the compound(s) and any other therapeutic agents. The kit may optionally include instructions for storage, reconstitution (if applicable), and administration of any or all of the included therapeutic agents. The kit may include multiple containers reflecting the number of doses to be given to a subject.

[0096] In some embodiments, the compound of Formula (I) or Formula (II) is administered at a dose in the range of about 0.1 to 200 mg / kg body weight. In some embodiments, the compound of Formula (I) or Formula (II) is administered in an amount of about 0.1 to 1, 0.5 to 1, 0.1 to 10, 0.5 to 10, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 1 to 200, 1 to 300, 1 to 400, 1 to 500, 1 to 600, 1 to 700, 1 to 800, 1 to 900, 1 to 1000, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 10 to 20, 10 to 30, 10 to 40, 10 to 50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-200, 10-300, 10-400, 10-500, 10-600, 10-700, 10-800, 10-900, 10-1000, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-200, 20-300, 20-400, 20-500, 20-600, 20-700, 20-800, 20-900, 20-1000, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-200, 30-300, 30-400, 30-500, 30-600, 30-700, 30-800, 30-900, 30-1000, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-200, 40-300, 40-400, 40-500, 40-600, 40-700, 40-800, 40-900, 40-1000, 50-60, 50-70, 50-80, 50-90, 50-100, 50-200, 50-300, 50-400 , 50~500, 50~600, 50~700, 50~800, 50~900, 60~70, 60~80, 60~90, 60~100, 60~200, 60~300, 60~400, 60~500, 60~600, 60~700, 60~800, 60~900, 60~1000, 70~80, 70~90, 70~100, 70~200, 70~300, 70~400, 70~500, 70~600, 70~700, 70~800, 70~900, 70~1000, 80~90, 80~100, 80~200, 80~300,It may be provided or administered at a dose within the range of 80-400, 80-500, 80-600, 80-700, 80-800, 80-900, 80-100, 90-100, 90-200, 90-300, 90-400, 90-500, 90-600, 90-700, 90-800, 90-900, 90-1000, 100-150, 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, or 100-1000 mg / kg body weight. In some embodiments, the compound of Formula (I) or Formula (II) is administered at a concentration of about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, provided or administered at a dose of 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 80, 90, or 95 mg / kg body weight. In some embodiments, the compound of Formula (I) or Formula (II) is administered in an amount of about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, .5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5 , 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m, 2In some embodiments, the compound of Formula (I) or Formula (II) is provided or administered in a dose less than the body surface area. In some embodiments, the compound of Formula (I) or Formula (II) is provided or administered in a dose less than about 0.01, 0.02, 0.03, 0.05, 0.07, 0.1, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, provided or administered at a dose greater than 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg of subject body weight.

[0097] In some embodiments, the dose of the compound of Formula (I) or Formula (II) is about 0.1 mg to 10 mg, 0.1 mg to 25 mg, 0.1 mg to 30 mg, 0.1 mg to 50 mg, 0.1 mg to 75 mg, 0.1 mg to 100 mg, 0.5 mg to 10 mg, 0.5 mg to 25 mg, 0.5 mg to 30 mg, 0.5 mg to 50 mg, 0.5 mg to 75 mg, 0.5 mg to 100 mg, 1 mg to 10 mg, 1 mg g~25mg, 1mg~30mg, 1mg~50mg, 1mg~75mg, 1mg~100mg, 2mg~10mg, 2mg~25mg, 2mg~30mg, 2mg~50mg, 2mg~75mg, 2 mg~100mg, 3mg~10mg, 3mg~25mg, 3mg~30mg, 3mg~50mg, 3mg~75mg, 3mg~100mg, 4mg~100mg, 5mg~10mg, 5mg~25m g, 5mg~30mg, 5mg~50mg, 5mg~75mg, 5mg~300mg, 5mg~200mg, 7.5mg~15mg, 7.5mg~25mg, 7.5mg~30mg, 7.5mg~50 mg, 7.5mg~75mg, 7.5mg~100mg, 7.5mg~200mg, 10mg~20mg, 10mg~25mg, 10mg~50mg, 10mg~75mg, 10mg~100mg, 1 In some embodiments, the compound of Formula (I) or Formula (II) is provided or administered in an amount of about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the compound of Formula (I) or Formula (II) provided or administered is about 1 mg to 5 mg, 1 mg to 7.5 mg, 2.5 mg to 5 mg, 2.5 mg to 7.5 mg, 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg,5mg~28mg、5mg~30mg、5mg~32mg、5mg~34mg、5mg~36mg、5mg~38mg、5mg~40mg、5mg~42mg、5mg~44mg、5mg~46mg、5mg~48mg、5mg~50mg、5mg~52mg、5mg~54mg、5mg~56mg、5mg~58mg、5mg~60mg、7mg~7.7mg、7mg~9mg、7mg~10mg、7mg~12mg、7mg~14mg、7mg~15mg、7mg~16mg、7mg~18mg、7mg~20mg、7mg~22mg、7mg~24mg、7mg~26mg、7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg、40mg~52mg、40mg~54mg、40mg~56mg、40mg~58mg、40mg~60mg、43mg~46mg、43mg~48mg、43mg~50mg、43mg~52mg、43mg~54mg、43mg~56mg、43mg~58mg、42mg~60mg、45mg~48mg、45mg~50mg、45mg~52mg、45mg~54mg、45mg~56mg、45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. In some embodiments, the dose of the compound of Formula (I) or Formula (II) is about 0.1 mg, 0.3 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg g, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the dose of the compound of Formula (I) or Formula (II) is less than about 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0098] In some embodiments, the formulation includes an excipient. In some embodiments, the excipient is a nutritionally acceptable excipient. In some embodiments, the nutritionally acceptable excipient is selected from medium chain triglycerides, diglycerides, and monoglycerides, caprylic acid, linoleic acid, oleic acid, and ketooleic acid. In some embodiments, the nutritionally acceptable excipient further includes a second fatty acid component having one or more non-activated fatty acids selected from linoleic acid, α-linoleic acid, γ-linoleic acid, oleic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DEIA), or derivatives thereof.

[0099] In some embodiments, the formulation includes a carrier. In some embodiments, the carrier is a nutritionally acceptable carrier. Each carrier must be "acceptable" in that it is compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of substances that can function as carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, and hydroxypropylmethylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and (10) gluten. Examples of suitable carriers include glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) pH buffers, (21) polyesters, polycarbonates, and / or polyanhydrides, and (22) other non-toxic, compatible substances used in pharmaceutical formulations. In some embodiments, the carrier is about 0.5% to about 80% (w / w) of the formulation. In some embodiments, the carrier is about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 70%, 75%, about 80% (w / w) of the formulation, or a range including, between, and / or spanning the aforementioned values.

[0100] When preparing solid compositions such as tablets or capsules, the compound or extract is mixed with a carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums) and other diluents (e.g., water) to form a solid composition. This solid composition is then subdivided into unit dosage forms containing an effective amount of the compound of the present disclosure. The tablets or pills of the present invention are coated or otherwise compounded to provide a dosage form that offers the advantage of prolonged action.

[0101] In certain embodiments of the present disclosure, consumable compositions include one or more compounds or extracts containing one or more compounds described herein, a carrier, and a preservative that reduces or retards microbial growth. In some embodiments, the preservative is about 0.01% to about 5% (w / w) of the formulation. In some embodiments, the preservative is about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5.0% w / w of the formulation, or a range including, between, and / or spanning the aforementioned values. In some embodiments, the preservative is added in an amount up to about 5%, e.g., about 0.01% to 1% (w / w). In some embodiments, the preservative may include sodium benzoate, methylparaben, propylparaben, sodium nitrite, sulfur dioxide, sodium sorbate, and potassium sorbate. Other suitable preservatives include, but are not limited to, edetate (also known as ethylenediaminetetraacetate, or EDTA, eg, disodium EDTA), or combinations thereof.

[0102] In some embodiments, the formulation is a liquid. In some embodiments, the formulation is a liquid formulation. In some embodiments, the liquid formulation is produced from hemp husks. In some embodiments, the liquid formulation is produced from recombinant cells. In some embodiments, the liquid formulation is a beverage. In some embodiments, the formulation can be incorporated into a dairy drink. In some embodiments, the formulation can be incorporated into a sports drink. In some embodiments, the formulation can be incorporated into a fruit juice drink. In some embodiments, the formulation can be incorporated into an alcoholic drink. In some embodiments, the formulation can be incorporated into an aqueous drink. In some embodiments, the formulation is a smoothie. In some embodiments, the liquid can include one or more compounds or extracts of the present disclosure. In some embodiments, the liquid can be incorporated for oral administration or consumption. In some embodiments, the liquid can include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils, as well as elixirs and similar vehicles. Suitable dispersants or suspending agents for aqueous suspensions include synthetic natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.Liquid preparations for oral administration or consumption can be in the form of, for example, solution, syrup or suspension, or they can be provided as a dry product for reconstitution with water or other suitable vehicle before use.Liquid preparations can be prepared by conventional means with suspending agents (for example, sorbitol syrup, methylcellulose or edible hydrogenated oil); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters or ethyl alcohol); preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); and artificial or natural coloring agents and / or sweeteners and other pharmaceutically acceptable additives.

[0103] The method for preparing the formulation or composition of the present disclosure comprises the step of bringing the compound or extract of the present disclosure into association with a carrier and optionally one or more accessory ingredients and / or active ingredients.Generally, the formulation is prepared by uniformly and intimately bringing the compound or extract of the present disclosure into association with a liquid carrier, or a finely divided solid carrier, or both, and then, if necessary, shaping the product.Thus, the disclosed formulation may consist of or consist essentially of the compound or extract described herein in combination with a suitable carrier.

[0104] In some embodiments, the formulation comprises about 0.1, 0.5, 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, 91, 92, 93, 94, 95, 96, 97, 98, or 99% w / w of one or more compounds or extracts disclosed herein, or a range including and / or spanning the aforementioned values. In some embodiments, the formulation comprises about 0.1% to about 10% of one or more compounds or extracts described herein. In some embodiments, the formulation comprises about 0.1% to about 5% of one or more compounds or extracts described herein. In some embodiments, the formulation comprises about 1% to about 10% of one or more compounds or extracts described herein. In some embodiments, when one or more compounds or extracts of the present disclosure are provided or administered to humans and animals as a pharmaceutical, nutritional supplement, or dietary supplement, they may be provided by themselves or in combination with, for example, 0.1-99% active ingredient(s) and an acceptable carrier. In some embodiments, the compounds or extracts of the present disclosure may be provided or administered at about 0.1, 0.5, 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, 91, 92, 93, 94, 95, 96, 97, 98, 99% w / w, or ranges including and / or spanning the aforementioned values.

[0105] The consumable product can be consumed by a subject to provide less than 100 mg of one or more compounds disclosed herein per day. In certain embodiments, the consumable product provides about 1 mg / day to about 60 mg / day of a tyramine-containing hydroxycinnamic acid amide. In certain embodiments, the consumable product provides about 10 mg / day to about 60 mg / day of a tyramine-containing hydroxycinnamic acid amide. The effective amount can be established by methods known in the art and may depend on bioavailability, toxicity, etc.

[0106] While it is contemplated that individual tyramines containing hydroxycinnamic acid amides may be used in the consumables of the present disclosure, it is further contemplated that two or more of the compounds or extracts may be combined in any relative amounts to create a custom combination of ingredients, and that the inclusion of two or more tyramines containing hydroxycinnamic acid amides in a desired ratio may enhance the efficacy of the product, improving organic properties or other quality indicators important to the end use of the product.

