COMPOSITION FOR USE IN THE PREVENTION AND/OR TREATMENT OF DYSBIOSIS

Abstract

A nutraceutical composition including one or more sources of fiber, glutamine, one or more probiotics, one or more sources of omega-3, and one or more antioxidants, for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota. Also, a method for preventing and/or treating dysbiosis including a step of administering the nutraceutical composition to a patient in need thereof. Further, a three-part kit for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

Claims

1-10. (canceled)

11. Nutraceutical or pharmaceutical composition comprising: a. one or more sources of dietary fibers, b. glutamine, c. one or more probiotics, d. one or more sources of omega-3, and e. one or more antioxidants, for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

12. The composition according to claim 11, wherein the source(s) of dietary fibers are selected from sources of vegetable fibers, preferably are selected from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds.

13. The composition according to claim 11, wherein the probiotic(s) are selected from lactic acid bacteria, preferably are selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof, and more preferably are selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof.

14. The composition according to claim 11, wherein the source(s) of omega-3 are selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds, and preferably are selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds.

15. The composition according to claim 11, wherein the antioxidant(s) are selected from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably are selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds.

16. The composition according to claim 11, said composition being in three parts, a first part comprising the source(s) of dietary fibers and glutamine, a second part comprising the probiotic(s), a third comprising the source(s) of omega-3, the antioxidant(s) being included in the first part of the composition and/or in the third part of the composition, preferably included in the first part and in the third part of the composition.

17. The composition according to claim 16, wherein the first part of the composition has a total content of sources of fibers ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition.

18. The composition according to claim 16, wherein the first part of the composition has a total content of glutamine ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition.

19. The composition according to claim 16, wherein the third part of the composition has a total content of sources of omega-3 ranging from 10 to 50% by weight, preferably ranging from 20 to 40% by weight, relative to the total weight of the third part of the composition.

20. The composition according to claim 11, wherein the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome (IBS), type I diabetes, type II diabetes, obesity, non-alcoholic fatty liver disease (NAFLD) and Crohn's disease, preferably associated with Irritable Bowel Syndrome (IBS), type I diabetes, type II diabetes, obesity and non-alcoholic fatty liver disease (NAFLD), and more preferably associated with Irritable Bowel Syndrome (IBS).

21. A method of preventing and/or treating dysbiosis of the intestinal microbiota in a patient comprising administering the nutraceutical or pharmaceutical composition according to claim 11 to a patient in need thereof.

22. The method according to claim 21, wherein the source(s) of dietary fibers of the nutraceutical or pharmaceutical composition are selected from sources of vegetable fibers, preferably are selected from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds.

23. The method according to claim 21, wherein the probiotic(s) of the nutraceutical or pharmaceutical composition are selected from lactic acid bacteria, preferably are selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof, and more preferably are selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof.

24. The method according to claim 21, wherein the source(s) of omega-3 of the nutraceutical or pharmaceutical composition are selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds, and preferably are selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds.

25. The method according to claim 21, wherein the antioxidant(s) of the nutraceutical or pharmaceutical composition are selected from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably are selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds.

26. The method according to claim 21, said nutraceutical or pharmaceutical composition being in three parts, a first part comprising the source(s) of dietary fibers and glutamine, a second part comprising the probiotic(s), a third comprising the source(s) of omega-3, the antioxidant(s) being included in the first part of the nutraceutical or pharmaceutical composition and/or in the third part of the nutraceutical or pharmaceutical composition, preferably included in the first part and in the third part of the nutraceutical or pharmaceutical composition.

27. The method according to claim 26, wherein the first part of the nutraceutical or pharmaceutical composition has a total content of sources of fibers ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to the total weight of the first part of the nutraceutical or pharmaceutical composition.

28. The method according to claim 26, wherein the first part of the nutraceutical or pharmaceutical composition has a total content of glutamine ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to the total weight of the first part of the nutraceutical or pharmaceutical composition.

29. The method according to claim 26, wherein the third part of the nutraceutical or pharmaceutical composition has a total content of sources of omega-3 ranging from 10 to 50% by weight, preferably ranging from 20 to 40% by weight, relative to the total weight of the third part of the nutraceutical or pharmaceutical composition.

30. The method according to claim 21, wherein the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome (IBS), type I diabetes, type II diabetes, obesity, non-alcoholic fatty liver disease (NAFLD) and Crohn's disease, preferably associated with Irritable Bowel Syndrome (IBS), type I diabetes, type II diabetes, obesity and non-alcoholic fatty liver disease (NAFLD), and more preferably associated with Irritable Bowel Syndrome (IBS).