[0107] In some embodiments, the formulation may include one or more compounds described herein and a suitable carrier or excipient, in some embodiments, the one or more compounds described herein may be in a ratio of about 10:1 to about 1:10, or may be in a range including and / or spanning the aforementioned values. In some embodiments, one or more compounds described herein can be about 10:1, 9.5:1, 8.5:1, 8.0:1, 7.5:1, 7:1, 6.5:1, 6:1, 5.5:1, 5:1, 4.5:1, 4:1, 3.5:1, 3.0:1, 2.5:1, 2.0:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5.

[0108] method In certain aspects, the present disclosure also provides methods for improving, restoring, or maintaining gut health in a subject. According to such methods, an effective amount of one or more compounds, formulations, or extracts containing one or more compounds of the present disclosure is provided to a subject in need thereof, thereby improving or maintaining the subject's digestive function, thereby underlying the pathogenesis of one or more gut health disorders and promoting the health, wellness, and quality of life of the subject. Accordingly, provided herein are compounds, compositions, formulations, and methods for treating, maintaining, improving, or ameliorating symptoms of, including but not limited to, metabolic syndrome, reducing intestinal inflammation, increasing epithelial turnover, reducing microbial dysbiosis, modulating tight junctions, secreting microbial peptides, goblet cell mucus production, gut barrier function, gut barrier integrity, intestinal permeability, gut barrier function, and targeting gut pathogens.

[0109] In some embodiments, methods are provided for treating, ameliorating, reversing, preventing, or reducing metabolic syndrome or a metabolic disorder. In some embodiments, the method for treating, ameliorating, reversing, preventing, or reducing a metabolic disorder in a subject in need thereof includes providing or administering one or more compounds, compositions, formulations, or extracts containing one or more compounds described herein. In some embodiments, the one or more compounds, compositions, formulations, or extracts are administered in amounts that, taken together, are sufficient to treat, prevent, or reduce metabolic syndrome or a metabolic disorder. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per administration. In some embodiments, the food is a food bar. Use of a composition for treating, ameliorating, reversing, preventing, or reducing metabolic syndrome or a metabolic disorder, wherein the composition comprises N-trans-caffeoyltyramine. Use of a composition for treating, ameliorating, reversing, preventing, or reducing metabolic syndrome or a metabolic disorder, wherein the composition comprises N-trans-feruloyltyramine. Use of a composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine for treating, ameliorating, reversing, preventing, or reducing metabolic syndrome or a metabolic disorder.1. Use of a composition for treating, ameliorating, reversing, preventing, or reducing metabolic syndrome or a metabolic disorder, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0110] In some embodiments, methods are provided for treating, ameliorating, preventing, or reducing intestinal inflammation. Intestinal inflammation is a response to harmful stimuli throughout the intestine. It is typically characterized by an increase in interleukin (IL-6), which results in tissue swelling. This swelling is associated with many intestinal disorders, such as inflammatory bowel disease, ulceration, and irritable bowel syndrome, to name a few. Furthermore, inflammation inhibits nutrient absorption by impairing intestinal barrier communication. In some embodiments, the intestinal inflammation is bowel inflammation. In some embodiments, methods for treating, ameliorating, ameliorating, preventing, or reducing intestinal inflammation in a subject in need thereof include providing or administering one or more compounds, compositions, formulations, or extracts comprising the compounds described herein. In some embodiments, the one or more compounds, compositions, formulations, or extracts are provided or administered in amounts that, together, are sufficient to treat, ameliorate, prevent, or reduce intestinal inflammation. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is from about 2.5:1 to about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar.Use of a composition for treating, ameliorating, ameliorating, preventing, or reducing intestinal inflammation, wherein the composition comprises N-trans-caffeoyltyramine.Use of a composition for treating, ameliorating, reversing, preventing, or reducing intestinal inflammation, the composition comprising N-trans-feruloyltyramine. Use of a composition for treating, ameliorating, reversing, preventing, or reducing intestinal inflammation, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine. 1. Use of a composition for treating, ameliorating, reversing, preventing, or reducing intestinal inflammation, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0111] In some embodiments, methods are provided for treating, improving, restoring, preventing, or increasing epithelial turnover. Epithelial turnover is the process of cell loss to balance new cell production. This is essential for maintaining epithelial health and avoiding mutations that can lead to many negative health indications. In some embodiments, methods for treating, improving, restoring, preventing, or increasing epithelial turnover in a subject in need thereof include administering one or more compounds, compositions, formulations, or extracts containing one or more compounds described herein. In some embodiments, the compositions are provided or administered in amounts, taken together, sufficient to treat, improve, restore, prevent, or increase epithelial turnover. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, one or more compounds are N-trans-caffeoyltyramine. In some embodiments, one or more compounds are N-trans-feruloyltyramine. In some embodiments, one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in a unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per administration. In some embodiments, the food is a food bar. Use of a composition for treating, ameliorating, restoring, preventing, or reducing epithelial turnover, wherein the composition comprises N-trans-caffeoyltyramine. Use of a composition for treating, ameliorating, restoring, preventing, or reducing epithelial turnover, wherein the composition comprises N-trans-feruloyltyramine.Use of a composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine for treating, ameliorating, restoring, preventing, or reducing epithelial turnover. 1. Use of a composition for treating, ameliorating, restoring, preventing, or reducing epithelial turnover, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0112] In some embodiments, methods are provided for treating, ameliorating, reversing, preventing, or alleviating microbial dysbiosis. The gut microbiome is the collection of bacteria and other microorganisms present in the gastrointestinal tract. A healthy microbiome has been shown to dramatically improve overall health by breaking down unabsorbable compounds into healthy products that can easily cross the intestinal epithelium. As such, a healthy microbiome is essential for proper nutrient absorption. In some embodiments, methods for treating, ameliorating, reversing, preventing, or reducing microbial dysbiosis in a subject in need thereof include providing or administering one or more compounds, compositions, formulations, or extracts comprising one or more compounds described herein. In some embodiments, the one or more compounds, compositions, formulations, or extracts are provided or administered in amounts that, together, are sufficient to treat, prevent, or reduce microbial dysbiosis. In some embodiments, the gastrointestinal epithelial cell barrier dysfunction is associated with inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, irritable bowel syndrome, intestinal infection, Clostridium difficile infection, metabolic disease, obesity, type 2 diabetes, metabolic dysfunction-associated steatohepatitis, nonalcoholic fatty liver disease, liver damage, alcoholic steatohepatitis, celiac disease, necrotizing enterocolitis, gastrointestinal disorders, short bowel syndrome, stomatitis, chemotherapy-induced mucositis, radiation-induced mucositis, oral mucositis, interstitial cystitis, neurological disorders, cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, chemotherapy-associated steatohepatitis (CASH), and pediatric versions of the diseases. In some embodiments, the subject experiences relief of at least one symptom associated with gastrointestinal epithelial cell barrier dysfunction selected from the group consisting of abdominal pain, bloody stool, suppuration, fever, weight loss, frequent diarrhea, fatigue, decreased appetite, tenesmus, and rectal bleeding. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferroyltyramine, salts, or isomers thereof, hi some embodiments, the one or more compounds is N-trans-caffeoyltyramine.In some embodiments, the one or more compounds is N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per dose. In some embodiments, the food is a food bar. Use of a composition for treating, ameliorating, reversing, preventing, or reducing microbial microbial dysbiosis, wherein the composition comprises N-trans-caffeoyltyramine. Use of a composition for treating, ameliorating, reversing, preventing, or reducing microbial microbial dysbiosis, wherein the composition comprises N-trans-caffeoyltyramine. Use of a composition for treating, ameliorating, reversing, preventing, or reducing microbial microbial dysbiosis, wherein the composition comprises N-trans-caffeoyltyramine. 1. Use of a composition for treating, ameliorating, reversing, preventing, or reducing microbial dysbiosis, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0113] In some embodiments, methods are provided for treating, improving, restoring, preventing, or improving tight junction regulation. Intestinal epithelial cells are connected to each other by tight junction proteins, which alter the tightness of the cell layer. When these junctions function properly, they allow the passage of nutrients essential for maintaining human health while blocking harmful compounds from entering the circulation. Dysfunction of tight junction proteins can result in loose junctions and leaky gut, or excessive tight junctions, which can interfere with nutrient absorption. In some embodiments, methods for treating, preventing, or improving tight junction regulation in a subject in need thereof include providing or administering one or more compounds, compositions, formulations, or extracts comprising one or more compounds described herein. In some embodiments, the one or more compounds, compositions, formulations, or extracts are administered in amounts that, together, are sufficient to treat, improve, restore, prevent, or improve tight junction regulation. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is from about 2.5:1 to about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar.Use of a composition for treating, ameliorating, reversing, preventing, or alleviating tight junction regulation, wherein the composition comprises N-trans-caffeoyltyramine.Use of a composition for treating, ameliorating, restoring, preventing, or reducing tight junction modulation, the composition comprising N-trans-feruloyltyramine. Use of a composition for treating, ameliorating, restoring, preventing, or reducing tight junction modulation, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine. 1. Use of a composition for treating, ameliorating, restoring, preventing, or reducing tight junction regulation, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0114] In some embodiments, methods are provided for treating, ameliorating, preventing, or reducing the secretion of antimicrobial peptides. Antimicrobial peptides are secreted throughout the GI tract to protect the body from harmful compounds in the intestine. These peptides are essential for reducing pathogens in the body that can lead to infection. In some embodiments, a method for treating, ameliorating, preventing, or reducing the secretion of antimicrobial peptides in a subject in need thereof includes providing or administering one or more compounds, compositions, formulations, or extracts containing one or more compounds described herein. In some embodiments, the compositions are provided or administered in amounts that, taken together, are sufficient to treat, ameliorate, prevent, or reduce the secretion of antimicrobial peptides. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, one or more compounds is N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine and N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per administration. In some embodiments, the food is a food bar.

[0115] In some aspects, methods are provided for treating, improving, restoring, preventing, or increasing goblet cell mucus production. The epithelial lining is protected by a layer of mucus, which is the first line of defense against irritants that can damage the intestinal barrier. Goblet cells are essential for the production and maintenance of this mucus layer and therefore are essential for protecting the epithelium from damage. In some embodiments, methods for treating, improving, restoring, preventing, or increasing goblet cell mucus production in a subject in need thereof include providing or administering one or more compounds, compositions, formulations, or extracts comprising one or more compounds described herein. In some embodiments, the compositions are provided or administered in amounts that, taken together, are sufficient to treat, improve, restore, prevent, or increase goblet cell mucus production. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in a unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per administration. In some embodiments, the food is a food bar. Use of a composition for treating, ameliorating, ameliorating, preventing, or increasing goblet cell mucus production, wherein the composition comprises N-trans-caffeoyltyramine. Use of a composition for treating, ameliorating, ameliorating, preventing, or increasing goblet cell mucus production, wherein the composition comprises N-trans-feruloylthiamine.Use of a composition for treating, ameliorating, ameliorating, preventing, or increasing goblet cell mucus production, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for treating, ameliorating, ameliorating, preventing, or increasing goblet cell mucus production, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0116] In some embodiments, methods are provided for treating, ameliorating, reversing, preventing, or targeted reduction of enteric pathogens. Similar to antimicrobial secretion and microbiome health, the reduction of enteric pathogens is a process by which the GI tract protects itself from damage by harmful compounds. Enteric pathogens are known to cause inflammation, damage the epithelium, and lead to systemic infections. Reducing the population of enteric pathogens throughout the GI tract is essential for maintaining systemic health and proper nutrient uptake. In some embodiments, a method for treating, ameliorating, reversing, preventing, or targeted reduction of enteric pathogens in a subject in need thereof includes providing or administering one or more compounds, compositions, formulations, or extracts comprising one or more compounds described herein. In some embodiments, the one or more compounds, compositions, formulations, or extracts are administered in amounts, taken together, sufficient to treat, ameliorate, reversing, prevent, or targeted reduction of enteric pathogens. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds comprise N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is from about 2.5:1 to about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per dose. In some embodiments, the food is a food bar. Use of a composition comprising N-trans-caffeoyltyramine for treating, ameliorating, reversing, preventing, or reducing enteric pathogens. Use of a composition comprising N-trans-feruloylthiamine for treating, ameliorating, reversing, preventing, or reducing enteric pathogens.Use of a composition for treating, ameliorating, ameliorating, preventing, or increasing goblet cell mucus production, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for treating, ameliorating, ameliorating, preventing, or reducing enteric pathogens, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0117] In some aspects, providing or administering one or more compounds or formulations described herein promotes a strong intestinal barrier. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar. Use of a composition for promoting a strong intestinal barrier, the composition comprising N-trans-caffeoyltyramine. Use of a composition for promoting a strong intestinal barrier, the composition comprising N-trans-feruloylthiamine. Use of a composition for promoting a strong intestinal barrier, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for promoting a strong intestinal barrier, the composition comprising N-trans-caffeoyltyramine and N-trans-ferroyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0118] In some aspects, providing or administering one or more compounds or formulations described herein modulates the transport of essential molecules and limits the passage of harmful substances. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar. Use of a composition for treating, improving, restoring, preventing, or modulating the transport of essential molecules and limiting the passage of harmful substances, the composition comprising N-trans-caffeoyltyramine. Use of a composition for treating, improving, restoring, preventing, or modulating the transport of essential molecules and limiting the passage of harmful substances, the composition comprising N-trans-feruloylthiamine. Use of a composition for treating, improving, restoring, preventing, or modulating the transport of essential molecules and limiting the passage of harmful substances, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine.1. Use of a composition for treating, ameliorating, restoring, preventing, or modulating the transport of essential molecules and limiting the passage of harmful substances, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0119] In some aspects, providing or administering one or more compounds or formulations described herein maintains intestinal barrier function. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and configured for administration of 0.1 to 100 mg / kg (body weight of a subject of Formula (I)) per dose. In some embodiments, the food is a food bar. Use of a composition for treating, improving, restoring, preventing, or maintaining intestinal barrier function, the composition comprising N-trans-caffeoyltyramine. Use of a composition for treating, improving, restoring, preventing, or maintaining intestinal barrier function, the composition comprising N-trans-feruloylthiamine. Use of a composition for treating, improving, restoring, preventing, or maintaining intestinal barrier function, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for treating, improving, restoring, preventing, or maintaining intestinal barrier function, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0120] In some embodiments, the integrity of the intestinal barrier is modulated by providing or administering one or more compounds or formulations described herein. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier integrity, the composition comprising N-trans-caffeoyltyramine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier integrity, the composition comprising N-trans-feruloylthiamine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier integrity, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier integrity, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0121] In some aspects, providing or administering one or more compounds or formulations described herein improves intestinal permeability. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal permeability, the composition comprising N-trans-caffeoyltyramine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal permeability, the composition comprising N-trans-feruloylthiamine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal permeability, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloyltyramine. 1. Use of a composition for treating, ameliorating, restoring, preventing, or modulating intestinal permeability, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0122] In some embodiments, intestinal barrier function is modulated by providing or administering one or more compounds or formulations described herein. In some embodiments, the one or more compounds may be selected from N-trans-caffeoyltyramine, N-cis-caffeoyltyramine, N-trans-feruloyltyramine, N-cis-feruloyltyramine, p-coumaroyltyramine, cinnamoyltyramine, sinapoyltyramine, and 5-hydroxyferuloyltyramine, salts, or isomers thereof. In some embodiments, the one or more compounds are N-trans-caffeoyltyramine. In some embodiments, the one or more compounds are N-trans-feruloyltyramine. In some embodiments, the one or more compounds include N-trans-caffeoyltyramine and N-trans-feruloyltyramine. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 10:1 to about 1:10. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 1:2.5. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 4:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 3:1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2: 1. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2:1.In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:2.2. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:3. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:4. In some embodiments, the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 1:5. In some embodiments, the composition is formulated as a dietary supplement, a food ingredient or additive, a food, a medical food, a nutraceutical composition, or a pharmaceutical composition. In some embodiments, the composition of Formula (I) is in unit dosage form and is configured for administration of 0.1 to 100 mg / kg (body weight of the subject of Formula (I)) per administration. In some embodiments, the food product is a food bar. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier function, the composition comprising N-trans-caffeoyltyramine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier function, the composition comprising N-trans-feruloylthiamine. Use of a composition for treating, improving, restoring, preventing, or modulating intestinal barrier function, the composition comprising N-trans-caffeoyltyramine and N-trans-feruloylthiamine. 1. Use of a composition for treating, improving, restoring, preventing, or regulating intestinal barrier function, wherein the composition comprises N-trans-caffeoyltyramine and N-trans-feruloyltyramine in a ratio of about 10:1 to about 1:10, or about 5:1 to about 1:5, or about 5:1 to about 1:1, or about 2.5:1 to about 1:1, or about 2:5:1 to about 2:1, or about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2.5:1, about 2.2:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, or about 1:10.

[0123] The present disclosure also provides for improving transepithelial electrical resistance (TEER) by providing one or more compounds, formulations, or consumable compositions described herein and at least one carrier. According to such methods, an effective amount of an extract comprising a composition described herein is provided to a subject in need thereof, thereby improving TEER in the subject. As used herein, the term "subject" refers to an animal, preferably a mammal. In some embodiments, the subject is a veterinary animal, a companion animal, a livestock animal, an experimental animal, or an animal. In other embodiments, the subject is a human.

[0124] In some aspects, administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, isomer, homodimer, heterodimer, or conjugate thereof, improves TEER and reduces intestinal permeability in a subject. In some embodiments, a composition comprising a compound of Formula (I) or Formula (II) treats or ameliorates a disease or condition associated with TEER or intestinal permeability in a subject. In some embodiments, a composition comprising a compound of Formula (I) or Formula (II) treats or ameliorates a disease or condition associated with increased intestinal permeability in a subject.

[0125] In one embodiment, administering a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, treats or improves at least one factor related to TEER or intestinal permeability in a subject. In other aspects, a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, disclosed herein treats, improves, or enhances a condition or disease related to TEER or intestinal permeability in a subject, for example, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%, or a range ranging between or including the aforementioned values. In still other embodiments, a composition comprising Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, improves a subject's TEER or intestinal permeability related condition or disease by, for example, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, or about 10% to about 100%. %, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[0126] Dosages can vary widely depending on the desired effect and therapeutic indication, e.g., marker levels. Alternatively, as will be understood by those skilled in the art, dosages can be calculated based on the patient's surface area or weight. The exact dosage can be determined on an individual basis, or in some cases, left to the subject's informed judgment. A daily dosage regimen for an adult human patient can be, for example, an oral dose of a compound or composition described herein from about 0.01 mg to about 10,000 mg, about 1 mg to about 5,000 mg, about 5 mg to about 2,000 mg, about 10 mg to about 1,000 mg, or about 50 mg to about 500 mg. A single dose can contain about 0.01 mg, about 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 900 mg, about 1000 mg, about 2000 mg, about 5000 mg, or more of a compound or composition described herein. The dosage may be adjusted according to the body weight of the subject, for example, the dosage may be about 0.001 mg / kg, about 0.01 mg / kg, about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, or more.

[0127] Doses may be given once or twice or more consecutively, as appropriate for the individual subject. In some embodiments, the compounds or compositions described herein are administered for a period of continuous therapy, for example, for about one week or more (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks or more), several weeks, about one month or more (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or more), about one year or more, or multiple years. In some embodiments, the compounds or compositions described herein can be administered or taken once a day, twice a day, three times a day, or more.

[0128] As will be appreciated by those skilled in the art, in certain circumstances it may be necessary to administer the compounds disclosed herein in amounts outside the above preferred dosage ranges to effectively treat a subject.

[0129] Unit dosage forms, such as individual packages containing pre-measured amounts of the composition, configured for administration on a predetermined schedule, can also be provided. Unit dosage forms configured for administration once to three times per day are preferred. However, in certain embodiments, it may be desirable to configure the unit dosage form for administration more than three times per day or less than once per day.

[0130] Dosage and administration interval can be adjusted for each individual subject, and can obtain the plasma level of active moiety that is sufficient to maintain a predetermined parameter, indicator, or marker value, or minimum effective concentration (MEC).The dosage required to achieve desired results will depend on individual characteristics and administration route.However, serum concentration can also be determined using assays, such as HPLC assays or bioassays.

[0131] Combination therapy In some embodiments, the compounds, compositions, or pharmaceutical compositions disclosed herein, including the compounds described herein, or salts or derivatives thereof, can be used in combination with one or more additional active agents. Examples of additional active agents that can be used in combination with the compounds or compositions described herein include, but are not limited to, agents currently used to treat metabolic syndrome and related disorders, or agents that regulate metabolism, as described herein or otherwise known in the medical sciences. In some embodiments, the compounds or compositions described herein can be used with one, two, three, or more additional active agents described herein.