Description

DETAILED DESCRIPTION

[0061] The invention relates to a nutraceutical or pharmaceutical composition comprising: [0062] a. one or more sources of dietary fibers, [0063] b. glutamine, [0064] c. one or more probiotics, [0065] d. one or more sources of omega-3, and [0066] e. one or more antioxidants, [0067] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0068] The Applicant has found out that the composition according to the invention makes it possible to prevent and/or treat dysbiosis of the intestinal microbiota.

[0069] By acting on the four axes identified in parallel: [0070] increase in bacterial diversity, [0071] decrease in intestinal permeability, [0072] reduction of oxidative stress, and [0073] decrease in low-grade inflammation, [0074] the composition according to the invention makes it possible to restore the symbiosis of the intestinal microbiota and the body.

[0075] Sources of Dietary Fibers

[0076] The composition according to the invention comprises one or more sources of dietary fiber. In one embodiment according to the invention, the dietary fibers serve as the primary substrate of the microbial trophic chain. They constitute thereby an ingredient of choice for opening up ecological niches and enabling a great diversity of microorganisms suitable for hydrolyzing various complex polysaccharide structures to become dominant.

[0077] In one embodiment, the sources of dietary fibers are selected from sources of vegetable fibers.

[0078] In one embodiment, the sources of dietary fibers are selected from sources of soluble dietary fibers.

[0079] In one embodiment, the sources of dietary fibers are selected from sources of insoluble dietary fiber.

[0080] In one embodiment, the sources of dietary fibers are selected from sources of celluloses, hemicellulose, starch, pectins, beta-glucans, and a mixture of these compounds.

[0081] In one embodiment, the sources of fibers can be selected from fruits, vegetables, legumes, cereals or a mixture of these sources.

[0082] In one embodiment, the fruits are selected from almonds, currants, prunes, walnuts, bananas and a mixture of these sources.

[0083] In one embodiment, the vegetables are selected from artichokes, carrots, potatoes, green cabbages, cauliflowers, and a mixture of these sources.

[0084] In one embodiment, the legumes are selected from white beans, split peas, chickpeas, lentils, peas, and a mixture of these sources.

[0085] In one embodiment, the cereals are selected from wheat bran, oat bran, oatmeal, rice, and a mixture of these sources.

[0086] In one embodiment, the sources of dietary fibers that can be used according to the invention are directly dietary fibers as defined above.

[0087] Thus, in one embodiment, the sources of dietary fibers are chosen from celluloses, hemicelluloses, starches, pectins, beta-glucans, and a mixture of these compounds.

[0088] In one embodiment, the sources of dietary fibers are celluloses.

[0089] In one embodiment, the sources of dietary fibers are hemicelluloses.

[0090] In one embodiment, the sources of dietary fibers are starches. In one embodiment, the sources of dietary fibers are resistant starches.

[0091] In one embodiment, the sources of dietary fibers are pectins.

[0092] In one embodiment, the sources of dietary fibers are beta-glucans.

[0093] In one embodiment, the sources of dietary fibers are a mixture of celluloses, pectins, and beta-glucans.

[0094] In one embodiment, the sources of dietary fibers comprise at least 3 g of fibers per 100 g of sources of dietary fibers.

[0095] In one embodiment, the sources of dietary fibers comprise at least 6 g of fibers per 100 g of sources of dietary fibers.

[0096] In one embodiment, the sources of dietary fibers are directly dietary fibers and comprise 100 g of fibers per 100 g of dietary fibers sources.

[0097] Glutamine

[0098] The composition according to the invention comprises glutamine. In one embodiment, the term “glutamine” denotes the amino acid of formula:

##STR00002##

i.e., L or S(+)-glutamine.

[0099] In one embodiment, glutamine helps maintain and/or restore the intestinal barrier. Indeed, dysbiosis can result in hyperpermeability of the intestinal wall.

[0100] In one embodiment, glutamine is an energy source for intestinal epithelial cells.

[0101] Glutamine is commercially available in different pack sizes and in different amounts.

[0102] Probiotics

[0103] The composition according to the invention comprises one or more probiotics. In one embodiment, the probiotics help reduce inflammation. In one embodiment, the probiotics help restore intestinal permeability. In one embodiment, the probiotics have an action on the composition of the microbiota. In one embodiment, the probiotics increase the diversity of the composition of the microbiota.

[0104] In one embodiment, the probiotic(s) are selected from lactic acid bacteria.

[0105] In one embodiment, the probiotic(s) are selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof.