[0132] In some embodiments, one or more immunomodulatory agents or compositions described herein may be used (e.g., administered or ingested) in combination with another agent or drug for the treatment, prevention, maintenance, or prophylaxis of a disease or condition described herein. For example, the compounds disclosed herein may be used in combination with other agents or drugs, including albiglutide, aleglitazar, balaglitazone, canagliflozin, CJ-30001 (CJ Cheiljedang Corporation), CJ-30002 (CJ Cheiljedang Corporation), Diamyd® (glutamic acid decarboxylase (rhGAD65)), dulaglutide, exendin 4, gemigliptin, lixisenatide, lobeglitazone, Shenke I (Tibet Pharmaceuticals), SK-0403 (Sanwa Chemical Research Institute), teneligliptin, teplizumab, tofogliflozin, acarbose, alogliptin benzoate, chlorpropamide, Diab II (Biotech), or other drugs. Holdings), exenatide, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, glisentide, glisolamide, HL-002 (HanAII Biopharma), insulin (human), insulin, insulin analogues (Eli Lilly®), insulin aspart, insulin detemir, insulin glargine, insulin lispro, Janumet®, linagliptin, liraglutide, metformin, miglitol, mitiglinide, nateglinide, Novo Mix 30® (Novo nordisk®) pioglitazone, pramlintide, repaglinide, rosiglitazone maleate, saxagliptin, sitagliptin, tresiba, tolazamide, tolbutamide, vildagliptin, voglibose, bezafibrate, diflunisal, cinnamic acid, carbutamide, glyburide (glibenclamide), glibomuride, glyhexamide, fenbutamide, and tolcyclamide, or one or more medications selected from drug classes including sulfonylureas, non-sulfonylurea secretagogues, glucagon-like peptides, exendin-4 polypeptides, beta-3 adrenergic receptor agonists, PPAR agonists,Dipeptidyl peptidase IV inhibitors, biguanides, alpha-glucosidase inhibitors, immunomodulators, statins and statin-containing combinations, angiotensin-converting enzyme inhibitors, adenosine A1 receptor agonists, adenosine A2 receptor agonists, aldosterone antagonists, alpha 1 adrenoceptor antagonists, alpha 2 adrenoceptor agonists, alpha 2 adrenoceptor agonists, angiotensin receptor antagonists, antioxidants, ATPase inhibitors, atrial peptide agonists, beta adrenoceptor antagonists, Calcium channel agonists, calcium channel antagonists, diguanides, diuretics, dopamine D1 receptor agonists, endopeptidase inhibitors, endothelin receptor antagonists, guanylate cyclase stimulators, phosphodiesterase V inhibitors, protein kinase inhibitors, Cdc2 kinase inhibitors, renin inhibitors, thromboxane synthase inhibitors, vasopeptidase inhibitors, vasopressin I antagonists, vasopressin 2 antagonists, angiogenesis inhibitors, advanced glycation end product inhibitors, bile acid binders, bile acid transport inhibitors, bone formation stimulators, Apolipoprotein A1 agonists, DNA topoisomerase inhibitors, cholesterol absorption inhibitors, cholesterol antagonists, foldamyl derivative transfer protein antagonists, cytokine synthesis inhibitors, DNA polymerase inhibitors, dopamine D2 receptor agonists, endothelin receptor antagonists, growth hormone antagonists, insulin sensitizers, lipase inhibitors, lipid peroxidation inhibitors, lipoprotein A antagonists, microsomal transfer protein inhibitors, microsomal triglyceride transfer protein inhibitors, nitric oxide synthase inhibitors, oxidants, phospholipases enzyme A2 inhibitors, radical-forming agonists, platelet aggregation antagonists, prostaglandin synthase stimulators, reverse cholesterol transport activators, rho kinase inhibitors, selective estrogen receptor modulators, squalene epoxidase inhibitors, squalene synthase inhibitors, thromboxane A2 antagonists, amylin agonists, cannabinoid receptor antagonists, cholecystokinin A agonists, corticotropin-releasing factor agonists, dopamine uptake inhibitors, G protein-coupled receptor modulators, glutamate antagonists,This may include administering with other medications such as glucagon-like peptide-1 agonists, lipase inhibitors, melanin-concentrating hormone receptor antagonists, nerve growth factor agonists, neuropeptide Y agonists, neuropeptide Y antagonists, SNRIs, protein tyrosine phosphatase inhibitors, serotonin 2c receptor agonists, or central nervous system medications that affect neurotransmitters or neural ion channels, including antidepressants, steroids, steroid hormone receptor antagonists, steroid hormone receptor inhibitors, steroid hormone receptor agonists ... Leptin / insulin / central nervous system pathway agents including 2c receptor agonists, anticonvulsants (topiramate, zonisamide), dopamine antagonists, cannabinoid-1 receptor antagonists (CB-1 receptor antagonists) (rimonabant), including leptin analogs, leptin transporter and / or leptin receptor promoters, ciliary neurotrophic factor (axokine), neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and cocaine- and amphetamine-regulated transcription promoters, alpha-melanocyte-stimulating hormone analogs, melanocolitin-4 receptor agonists, and agents that affect insulin metabolism / activity, including protein tyrosine phosphatase-IB inhibitors, peroxisome proliferator-activated receptor-gamma. receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin / Acrp30 (famoxine or fatty acid metabolic oxidation inducers); gastrointestinal-neural pathway agents, including those that increase cholecystokinin activity (CCK), PYY activity, NPY activity, and PP activity, increase glucagon-like peptide-1 activity (exendin 4, dipeptidyl peptidase IV inhibitors), and decrease ghrelin activity, and amylin analogs (pramlintide); agents that can increase resting metabolic rate (selective beta-3 agonists / agonists, uncoupling protein homologs, and thyroid receptor agonists); melanin-concentrating hormone antagonists, phytostanol analogs, functional oils, P57, amylase inhibitors, growth hormone fragments, dehydroepiandrosterone sulfate synthetic analogs,Adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity antagonists, corticotropin-releasing hormone agonists, other more diverse drugs, fatty acid synthesis inhibitors (cerulenin and C75), carboxypeptidase inhibitors, indanones / indanols, aminosterols (trodasquemine / troduramine), and other gastrointestinal lipase inhibitors (ATL962), amphetamines, e.g., dextroamphetamine; phentermine, benzphetamine, phendimetrazine, mazindo Other sympathomimetic adrenergic agonists, including benzodiazepine and diethylpropion, or ecopipam; oxytomodulin (OM), glucose-dependent insulinotropic polypeptide (GIP) inhibitor; gastrin-releasing peptide, neuromedin B; enterostatin; amfebutamone; SR-58611; CP-045598; AOD-0604; QC-BT16; rGLP-1; 1426 (HMR-1426); N-5984; ISIS-1 13715; solabegron; SR-147778; Org-34517; melanotan-II; cetilistat; c-2735; c-5093; c-2624; APD-356; radafaxine; flusterone; GP-389255; 856464; S-2367; AVE-1625; T-71; oleoyl-estrone; intranasal peptide YY[3-36]; androgen receptor agonist; PYY3-36; DOV-102677; tagatose; SLV-319; 1954 (Aventis Pharma AG); oxytomodulin, thiamex, bromocriptine, PLIVA; diabetes / hyperlipidemia therapy,Yissum; CKD-502; Thyroid receptor beta agonist; Beta-3 adrenergic receptor agonist; CDK-A agonist; Galanin antagonist; Dopamine D1 / D2 agonist; Melanocortin modulator; Veronamine; Neuropeptide Y antagonist; Melanin-concentrating hormone receptor antagonist; PPAR alpha / gamma dual agonist; CGEN-P-4; Kinase inhibitor; Human MCH receptor antagonist; GHS-R antagonist; Ghrelin receptor agonist; DG70 inhibitor; Cotinine; CRF-BP inhibitor; Urocortin agonist; UCL-2000; Inpentamine; Beta-3 adrenergic receptor; Pentapeptide MC4 agonist; Trodasquemine; GT-2016; C-75; CPOP; MCH-1 receptor antagonist; RED-103004; Aminosterol; Oligosaccharides Xin-1 antagonists; neuropeptide Y5 receptor antagonists; DRF-4158; PT-15; PTPase inhibitors; A37215; SA-0204; glycolipid metabolites; MC-4 agonists; produrestan; PTP-1B inhibitors; GT-2394; neuropeptide Y5 antagonists; melanocortin receptor modulators; MLN-4760; PPAR gamma / delta dual agonists; NPY5RA-972; 5-HT2C receptor agonists; neuropeptide Y5 receptor antagonists (phenylurea analogs); AGRP / MC4 antagonists; neuropeptide Y5 antagonists (benzimidazoles); glucocorticoid antagonists,MCHR1 antagonist; acetyl-CoA carboxylase inhibitor; R-1496; HOB1 modulator; NOX-B11; peptide YY3-36 (Eligen); 5-HT 1 modulator; pancreatic lipase inhibitor; GRC-1087; CB-1 antagonist; MCH-1 antagonist; LY-448100; bombesin BRS3 agonist; ghrelin antagonist; MC4 antagonist; stearoyl-CoA desaturase modulator; PPAR pan agonist; EP-01492; hormone-sensitive lipase inhibitor; fatty acid binding protein 4 inhibitor; thiolactone derivative; protein tyrosine phosphatase IB inhibitor; MCH-1 antagonist; P-64; PPARγ ligand; melanin-concentrating hormone antagonist; thiazole gastrointestinal kinetics; PA-452; T-226296; A-331440; immunological vaccine; diabetes / obesity treatment (BioAgency, BioFrontera Discovery) GmbH); P-7 (GenFIT); DT-011M; PTP1B inhibitor; antidiabetic peptide conjugate; KATP agonist; obesity treatment (Lexcon); 5-HT2 agonist; MCH-1 receptor antagonist; GMAD-1 / GMAD-2; STG-a-MD; angiogenesis inhibitor; G protein-coupled receptor agonist; nicotinic treatment (ChemGenex); antiobesity drug (Abbott); melanin-concentrating hormone ;GW-594884A;MC-4R agonist;histamine H3 antagonist;orphan GPCR modulator;MITO-3108;NLC-002;HE-2300;IGF / BBP-2-13;5-HT2C agonist;ML-22952;neuropeptide Y receptor antagonist;AZ-40140;anti-obesity therapy (Nissin Foods);GNTI;melanocortin receptor modulator;alpha-amylase inhibitor;beta-3 ad, Renaline receptor agonist; op gene product (Eli Lilly & Co.); SWR-0342-SA; SWR-0335; SP-18904; oral insulin mimetic; obesity treatment (7TM Pharma); beta-hydroxysteroid dehydrogenase (HSD) inhibitors; QRX-431; E-6776; M-450, melanocortin-4 antagonists; melanocortin-4 receptor agonists, obesity treatments (CuraGen); leptin mimetics; A-74498; second-generation leptins; NBI-103; CL-314698; CP-114271; beta-3 adrenergic receptor agonists; NMI-8739; UCL-1283; BMS-192548; CP-94253; PD-160170; nicotinic agonists; LG-100754; SB-226552; LY-355124; CKD-711; L-751250; PPAR inhibitors; G protein therapeutics; obesity treatments (Amylin Pharmaceuticals Inc.); BW-1229; monoclonal antibody (ObeSys / CAT); L-742791; (S)-sibutramine; MBU-23; YM-268; BTS-78050; tubby-like protein gene; genomics (eating disorders, Alerix / Lilly); MS-706; GI-264879A; GW-409890; FR-79620 analogs; obesity therapy (Hybrgenics SA); ICI-198157; ESP-A; 5-HT2C agonist; PD-170292; AIT-202; LG-100641; GI-181771; anti-obesity therapeutic drug (Genzyme); leptin modulator, GHRH mimetic obesity therapy (Yamanouchi Pharmaceutical Co., Ltd.); SB-251023; CP-331684; BIBO-3304; holestene-3-ones; LY-362884; BRL-48962; PY-1 antagonist; A-71378; RTM.-Didesmethylsibutramine; Antiobesity drug (Bristol-Myers Squibb); Antiobesity drug (Lygand); LY-226936; NPY antagonist; CCK-A agonist; FPL-14294; PD-145942; ZA-7114; CL-316243; SR-58878; R-1065; BDBP-3226; HP-228; Talibegron; FR-165914; AZM-008; AZM-016; AZM-120; AZM-090; AZM-131; AZM-132; AZM-134; AZM-127; AZM-0 83; AZM-115; AZM-140; vemeroferrin; BMS-187257; D-3800; Gene Discovery (Axys / Glaxo); BRL-26830A; SX-013; ERR modulator; adipsin; AC-253; A-71623; A-68552; BMS-210285; TAK-677; MPV-1743; obesity therapy (Modex); GI-248573; exopipam; SSR-125180; obesity therapy (Melacure Therapeutics AB); BRL-35135; SR-146131; P-57; CGP-71583A; RF-1051; BMS-196085; manifaxin; DMNJ (Korea Research Institute of Bioscience and Biotechnology); BVT-5182; LY-255582; SNX-024; galanin antagonists; neurokinin 3 antagonists; dexfenfluramine; mazindol; diethylpropion; phendimetrazine; benzophenantamine; amfebutomone; sertraline; AOD-9604; ATL-062; BVT-933; GT389-255; SLV319; HE-2500; PEG-axokine; L-796568; and ABT-239; rimonabant, sibutramine, orlistat, PYY or its analogs, CB-1 antagonists, leptin, phentermine, and exendin analogs; GPR1 These include agonists (e.g., anandamide; AR-231,453; MBX-2982; oleoylethanolamide; PSN-365,963; PSN-632,408; palmitoylethanolamide); GPR120 agonists; and GPR40 agonists.

[0133] In some embodiments, one or more immunomodulatory agents or compositions described herein may be used (e.g., administered or ingested) in combination with an antibiotic for the treatment, prevention, maintenance, or prophylaxis of a disease or condition described herein, such as azithromycin, phenoxymethylpenicillin, dicloxacillin, amoxicillin with clavulanic acid, ampicillin, nafcillin, oxacillin, penicillin V, penicillin G, doxycycline, minocycline, sarecycline, erythromycin, clarithromycin, fidaxomicin, roxithromycin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, sulfamethoxazole with trimethoxazole, sulfasalazine, sulfacetamide, silver sulfadiazine, vancomycin, dalbavantin, oritavantin, and telavantin. [Example]

[0134] The following examples are intended to illustrate various embodiments of the present disclosure and are not intended to limit the disclosure in any way. Those skilled in the art will readily appreciate that the present disclosure is well adapted to carry out the objects and obtain the objects and advantages mentioned, as well as those inherent therein. Modifications and other uses within the spirit of the present disclosure, as defined by the scope of the claims, will occur to those skilled in the art.

[0135] Example 1 In this example, compounds described herein were tested to determine the effect of TNFα on barrier function, and supernatants and cell lysates were analyzed for subsequent analysis.

[0136] reagent Cell information: Donor 5 transverse colon, HISC-0033, passage 10. Plated into 4x 96-well RepliGut® Transwell plates coated with a thin hydrogel coating. 2x RepliGut® Transwell plates had 1.0 μm pore size (Corning 3380) and 2x RepliGut® Transwell plates had 0.4 μm pore size (Corning 7369).

[0137] Compound information: TNFα was supplied by Altis Biosystems and reconstituted according to the manufacturer's instructions. All other compounds were provided by Brightseed in DMSO (Table 1). Stocks were made for each treatment so that the final concentration of each compound in the medium was 0.1% of the medium volume for all compounds (Table 2). [Table 1]

[0138] Proliferative human transverse colon epithelial cells were plated in Altis Growth Medium onto 4 x 96-well RepliGut® Transwell plates coated with a thin layer of hydrogel, using Altis' established protocol. Cultures were observed daily using a brightfield microscope. The transverse colon epithelial monolayer became confluent on day 4, at which point the medium was replaced with Altis Differentiation Medium. Cells were cultured for an additional 2 days. Bright seed compounds and TNFα, listed in Table 2, were diluted in Altis Differentiation Medium, mixed thoroughly, and added to the apical and basal compartments of the Transwell cultures at t = 0 hours. All conditions were performed in triplicate. Cells were treated with compounds for a total of 48 hours. [Table 2]

[0139] In this initial experiment, only the treatment and delivery for "Plate Set 2" was performed to determine the optimal Transwell membrane pore size for subsequent experimental plates. To obtain data to further explore the imaging capabilities of immunofluorescence staining in both Transwell membrane types, it was suggested to run both 0.4 μm and 1.0 μm pore size Transwell membrane plates.

[0140] Transepithelial Electrical Resistance (TEER) Prior to compound addition, transepithelial electrical resistance was measured in all transwell cultures at t = 0 h using an epithelial volt / ohm meter (World Precision Instruments, EVOM2) and an STX100C96 electrode to determine baseline TEER. TEER was also measured at t = 24 h, t = 45 h, and t = 48 h. The surface area of ​​the 96-well transwells was 0.143 cm per well. 2 The corrected TEER was calculated using the following formula:

[0141] (Raw measured TEER / sample transwell - Raw measured TEER / blank transwell) x surface area Supernatant collection

[0142] After the t = 48 h TEER time point, apical and basal supernatants were transferred to 96-well polypropylene storage microplates (Thermo Fisher, catalog no. 267334), sealed with sterile AlumaSeal II sealing film (Genesee, catalog no. 12-531), and stored at -80° C. The layout of the supernatant collection plate was the same as that of the treatment plate.

[0143] Permeability assay After collecting the supernatant, a permeability assay was performed on all transwells. Forty-five hours after compound addition, 75 μL of a 0.5 mg / mL 40 kDa MW FITC-dextran (Sigma, catalog no. FD40S) solution prepared in Altis differentiation medium was placed in the apical compartment of each transwell, and 210 μL of Altis differentiation medium was placed in the basal compartment of each transwell. The transwell cultures were incubated at 37°C with 5% CO2 for 3 hours to transfer the FITC-dextran to the basal compartment. Two 90 μL aliquots of medium were collected from the basal compartment of each transwell, and fluorescence was measured for each sample (n=2 samples / well) using a Synergy H1 plate reader (Ex: 485, Em: 535).

[0144] "Raw medium fluorescence (RF)" was obtained by measuring Altis DM without FITC-dextran to determine background medium fluorescence. "RF without cells control" was obtained from the basal compartment medium of hydrogel-coated transwells without seeding epithelial cells to normalize permeability measurements. "Relative permeability (% of no-cell control)" was calculated using the following formula:

[0145] ((RF in RF-medium of sample) / (RF in RF-medium of control without cells)) x 100

[0146] statistical analysis Statistical analysis was performed using GraphPad Prism software version 9.4.1 (GraphPad Inc., La Jolla, CA, USA). Two-way analysis of variance of means from n = 3 samples per group was performed to determine simple effects within treatment groups. Tukey's range test was performed to correct for multiple comparisons. Differences between groups were considered significant at p < 0.05.

[0147] result Administration of NCT improved the change in TEER as a result of TNF administration in a dose-dependent manner after 48 hours, with the improvement increasing from 10 μM to 20 μM to 40 μM (Panel (a) of Figure 13). Values ​​shown are relative to t=0. As little as 10 μM NCT resulted in a % improvement in permeability that nearly offset the effect of TNF administration (Panel (b) of Figure 13). Higher doses of NCT (20 μM and 40 μM) showed similar improvement as the 10 μM NCT dose.

[0148] Administration of 10 μM NFT improved TEER. However, increasing the concentration of NFT to 20 μM and 40 μM did not exhibit the same dose-dependent effect as NCT (Figure 14, panel (a)). Similarly, the lowest dose of NFT improved % permeability to such an extent that the effect of TNF was almost completely alleviated (Figure 14, panel (b)). As the dose of NFT increased, the variability of % permeability also increased, and no dose-dependent effect was observed.

[0149] When administered in combination, NCT and NFT showed the greatest beneficial effect at 20 μM in reversing TNF-induced TEER changes (Figure 15, panel (a)). The lowest doses (10 μM, 20 μM) provided the greatest benefit on % permeability, while the highest dose (40 μM) did not substantially alter % permeability compared to the control (Figure 15, panel (b)).

[0150] The data presented in this contribution demonstrate that NCT, and to a lesser extent NFT, positively impact intestinal barrier function under conditions of elevated inflammation. This example confirms that NCT and NFT improve markers of intestinal barrier function under conditions of elevated inflammation in vitro. These two bioactive compounds have the potential to have significant impacts on human health. Several preclinical studies, including the data presented in this example, demonstrate the potential for NCT to exert HNF4α-mediated effects on intestinal function. Furthermore, it is well documented that HNF4α exerts appropriate influences on epithelial cell transcriptional activity and the associated transcriptome (Ntunzhenimana et al., 2021). HNF4α is significantly downregulated in patients with ulcerative colitis compared to controls, suggesting a role in pathology (Vancamlbeke et al., 2017). Thus, the case for a role for HNF4α in intestinal inflammation and overall intestinal health is clear. Without wishing to be bound by theory, NCTs and NFTs have the potential to mediate gut health and intestinal barrier integrity via HNF4α. Inclusion of bioactive compounds in dietary recommendations could inform new national standards and dietary guidelines for nutrition and enable a new food-as-medicine paradigm for preventative health.

[0151] Data from this example are further illustrated in Figures 1-12. Compound 1 was determined to be most effective, followed by Compound 2-1 and Compound 2. The optimal test concentration for Compound 1 was determined to be 40 μM, and for Compound 2-1 it was determined to be 20-40 μM. For Compound 2 it was 10-20 μM. Thus, in untreated and 0.1% DMSO transwells, a significant decrease in TEER was observed with increasing addition of TNFα, indicating increased permeability. The addition of N-trans-caffeoyltyramine and N-trans-feruloyltyramine was shown to reverse this decrease in a dose-dependent and statistically significant manner. Significant HNF4α expression was found in colonocytes. Thus, the novel bioactive N-trans-caffeoyltyramine and N-trans-feruloyltyramine demonstrated significant improvement in TEER and decreased intestinal permeability.

[0152] Example 2 This example is a randomized, double-blind, placebo-controlled, parallel study to investigate the effects of compounds described herein on gastrointestinal barrier function.

[0153] Background technology

[0154] HNF4α is a signaling compound known as a nuclear transcription factor involved in regulating metabolism in the liver. It has also been identified in the intestine, pancreas, and kidney, where it performs other functions. HNF4α influences intestinal permeability and is associated with inflammatory bowel disease, although its role remains unclear. HNF4α has been reported to have numerous effects, particularly on the intestinal barrier and intestinal function. Specifically, HNF4α influences mucin production, a key component of the intestinal barrier. It also regulates tight junction protein expression and Paneth cell differentiation. Direct interaction of NCT and NFT with HNF4α makes them potent agonists of HNF4α.

[0155] As described in Example 1, primary intestinal epithelial tissue derived from adult human stem cells was used to assay permeability and transport, cytokine secretion, toxicity, and gene / protein expression. A human stem cell-based in vitro model using human transverse colon epithelial cells was exposed to the inflammatory cytokine TNFα, resulting in increased intestinal permeability and decreased transepithelial electrical resistance (TEER). Co-administration of NCT and NFT demonstrated a dose-dependent and statistically significant recovery of impaired TEER and intestinal permeability. NCT and NFT demonstrated physiologically relevant reversal of impaired intestinal barrier function in inflammation through significant improvements in TEER and percent permeability.

[0156] The safety of NCT / NFT has been evaluated within the matrix of hemp husk fiber components. Based on hemp consumption history, published literature, and unpublished data, the safety of phenolic content, including NCT and NFT, was demonstrated in five studies in male rodents receiving doses of 400–600 mg / kg body weight / day for 10 days to 4 months, and in a human study in which adult males (18–42 years) received 10 mg / day for 7 days. Given the maximum allowable phenol specification of 100 mg GAE / g and that NCT and NFT constitute approximately 4.5% of the phenolic fraction in hemp husk, a cumulative 90th percentile estimated daily intake of 176 mg / d of NCT and NFT from hemp husk fiber for adult males is permitted under GRAS evaluation (Leonard et al., 2021). Hemp husk fiber may contain trace amounts of THC and CBD comparable to the levels reported in the FDA-notified GRAS for the above-mentioned hemp constituents, which the FDA has recognized as not posing safety concerns. One objective of this study is to investigate the effects of a hemp husk extract standardized to contain 10-15% NCTs and NFTs. Based on the safety conclusion reached in the GRAS for hemp husk fiber, it can be reasonably concluded that the dose levels of NCTs and NFTs assessed do not pose safety concerns to study participants.

[0157] the purpose

[0158] The purpose of this clinical trial is to investigate the effects of 6 weeks of supplementation with the compositions described herein on parameters of gastrointestinal (GI) health in otherwise generally healthy adults with risk factors for increased GI permeability. The primary hypothesis is that supplementation with the compositions described herein will reduce small intestinal permeability compared to placebo. Lactulose is a disaccharide that is not normally absorbed by the intestine, whereas the monosaccharide mannitol is. The 2-hour urinary LMR ratio serves as a measure of small intestinal permeability; a higher ratio indicates more lactulose in the urine and therefore greater small intestinal permeability. The study also includes distal GI permeability (2-8 hours), GI microbiome composition profile, bowel habits, safety assessments (blood chemistry / hematology, vital signs, and adverse events), and general GI symptoms, such as gas / flatulence and abdominal bloating, which are commonly associated with increased GI permeability.