[0106] In one embodiment, the probiotic(s) of the composition according to the invention are selected from Lactobacillus rhamnosus, preferably Lactobacillus rhamnosus GG, Lactobacillus plantarum, preferably Lactobacillus plantarum LP01, Bifidobacterium breve, preferably Bifidobacterium breve BR03, and a mixture of these probiotics.

[0107] In one embodiment, the probiotic(s) of the composition according to the invention are the mixture consisting of Lactobacillus rhamnosus GG, Lactobacillus plantarum LP01 and Bifidobacterium breve BR03. Advantageously, this mixture of probiotics is present in the composition according to the invention in an amount of 5 billion CFU (daily amount), all strains of probiotics included. For example, if each strain is dosed at 100 billion CFU per gram, the composition includes 50 mg of probiotics comprising the three strains of probiotics.

[0108] In one embodiment, the probiotic of the composition according to the invention is Lactobacillus rhamnosus, preferably Lactobacillus rhamnosus GG.

[0109] In one embodiment, the number of colony-forming unit (or “CFU”) of probiotics is greater than or equal to 10.sup.6 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 5.10.sup.6 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 10.sup.7 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 5.10.sup.7 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 10.sup.8 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 5.10.sup.8 cells per gram of probiotics. In one embodiment, the number of colony-forming units of probiotics is greater than or equal to 10.sup.9 cells per gram of probiotics.

[0110] In one embodiment, the number of colony-forming units of probiotic is between 10.sup.6 and 10.sup.10 cells per gram of probiotics.

[0111] Omega-3 Sources

[0112] The composition according to the invention comprises one or more sources of omega-3. In one embodiment, the omega-3 help reduce inflammation. In one embodiment, the omega-3 help restore intestinal permeability. In one embodiment, the omega-3 have an action on the composition of the microbiota. In one embodiment, the omega-3 increase the compositional diversity of the microbiota.

[0113] In one embodiment, the source(s) of omega-3 is selected from fish oils such as salmon, halibut, herring, anchovies and sardines.

[0114] In one embodiment, the source(s) of omega-3 are selected from vegetable oils such as vegetable oils obtained from flax seeds, chia seeds, and hemp seeds, rapeseed oil and walnut oil.

[0115] In one embodiment, the source(s) of omega-3 are selected from algae.

[0116] In one embodiment, the source(s) of omega-3 are directly omega-3.

[0117] In one embodiment, the source (s) of omega-3 are selected from omega-3 polyunsaturated fatty acids comprising 18, 19, 20, 21, 22, 23, 24 or 25 carbon atoms, preferably 21, 22 or 23 carbon atoms.

[0118] In one embodiment, the source or sources of omega-3 are selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds.

[0119] In one embodiment, the source(s) of omega-3 are selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds.

[0120] Antioxidants

[0121] The composition according to the invention also comprises one or more antioxidants. In one embodiment, the antioxidant(s) decrease inflammation. In one embodiment, the antioxidant(s) reduce oxidative stress. In one embodiment, the antioxidant(s) reduce inflammation and oxidative stress. In one embodiment, the antioxidant(s) contribute to the restoration of intestinal permeability. In one embodiment, the antioxidant(s) have an action on the composition of the microbiota. In one embodiment, the antioxidant(s) increase the diversity of the composition of the microbiota.

[0122] In one embodiment, the antioxidant(s) are selected from curcuminoids such as curcumin, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds.

[0123] In one embodiment, the antioxidant(s) are selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds

[0124] In one embodiment, Boswellia is used as a source of boswellic acid.

[0125] In one embodiment, green tea is used as a source of catechins.

[0126] In one embodiment, milk thistle is used as a source of silybin.

[0127] In one embodiment, turmeric is used as a source of curcumin. In one embodiment, Sophora japonica is used as a source of quercetin.

[0128] According to one embodiment, the antioxidant(s) is a mixture, administered to the subject in need thereof via a single dosage form or administered by distributing the antioxidants in at least two dosage forms, comprising at least two compounds selected from: [0129] silybin, or dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin, [0130] quercetin, [0131] curcumin, or extract of turmeric rhizome preferably titrated from 80% to 95% by weight in curcumin, and/or [0132] vitamin E.

[0133] According to one preferred embodiment, the antioxidant(s) is a mixture, administered to the subject in need thereof via a single dosage form or administered by distributing the antioxidants in at least two dosage forms, consisting of at least two compounds selected from: [0134] silybin, or dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin, [0135] quercetin, [0136] curcumin, or extract of turmeric rhizome preferably titrated from 80% to 95% by weight in curcumin, and/or [0137] vitamin E.