[0159] Study design

[0160] It was a randomized, double-blind, placebo-controlled, three-arm parallel design consisting of one screening visit (Visit 1, day -7) and three study visits (days 0, 21, and 42), with two stages including an interim analysis after 50% of study participants had been enrolled.

[0161] Subjects will be instructed to fast (≥10 hours) before arriving at the screening visit on Day -7. Those taking excluded products (Appendix 1) will be instructed to discontinue taking these products, and Visit 1 (Day -7) will be scheduled to allow for an appropriate washout period.

[0162] On Visit 1 (Day -7), subjects arrive at the clinic in a fasting state (≥10 hours). After subjects provide voluntary informed consent, they undergo an inquiry into medical history, previous and current medication / supplement use, assessment of inclusion and exclusion criteria, and last menstrual period, if applicable. Additionally, height, weight, and vital signs are measured, and BMI is calculated. An in-office urine pregnancy test is performed on all female subjects under 60 years of age. Blood samples are collected for chemistry, hematology, and hsCRP analysis.

[0163] Subjects will each be provided with a 3-day food and stool diary, including instructions to record all foods and beverages consumed and information about all bowel movements for 3 consecutive days immediately prior to Visit 2 (Day 0). Subjects will also be provided with a stool collection kit with instructions to collect three separate stool samples from one bowel movement during the same 3-day period in which they completed the food and stool diary. Subjects will also be instructed to maintain their physical activity and habitual diet as much as possible before leaving the study center, while limiting the introduction of novel foods into their habitual diet and foods known to cause GI distress in each individual subject, and to fast from supplements, beverages, or foods containing live probiotics (e.g., yogurt, kombucha) prior to Visit 2 (Day 0). Finally, prior to Visit 2 (Day 0), subjects are reminded to refrain from strenuous exercise, NSAIDs, and alcohol for 48 hours and to fast (≧10 hours, water only).

[0164] At Visit 2 (Day 0), subjects arrive at the clinic in a fasted state (≥10 hours) and undergo the clinic visit procedures (including concomitant medication / supplement use, inclusion / exclusion criteria assessment, weight, vital sign measurements, and last menstrual period query, if applicable), and adverse event (AE) assessment. Subjects are queried regarding compliance with study instructions. Subjects are also randomly assigned to one of three study product sequences. A 3-day food record and bowel diary are collected and reviewed. Three fecal samples are collected, and subjects complete a 7-day GITQ recall. Blood samples are collected for chemistry, hematology, and hsCRP. An additional plasma sample is collected for potential analysis of non-genotypic biomarkers of GI permeability and inflammation. Next, subjects complete a GI permeability test in which they ingest two glucose probes (1 g of 13C-mannitol and 5 g of lactulose) in approximately 240 mL of water. The time of glucose probe consumption is t=0 h. After consuming the glucose probe, subjects will collect all urine for 8 hours in the clinic, collecting one container between 0 and 2 hours and a second container between 2:01 and 8 hours. Urine collection containers will be kept at room temperature throughout the 8-hour collection period, and subjects will have free access to water. A standard snack will be served at t = 2 hours, and a standard dinner will be served at t = 4 hours. Subjects will be instructed to consume the dinner within 30 minutes and eat until comfortably full. Dinner and water intake will be recorded, and subjects will be required to replicate at Visit 4 (Day 42). Study product will be dispensed, the standard snack will be administered, and the first capsule(s) will be consumed in the clinic. An electronic study product log will begin documenting consumption at this visit and will be administered electronically daily throughout the remainder of the study period.

[0165] Prior to departure from the study center, AEs will be assessed and study instructions will be provided, including: 1) maintaining physical activity and habitual diet as much as possible, except for consumption of study products; 2) minimally adding novel foods to the habitual diet and foods known to cause GI distress in the individual subject; and 3) abstaining from live probiotic-containing supplements, beverages, or foods (e.g., yogurt, kombucha) throughout the study. Finally, subjects will be reminded to abstain from strenuous exercise, NSAIDs, and alcohol for 48 hours and to fast (≥10 hours, water only) prior to Visit 3 (Day 21).

[0166] At Visit 3 (Day 21), subjects will arrive at the clinic in a fasted state (≥10 hours) and undergo the clinic visit procedures (including assessment of concomitant medication / supplement use, inclusion / exclusion criteria, weight, vital sign measurements, and (if applicable) last menstrual period query and adverse event (AE) assessment). Subjects will be queried regarding adherence to study instructions. Compliance with study product consumption will be assessed by counting returned, unused tests and reviewing the electronic study product log. The day's study product will be consumed in-clinic, and new study product will be dispensed for the remainder of the study period. Blood samples will be collected for chemistry, hematology, and hsCRP analysis. Subjects will be provided with a blank 3-day dietary record, a copy of the dietary record completed 24 hours prior to Visit 2 to replicate food / drink intake in the 24 hours prior to Visit 4, and a bowel diary with the following instructions: Record information on all bowel movements over 3 consecutive days at Visit 4 (Day 42), including meals and drinks recorded and consumed. Prior to Visit 4 (Day 42), subjects will be provided with a stool collection kit with instructions for collecting three separate stool samples from one bowel movement during the same three-day period in which they completed their food and bowel diary. Prior to departure from the study center, subjects will be provided with study instructions, including: 1) maintaining physical activity and a habitual diet as much as possible, except for consumption of the study product; 2) minimizing the introduction of new foods into their habitual diet and foods known to cause GI distress in the individual subject; and 3) abstaining from live probiotic-containing supplements, beverages, or foods (e.g., yogurt, kombucha) throughout the study. Finally, subjects will be reminded to abstain from strenuous exercise, NSAIDs, and alcohol for 48 hours and to fast (≥10 hours, water only) prior to Visit 4 (Day 42).

[0167] At Visit 4 (Day 42), subjects will arrive at the clinic in a fasted state (≥10 hours) and undergo clinic visit procedures (including assessment of concomitant medication / supplement use, inclusion / exclusion criteria, weight, vital sign measurements, and (if applicable) last menstrual period query and adverse event (AE) assessment). Subjects will be queried regarding compliance with study instructions. A 3-day food record will be collected and reviewed, and the last 24 hours of food and beverage intake will be compared to the 24 hours prior to Visit 2 to ensure consistency. A bowel diary will be collected and reviewed. Three fecal samples will be collected, and subjects will complete a GITQ 7-day recall. Blood samples will be collected for chemistry, hematology, and hsCRP. An additional plasma sample will be collected for potential future analysis of non-genotypic biomarkers of GI permeability and inflammation. Compliance with study product consumption will be assessed by counting returned, unused study product and reviewing the electronic study product log. Subjects will then complete the GI permeability test following the same visit procedures and study instructions described for Visit 2. [Table 3-1] [Table 3-2] [Table 3-3]

[0168] Test sample To participate in this study, each subject must meet all of the following inclusion criteria and none of the exclusion criteria.

[0169] Inclusion criteria for patients

[0170] Male or female, aged 30-69 years at Visit 1 (Day -7). BMI ≥ 29.0 kg / m2 at Visit 1 (Day -7). Abdominal circumference > 102 cm for men or > 88 cm for women, or a family history of at least one first-degree relative with a diagnosed GI disorder associated with increased GI permeability, such as inflammatory bowel disease (Crohn's disease or ulcerative colitis). Non-user or former user (≥ 12 months discontinued) of tobacco or nicotine products (e.g., smoking, e-cigarettes, chewing tobacco) with no plans to initiate use during the study. Non-user or former user (≥ 6 months discontinued) of any marijuana or cannabis products with no plans to initiate use during the study. Willingness to maintain physical activity and exercise patterns, weight, and habitual diet throughout the study. Willingness to abstain from excluded medications, supplements, and products throughout the study. No health conditions that would prevent fulfilling the study requirements as determined by the clinical investigator based on medical history and routine laboratory test results. Understand the study procedures, sign a form providing informed consent to participate in the study, and authorize disclosure of relevant protected health information to the clinical investigator.

[0171] Randomization

[0172] A randomization sequence is prepared. Randomization is 1:1:1 and stratified by hsCRP group. This sequence is uploaded to an eCRF (electronic case report form) platform (Medio Inc, San Francisco, CA). Once a subject is determined to be eligible for the study, a randomization number and associated blinded treatment group are assigned to the subject through the randomization module of the platform. The randomization number is recorded in the subject's source document.

[0173] Test Products

[0174] Placebo treatment: 2 capsules / day, active low dose: 1 capsule / day + 1 placebo capsule / day, and active high dose: 2 capsules / day. Each day for 42 days, subjects are instructed to consume their assigned test product at least 30 minutes before their first meal after waking with water. If the subject misses the test product at that time (i.e., they normally consume it before a meal but forget), they are instructed to consume their assigned test product at least 30 minutes before their next meal (e.g., if they miss breakfast, they should consume the test product at least 30 minutes before dinner). Subjects are instructed not to consume more than 2 capsules / day.

[0175] Blinding

[0176] Subjects and study staff will remain blinded to the study product throughout the study. A set of sealed unblinded envelopes will be provided to the clinical investigator for use in emergency situations where knowledge of allocation is essential for emergency medical treatment of the subject. When unblinding is necessary, the clinical investigator and study staff will open the sealed unblinded envelopes and determine the subject's product allocation.

[0177] The study product blinding code should only be broken in exceptional circumstances, such as when knowledge of the study product is essential to treat the subject for a serious adverse event (SAE).

[0178] If it is necessary to unblind the subject's randomization sequence, the clinical investigator or other representative will be contacted immediately. Whenever possible, this should occur prior to such unblinding. The sponsor will also be notified if unblinding is required.

[0179] Documentation of the unblinding will be done in the source documents indicating the reason for unblinding and the date and time when unblinding occurred.

[0180] Clinic visit procedure

[0181] Clinic visit procedures (Visits 1, 2, 3, and 4; Days -7, 0, 21, and 42) included measurements of height (Visit 1 only), vital signs (resting blood pressure and heart rate), and weight, BMI calculation (Visit 1 only), assessment of inclusion and exclusion criteria, concomitant medication / supplement use, and last menstrual period query (if applicable).

[0182] Standardized vital sign measurements assessed at each clinic visit include resting blood pressure and heart rate, measured using an automated blood pressure device with an appropriate size cuff (the bladder in the cuff should encircle at least 80% of the arm) obtained after the subject has been sitting quietly for at least 5 minutes. Three measurements are taken approximately 3 minutes apart (e.g., at 0, 3, and 6 minutes), the last two measurements are averaged, and the first measurement is discarded. If an elevated blood pressure occurs at the screening visit (Visit 1, Day -7), the subject will be recorded as a failed screen and will not be allowed to be retested.

[0183] Clinical laboratory measurements

[0184] All clinical laboratory measurement procedures are outlined in the laboratory order document. Missing or not obtained laboratory parameters should be entered as "not performed" on the eCRF.

[0185] An in-office urine pregnancy test will be performed on all women under 60 years of age at Visit 1 (Day -7).

[0186] At Visits 1, 3, and 4 (Days -7, 21, and 42), the following will be performed:

[0187] Fasting Chemistry Profile: Albumin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, calcium, chloride, creatinine, blood urea nitrogen, potassium, sodium, total protein, carbon dioxide, osmolality, and glucose, measured by Elmhurst Memorial Reference Laboratory (Elmurst, IL). Fasting Hematology: White blood cell count, red blood cell count, hemoglobin concentration, hematocrit (as volume percent), mean red blood cell volume, mean red blood cell hemoglobin concentration, neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet count, measured by Elmhurst Memorial Reference Laboratory (Elmurst, IL).

[0188] Fasting hsCRP is measured by Elmhurst Memorial Reference Laboratory (Elmurst, IL).

[0189] At Visits 2 and 4 (Days 0 and 42), the following will be performed: GI permeability will be assessed using a disaccharide probe procedure. Two pooled urine samples (0-2 h and 2:01-8 h) will be collected over an 8-h period for subsequent analysis at The Mayo Clinic (Rochester, MN) Immunochemical Core Lab. Biofortis will measure total urine volume during the 0-2 h and 2:01-8 h collection intervals and provide records of urine volume and aliquots to the central laboratory. Urine sugars will be analyzed using established procedures at the core laboratory. Fecal samples will be stored at -80°C in Biofortis DNA Genotek OMNIgene® Gut tubes for future evaluation of microbiome composition (i.e., taxonomic profile) and / or functional profile at designated laboratories. Briefly, genomic DNA will be extracted using an appropriately optimized high-throughput fecal extraction method. DNA will then be quantified and stored at the appropriate temperature until genomic library preparation can begin. The genomic library is then sequenced on an appropriate platform, and the sequencing data is used for bioinformatics analysis to determine corresponding alpha- and beta-diversity metrics, facilitating bacterial / archaeal phylogenetic classification. Functional bioinformatics analysis may include metabolic pathways and related approaches. Two fecal samples (approximately 100 g each) are stored at -80°C in Biofortis for possible future analysis of non-genotypic biomarkers of GI permeability (e.g., calprotein, secreted IgA).

[0190] Six plasma samples (approximately 0.5 mL each) are stored at -80°C in Biofortis for possible future analysis (and back-up samples) of non-genetic biomarkers of GI permeability (eg, I-FABP, LBP, etc.).

[0191] Two plasma samples (approximately 0.5 mL each) will be stored at -80°C in Biofortis for possible future analysis (and backup samples) of non-genetic biomarkers of inflammation (e.g., TNF-α, IL-6, IL-1β, etc.).

[0192] Test Orders / Queries

[0193] Prior to Visit 1 (Day -7), subjects are instructed to abstain from exercise and alcohol (24 hours) and to fast (≥10 hours, water only).

[0194] At Visit 1 (Day -7), subjects are instructed to maintain physical activity and a habitual diet as much as possible while limiting the introduction of new foods to their habitual diet and foods known to cause GI distress in the individual, and fasting from supplements, beverages, or foods containing live probiotics (e.g., yogurt, kombucha) prior to Visit 2 (Day 0). Subjects are also reminded to abstain from strenuous exercise, NSAIDs, and alcohol for 48 hours and to fast (≥10 hours, water only) prior to Visit 2 (Day 0).

[0195] At Visit 2 (Day 0), subjects are instructed to maintain physical activity and their usual diet as much as possible, while limiting the introduction of new foods into their usual diet and foods known to cause GI problems in each individual subject. Subjects are also instructed to refrain from supplements, beverages, and foods containing live probiotics (e.g., yogurt, kombucha) for the duration of the study intervention. Prior to Visit 3 (Day 21), subjects are instructed to abstain from exercise and alcohol for the next 24 hours (24 hours).

[0196] At Visit 3 (Day 21), subjects were instructed to maintain their physical activity and habitual diet as much as possible, while limiting the introduction of new foods into their habitual diet and foods known to cause GI distress in each individual subject. Subjects were also instructed to refrain from supplements, beverages, and foods containing live probiotics (e.g., yogurt, kombucha) during the study intervention period. Subjects were also instructed to abstain from exercise and alcohol for the next 24 hours before Visit 4 (Day 42).

[0197] Enquiries regarding compliance with these instructions will be carried out at each visit.

[0198] 3-day food record

[0199] Subjects will be provided with a blank 3-day food log at Visits 1 and 3 (Days -7 and 21), and will complete a record of all food and beverage consumption for 3 consecutive days immediately prior to Visits 2 and 4 (Days 0 and 42), respectively. Food logs will be analyzed using Food Processor® Nutrition Analysis and Fitness Software (version 10.4 or later, Salem, OR) to assess the subject's habitual diet. At Visit 3, subjects will also be provided with a copy of the food log completed 24 hours prior to Visit 2 to reconstruct their food / beverage intake for the 24 hours prior to Visit 4. These two 24-hour food logs (i.e., the day before Visits 2 and 4) will be compared to ensure dietary consistency at baseline and at the end of the study.

[0200] The bowel diary (Appendix 4) provides information on the frequency and consistency of bowel movements, straining and discomfort during bowel movements, and any sensations of incomplete evacuation. The bowel diary will be distributed at Visits 1 and 3 (Days -7 and 21) and completed for 3 consecutive days, concurrently with the 3-day food record and fecal sample collection prior to Visits 2 and 4 (Days 0 and 42), respectively.

[0201] The Gastrointestinal Tolerance Questionnaire (GITQ) contains a series of questions regarding the presence and severity of GI symptoms that have occurred over the past 7 days. Individual components include the severity of gas / flatulence, nausea, vomiting, abdominal cramps, abdominal bloating / distention, abdominal pain / borborygmus, belching, and / or reflux (heartburn), which are rated on a 4-point scale ranging from none to severe. Subjects complete the GITQ at Visit 2 (Day 0) and Visit 4 (Day 42) prior to the start of the GI permeability study.

[0202] Instruct subjects to collect three fecal samples, one from one bowel movement over a three-day period, immediately prior to Visits 2 and 4 (Days 0 and 42), according to the instructions provided.

[0203] The date and time the specimen was collected will be recorded on the eCRF.

[0204] Lactulose / mannitol GI permeability test

[0205] At Visit 2 (Day 0) and Visit 4 (Day 42), after an overnight fast (≥10 hours) and 48 hours of abstinence from strenuous exercise, NSAIDs, and alcohol, subjects are instructed to completely empty their bladders. Next, subjects ingest two glucose probes (1 g of 13C-mannitol and 5 g of lactulose) in approximately 240 mL of water. At t = 0 hours after complete consumption of the glucose probes, subjects are to collect all urine in one container between hours 0 and 2 and two hours between hours 2:01 and 2:08 in a second container. Urine collection containers are kept at room temperature throughout the 8-hour collection period, and subjects are given free access to water. Female subjects who are menstruating at the time of urine sample collection are asked to wear a tampon during collection to minimize sample contamination with blood. A standard dinner is served at t = 4 hours. Subjects are instructed to consume the dinner within 30 minutes and eat until comfortably full. Dinner and water intake will be recorded and subjects will be required to replicate at Visit 4 (Day 42).

[0206] Procedures for each clinical visit

[0207] The steps listed are not necessarily performed in the order presented below.

[0208] Screening (Visit 1, Day -7) Obtain informed consent / HIPAA. Collect medical history. Conduct clinic visit procedures: Review previous and current medication / supplement use, assess inclusion and exclusion criteria, measure height, measure weight, measure vital signs, calculate BMI, query last menstrual period, and, if applicable, perform an in-clinic urine pregnancy test. If applicable, draw blood for a complete chemistry panel, draw blood for a complete hematology profile, draw blood for hsCRP, distribute a 3-day food record, distribute a stool collection kit, distribute a bowel habit diary, and provide study instructions: maintain physical activity, maintain a habitual diet as much as possible, with the following exceptions: minimize the introduction of new foods into the habitual diet and minimize foods known to cause GI distress in the individual subject throughout the study, and refrain from pre- and probiotic supplements, as well as live probiotics (e.g., yogurt, kombucha), and any foods or beverages, including dietary fiber supplements. Prior to Visit 2, refrain from strenuous exercise, NSAIDs, and alcohol (48 hours), fast (≥10 hours), and consume only water.

[0209] Study visit (visit 2; day 0) Perform clinic visit procedures: review previous and current medication / supplement use, review inclusion and exclusion criteria for protocol deviations, measure weight, measure vital signs, query last menstrual period if applicable, query compliance with study instructions, randomization, collect and review 3-day food records, collect bowel diaries, collect 3 stool samples for potential analysis of GI microbiome and GI permeability biomarkers, draw plasma samples for potential analysis of GI permeability and inflammatory biomarkers, administer 7-day recall GITQ, perform 2-sugar probe GI permeability test and collect 8-hour urine in-clinic, administer standard dinner at t=4 hours, administer standard snacks at t=2 hours and 8 hours, dispense study product and have subject consume that day's study product at clinic, administer electronic study product log and record study product consumption for that day, assess AEs (beginning and end of visit). Provide study instructions: maintain physical activity. Maintain habitual diet whenever possible, except for study product consumption. Minimize the introduction of new foods into the habitual diet and foods known to cause GI distress in each individual subject throughout the study. Avoid prebiotic and probiotic supplements, as well as foods or beverages containing live probiotics (e.g., yogurt, kombucha), and dietary fiber supplements. Avoid consumption of foods or beverages containing the sugar probe used in the intestinal permeability test for 24 hours. Avoid strenuous exercise, NSAIDs, and alcohol (48 hours) prior to Visit 3 (Day 21).

[0210] Study visit (visit 3; day 21) Perform clinic visit procedures: review past and current medication / supplement use, review inclusion and exclusion criteria for protocol deviations, measure weight, measure vital signs, query last menstrual period (if applicable), query compliance with study instructions, draw blood for complete chemistry panel, draw blood for complete hematology profile, draw blood for hsCRP, distribute blank 3-day food record and copy of 24-hour food record from the day prior to Visit 2 for duplication 24 hours prior to Visit 4, distribute stool collection kits, bowel diary, collect unused study product and assess compliance, review electronic study product log, distribute new study product and provide subject with that day's study product The study included: consuming all test products in-house; maintaining an electronic test product log to record the amount of test product consumed that day; assessing for AEs; providing study instructions: maintaining physical activity; maintaining a habitual diet as much as possible, except for the following: consumption of test products; minimizing the introduction of new foods into the habitual diet as well as foods known to cause gastrointestinal distress in the individual subject during the study; abstaining from pre- and probiotic supplements, foods or beverages containing live probiotics (e.g., yogurt, kombucha), and dietary fiber supplements; not consuming foods or beverages containing the sugar probe used in the intestinal permeability test for 24 hours; and abstaining from strenuous exercise, nonsteroidal anti-inflammatory drugs, and alcohol (48 hours) prior to Visit 4 (Day 42).

[0211] Study visit (visit 4; day 42) Perform clinic visit procedures: verify previous and current medication / supplement use, verify inclusion and exclusion criteria for protocol deviations, measure weight, measure vital signs, query last menstrual period (if applicable), query adherence to study instructions, draw blood for complete chemistry panel, draw blood for complete hematology profile, draw blood for hsCRP, draw blood for plasma sample for potential analysis of GI permeability and biomarkers of inflammation, collect and review 3-day food record, collect bowel diary, collect 3 fecal samples for potential analysis of GI microbiome and biomarkers of GI permeability, retrieve unused study product and assess compliance, administer 7-day recall GITQ, perform 2-sugar probe GI permeability test, collect 8-hour urine in clinic, administer standard dose dinner at t=4 hours, standard snacks at t=2 hours and 8 hours, assess AEs (beginning and end of visit).

[0212] Data Analysis and Statistical Methods

[0213] Difference between placebo and active treatment in 0-2 hour urinary 13C-mannitol excretion from baseline to day 42.