[0138] In prior art, certain antioxidants have been tested individually and at high doses in the treatment of NAFLD; the interest of the specific mixture consisting of at least two compounds among silybin, or dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin; quercetin; curcumin, or turmeric rhizome extract preferably titrated from 80% to 95% by weight in curcumin; and/or vitamin E, is that it allows synergistic action of said antioxidants in improving NAFLD.

[0139] Indeed, the antioxidants are used individually at doses lower than the individual doses used in prior art, and the combination of this particular mixture of antioxidants within a composition according to the present invention leads to a greater effect in the treatment. of NAFLD than the effect of each individual antioxidant tested at high dose in prior art.

[0140] In one embodiment, the antioxidant(s) is a mixture administered in one or more pharmaceutical forms, for example for use within the composition according to the invention in the prevention and/or treatment of non-alcoholic fatty liver disease, and is composed of a total daily dose of: [0141] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated to 80% by weight of silybin, [0142] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin, [0143] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of turmeric rhizome extract titrated from 80% to 95% by weight as curcumin, and [0144] less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU of vitamin E.

[0145] In one embodiment, the antioxidant(s) is a mixture administered in one or more pharmaceutical forms, for example for use within the composition according to the invention in the prevention and/or treatment of non-alcoholic fatty liver disease, and is composed of a total daily dose of: [0146] 200 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated at 80% by weight of silybin, [0147] 100 mg of quercetin, [0148] 1 g of turmeric rhizome extract titrated to at least 80% by weight in curcumin, preferably titrated from 80% to 95% by weight in curcumin, and [0149] 12 mg (181 U) of vitamin E.

[0150] Alternatively, the antioxidant(s) is a mixture administered in one or more pharmaceutical forms, for example for use within the composition according to the invention in the prevention and/or treatment of type II diabetes, and is composed of a total daily dose of: [0151] less than 5000 mg, preferably less than 1000 mg, more preferably less than 500 mg, even more preferably about 200 mg of berberine, [0152] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 100 mg of quercetin, [0153] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g, even more preferably about 1 g of turmeric rhizome extract titrated to at least 80%, preferably 80% at 95% by weight in curcumin, [0154] less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU, even more preferably about 12 mg (18 IU) of vitamin E.

[0155] Alternatively, the antioxidant(s) is a mixture administered in one or more pharmaceutical forms, for use within the composition according to the invention in the prevention and/or treatment of type II diabetes, and is composed of a daily dose total of: [0156] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 200 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated to 80% by weight of silybin, [0157] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 100 mg of quercetin, [0158] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g, even more preferably about 1 g of turmeric rhizome extract titrated from 80% to 95% by weight of curcumin, and [0159] less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU, even more preferably about 18 IU of vitamin E.

[0160] Formulation

[0161] In one embodiment, the composition according to the invention comprises or consists of: [0162] glutamine; [0163] silybin or a dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin; [0164] beta-glucans, for example oat beta-glucans; [0165] pectins; [0166] cellulose; [0167] a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021); [0168] fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0169] turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin; and [0170] quercetin.

[0171] According to one embodiment, the composition according to the invention also comprises vitamin E, preferably natural vitamin E and/or acacia fibers.

[0172] In one embodiment, the composition according to the invention comprises or consists of: [0173] glutamine; [0174] vitamin E, preferably natural vitamin E; [0175] silybin or a dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin; [0176] beta-glucans, for example oat beta-glucans; [0177] pectins; [0178] cellulose; [0179] a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021); [0180] acacia fibers; [0181] fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0182] turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin; and [0183] quercetin.

[0184] In one embodiment, the composition according to the invention comprises or consists of: [0185] less than 30 g, preferably less than 15 g, more preferably less than 8 g, even more preferably about 5 g of glutamine; [0186] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 200 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated at 80% by weight of silybin; [0187] less than 10 g, preferably less than 10 g, more preferably less than 2.5 g, even more preferably about 1.666 g of oat beta-glucans; [0188] less than 10 g, preferably less than 5 g, more preferably less than 2.5 g, even more preferably about 1.666 g of pectins; [0189] less than 10 g, preferably less than 5 g, more preferably less than 2.5 g, even more preferably about 1.666 g of cellulose; [0190] less than 100 g, preferably less than 75 g, more preferably less than 55 g, even more preferably about 50 mg (i.e., about 5 billion CFU) of a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021); [0191] less than 2000 mg, preferably less than 1500 mg, more preferably less than 1250 mg, even more preferably about 1000 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3s may comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0192] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g, even more preferably about 1 g of extract of turmeric rhizome (Curcuma longa) titrated at 80% by weight of curcumin; and [0193] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 100 mg of quercetin.