[0214] Secondary endpoint variables

[0215] Measure the difference in 2-8 hour urinary 13C-mannitol between placebo and active treatment from baseline to day 42. Measure the difference in 0-2 hour urinary LMR between placebo and active treatment from baseline to day 42. Measure the difference in 2-8 hour urinary LMR between placebo and active treatment from baseline to day 42. Measure the difference in biomarkers of GI permeability between placebo and active treatment from baseline to day 42: Measure blood biomarkers: I-FABP, LBP, soluble CD14, fecal biomarkers, calprotein, and secretory IgA. Measure the difference in blood biomarkers of inflammation: CRP, IL-6, IL-1β, and TNF-α between placebo and active treatment. Measure the difference in 7-day recall GI symptoms between placebo and active treatment from baseline to day 42. We will measure GITQ composite score (sum of all 8 individual scores), individual symptom GITQ scores, differences between placebo and active treatment, and differences in bowel function, defecation frequency, and stool consistency (Bristol Stool Scale). We will measure differences in taxonomic profile of fecal microbiota (e.g., within-intervention alpha diversity, within-subject alpha diversity, within-intervention beta diversity, Bray-Curtis dissimilarity, relative change in taxa) and metagenomics-informed metabolic or functional profile between placebo and active treatment from baseline to day 42. We will assess safety profile, chemistry panel, hematology profile, vital signs, weight, and incidence of AEs.

[0216] Sample Size

[0217] Previous studies using dietary interventions to modulate intestinal permeability have focused on changes in LMR. However, changes in lactulose are negligible and are therefore thought to be driven by the excretion of 13C-mannitol. Therefore, the primary comparison of interest is 13C-mannitol at 0 to 2 hours. While data on clinically meaningful differences in 13C-mannitol excretion are limited, responses are expected to be similar to LMR. Assuming a common standard deviation (SD) of approximately 0.008 for LMR, a reduction of approximately 35.0% from a control LMR ratio of 0.020 would result in an effect size of approximately 0.86. With a desired statistical power of 90% and using a 1:1 allocation in a three-arm parallel study, a sample size of 105 subjects (n = 35 per group) is sufficient to detect an estimated effect size using a two-sided t-test with an α = 0.025 (comparing each active group to placebo) with adjustment for multiple comparisons. To account for approximately 20% attrition, the sample size is increased to N=126 (n=42 per group).

[0218] statistical analysis

[0219] Details of the statistical analysis for this study are described in the statistical analysis plan. Briefly, all statistical analyses will be performed using SAS for Windows (version 9.4 or later, Cary, NC) and / or R 3.3.1 (R Core Team 2016). Analysis populations include intention-to-treat (ITT, all subjects randomized in the study who provide at least one outcome data point) and per protocol (PP, all subjects who compliantly completed the study). The ITT population will serve as the primary analysis population. Subjects may be excluded from the PP population due to noncompliance, including, but not limited to, missed appointments, use of prohibited substances or products believed to alter the primary outcome variable during the study, adherence to study product intake less than 80% or more than 120%, and non-adherence to instructions outlined in the protocol. All decisions regarding subject populations and data inclusion will be documented prior to database lock.

[0220] Baseline characteristics

[0221] Descriptive statistics [number of subjects, mean, standard deviation (SD), median, interquartile limits, minimum and maximum values ​​or frequency counts] will be presented for subject demographics and anthropometric measurements collected at screening / baseline for all analysis populations.

[0222] Outcome analysis

[0223] Descriptive statistics (i.e., number of subjects, minimum and maximum values, median, interquartile limits, mean, and standard deviation) are presented for all continuous outcomes for each study group. Unless otherwise indicated, all tests of significance are performed two-sided, with α=0.05.

[0224] Continuous outcomes measured at baseline and Day 42 are analyzed using an analysis of covariance (ANCOVA) approach. Note that treatment effect estimates are computationally identical to analyses utilizing change scores as response variables adjusted for baseline, intervention group, and stratification factors. However, if necessary, the Day 42 response variable is selected to allow for easier variance-stabilizing transformations. The model includes terms for baseline 0-2-h urinary LMR, intervention group, and the stratification factor hsCRP group. For each model, residuals are analyzed visually (QQ plots, residual plots) to verify that model assumptions (normality, constant variance, homogeneity) are met. Transformations (i.e., logarithms) may be considered if necessary. Model-derived pairwise comparisons between each active treatment group and placebo are estimated using least-squares means and tested for significance using t-tests. Model-derived mean estimates at Day 42 and corresponding 97.5% confidence intervals are estimated for each group.

[0225] Response profiles for continuous outcomes (fecal frequency, BSS, and hsCRP) measured at baseline, day 21, and day 42 will be analyzed using a repeated measures model. The model includes fixed effects for time point, intervention group, time point by intervention group interaction, and the stratification factor hsCRP group. Changes from baseline to each follow-up time point will be assessed for each safety measure, including chemistry and hematology panels. Differences within and between groups will be assessed using Wilcoxon signed-rank and rank-sum tests, respectively. Additional analytical details are specific to the statistical analysis plan (SAP) developed for this protocol.

[0226] clinical surveillance A start-up meeting will be held. Appropriate aspects of the protocol, eCRF, and GCP will be reviewed with the investigator and all study staff at this meeting. Remote and on-site monitoring visits will be conducted during the study, focusing on the study's human participant protection and data integrity risks. A clinical monitoring plan will be developed that identifies specific risk-based monitoring focuses. These may include informed consent, eligibility criteria, SAEs, serious protocol violations, endpoints, study article administration, and accountability.

[0227] The invention is, however, susceptible to modifications and alternative constructions from those discussed above that are fully equivalent. Consequently, the invention is not limited to the particular embodiments disclosed. On the contrary, the invention encompasses all modifications and alternative constructions that are within the spirit and scope of the invention as generally expressed by the following claims, which particularly point out and distinctly claim the subject matter of the invention. While the present disclosure has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive.

[0228] All references cited herein are incorporated by reference in their entirety. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or override any such conflicting material.

[0229] Unless otherwise defined, all terms (including technical and scientific terms) should be given their ordinary and customary meaning to those of ordinary skill in the art and are not limited to any special or particular meaning defined herein unless expressly so specified. It should be noted that the use of a particular term in describing a particular feature or aspect of the present disclosure should not be construed as limiting the term to be redefined herein to include the specific characteristics of any feature or aspect of the present disclosure with which the term is associated. Terms and phrases used in this application, and variations thereof, particularly as used in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example of the foregoing, the word "comprising" should be construed to mean "including, without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps; the term "having" should be interpreted as "having at least," and the term "including" should be interpreted as "including but not limited to." The term "examples" is used to provide illustrative examples of the items being discussed, not an exhaustive or limiting list thereof; adjectives such as "known," "conventional," "standard," and terms of similar import should not be interpreted to limit the described items to items available in or at a given period, but instead should be read to encompass known, conventional, or standard technology that may be available or known at any time now or in the future.Additionally, the use of terms such as "preferably," "preferred," "desired," or "desirable," and words of similar import, is merely intended to highlight that a particular feature is not critical, essential, or even important to the structure or function of the invention, but rather, to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Similarly, a group of items joined by the conjunction "and" should not be read as requiring each of those items to be present in that grouping, but should be read as "and / or" unless expressly stated otherwise. Similarly, a group of items joined by the conjunction "or" should not be read as requiring mutual exclusivity among the group, but should be read as "and / or" unless expressly stated otherwise.

[0230] When a range of values ​​is provided, it is understood that the upper and lower limits, and every intervening value between the upper and lower limits of the range, are encompassed within an embodiment.

[0231] With regard to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate to the context and / or application. For clarity, various singular / plural permutations may be expressly set forth herein. The indefinite article "a" or "an" does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0232] Where a particular number of introduced claim recitations is intended, such intent will be explicitly stated in the claim, and those skilled in the art will further understand that the absence of such a statement does not mean that such intent is not presented. For example, as an aid to understanding, the following claims may include the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed as implying that introducing a claim recitation with the indefinite article "a" or "an" limits any particular recitation containing such introduced claim recitation to an invention containing only one such recitation, even when that same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should generally be interpreted to mean "at least one" or "one or more"); the same applies to the use of definite articles used to introduce claim recitations. Additionally, where a specific number of recitations in a claim is explicitly recited, those skilled in the art will understand that such recitation should be interpreted to mean at least the recited number (e.g., a minimum recitation of "two recitations" without other modifiers generally means at least two recitations, or more than two recitations). Furthermore, where a convention similar to "at least one of A, B, and C, etc." is applied, such construction is generally intended in the sense that those skilled in the art understand the convention (e.g., "a system having at least one of A, B, and C" can mean, without limitation, A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a convention similar to "at least one of A, B, and C, etc." is applied, such construction is generally intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" can mean, without limitation, A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.).Those skilled in the art will further appreciate that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0233] All numbers expressing quantities of ingredients, reaction conditions, and so forth used herein should be understood to be modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations and may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims of any application claiming priority to this application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0234] Moreover, although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the descriptions and examples should not be construed as limiting the scope of the invention to the specific embodiments and examples described herein, but should also be construed to embrace all modifications and alternatives that come within the true scope and spirit of the invention.

Claims

1. A composition for treating or improving a disease or condition related to intestinal permeability, improving intestinal permeability, or improving intestinal barrier function, The composition comprises at least one carrier, N-trans-caffeoyltyramine or a pharmaceutically acceptable salt thereof, and N-trans-feruloyltyramine or a pharmaceutically acceptable salt thereof. A composition in which N-trans-caffeioyltyramine and N-trans-feruloyltyramine are in a ratio of 10:1 to 1:

10.

2. The composition according to claim 1, wherein the composition is formulated as a nutritional supplement, a food ingredient or additive, a food, a medical food, a nutritional supplement composition, or a pharmaceutical composition.

3. The composition according to claim 1 or 2, which is a unit dosage form and is intended for administering 0.1 to 100 mg / kg of the target's body weight per single dose.

4. The composition according to claim 1 or 2, wherein the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:

5.

5. The composition according to claim 4, wherein the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.5:1 to about 2:

1.

6. The composition according to claim 4, wherein the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is about 2.2:

1.

7. The composition according to claim 1, wherein the disease or condition related to intestinal permeability in the subject is related to impaired gastrointestinal epithelial cell barrier function.

8. The composition according to claim 7, wherein the gastrointestinal epithelial cell barrier dysfunction is a disease related to a decrease in the integrity of the intestinal epithelium.

9. The composition according to claim 8, wherein the gastrointestinal epithelial cell barrier dysfunction is selected from the group consisting of inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, irritable bowel syndrome, intestinal infection, Clostridium difficile infection, metabolic disease, obesity, type 2 diabetes, metabolic dysfunction-related steatohepatitis, non-alcoholic fatty liver disease, liver damage, alcoholic steatohepatitis, celiac disease, necrotizing enterocolitis, gastrointestinal disorders, short bowel syndrome, stomatitis, chemotherapy-induced mucositis, radiation-induced mucositis, oral mucositis, interstitial cystitis, neurological disorders, cognitive impairment, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, chemotherapy-related steatohepatitis (CASH), and pediatric versions of the aforementioned diseases.

10. A food for improving impaired intestinal barrier function, A food product in the form of a food bar, puff product, bakery product, pressed cake, cooked product, cereal, crispy, or spread, comprising 0.01 to 20% (w / w) N-trans-caffeoyltyramine and 0.01 to 20% (w / w) N-trans-feruloyltyramine, wherein the ratio of N-trans-caffeoyltyramine to N-trans-feruloyltyramine is 10:1 to 1:

10.

11. The food according to claim 10, wherein the ratio of N-trans-caffeioyltyramine to N-trans-feruloyltyramine is about 5:1 to about 1:

5.

12. The food according to claim 11, wherein the ratio of N-trans-caffeioyltyramine and N-trans-feruloyltyramine is about 2.5:1 to about 2:

1.

13. The food according to claim 10 or 11, comprising at least 10% fiber.

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