[0194] According to one embodiment, the composition according to the invention also comprises: [0195] less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU, even more preferably about 18 IU (12 mg) of vitamin E, preferably natural vitamin E; and/or [0196] less than 500 mg, preferably less than 400 mg, more preferably less than 300 mg, even more preferably about 200 mg of acacia fibers.

[0197] Advantageously, the fish oil of the composition according to the invention comprises 60% by weight of omega-3, in particular about 30% by weight of docosahexaenoic acid (DHA) relative to the weight of the fish oil, about 20% by weight of eicosapentaenoic acid (EPA) based on the weight of fish oil and about 10% by weight of omega-3 other than DHA and EPA based on the weight of fish oil.

[0198] The composition according to the invention can in particular be administered once a day to a subject in need thereof.

[0199] The various components of the composition according to the invention can be packaged in at least one part. Preferably, each part corresponds to a dosage form which can be administered in one or more dosage units, in particular for once daily administration of each part to a subject in need thereof. For example, the composition according to the invention can be packaged in three parts, one part being packaged in a sachet, one part being packaged in a capsule and one part being packaged in two soft capsules.

[0200] In one embodiment, the composition according to the invention is in three parts.

[0201] In one embodiment, the composition according to the invention is in three parts: [0202] a first part comprising one or more sources of dietary fibers, preferably as defined above, glutamine, preferably as defined above, [0203] a second part comprising one or more probiotics, preferably as defined above, [0204] a third part comprising one or more sources of omega-3, preferably as defined above, [0205] one or more antioxidants, preferably as defined above, the antioxidant(s) being included in the first part of the composition and/or in the second part of the composition.

[0206] In one embodiment, the first and the third part of the composition according to the invention comprise one or more antioxidants.

[0207] In one embodiment, only the first part of the composition according to the invention comprise one or more antioxidants.

[0208] In one embodiment, only the third part of the composition according to the invention comprise one or more antioxidants.

[0209] In one embodiment, the second part of the composition according to the invention does not comprise antioxidants.

[0210] In one embodiment, the first part of the composition according to the invention has a total content of sources of fibers ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition according to the invention.

[0211] In one embodiment, the first part of the composition according to the invention has a total content of sources of fibers ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition according to the invention.

[0212] In one embodiment, the first part of the composition according to the invention has a total content of glutamine ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition according to the invention.

[0213] In one embodiment, the first part of the composition according to the invention has a total content of glutamine ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition according to the invention.

[0214] In one embodiment, the first part of the composition according to the invention has a total content of antioxidants ranging from 0 to 40% by weight, relative to the total weight of the first part of the composition according to the invention.

[0215] In one embodiment, the first part of the composition according to the invention has a total content of antioxidants ranging from 0 to 20% by weight, relative to the total weight of the first part of the composition according to the invention.

[0216] In one embodiment, the first part of the composition according to the invention has a total content of antioxidants ranging from 0 to 10% by weight, relative to the total weight of the first part of the composition according to the invention.

[0217] In one embodiment, the first part of the composition according to the invention has a total content of antioxidants ranging from 1 to 5% by weight, relative to the total weight of the first part of the composition according to the invention.

[0218] In one embodiment, the second part of the composition according to the invention has a total content of probiotics ranging from 80 to 100% by weight, relative to the total weight of the second part of the composition according to the invention.

[0219] In one embodiment, the second part of the composition according to the invention has a total content of probiotics ranging from 90 to 100% by weight, relative to the total weight of the second part of the composition according to the invention.

[0220] In one embodiment, the second part of the composition according to the invention has a total content of probiotics of 100% by weight, relative to the total weight of the second part of the composition according to the invention.

[0221] In one embodiment, the third part of the composition according to the invention has a total content of sources of omega-3 ranging from 10 to 50% by weight, relative to the total weight of the third part of the composition according to the invention.

[0222] In one embodiment, the third part of the composition according to the invention has a total content of sources of omega-3 ranging from 20 to 40% by weight, relative to the total weight of the third part of the composition according to the invention.

[0223] In one embodiment, the third part of the composition according to the invention has a total content of antioxidants ranging from 50 to 90% by weight, relative to the total weight of the third part of the composition according to the invention.

[0224] In one embodiment, the third part of the composition according to the invention has a total content of antioxidants ranging from 60 to 80% by weight, relative to the total weight of the third part of the composition according to the invention.

[0225] In one embodiment, the composition according to the invention comprises: [0226] a first part comprising 30 to 70% by weight, preferably from 40 to 60% by weight of sources of fibers, from 30 to 70% by weight, preferably from 40 to 60% by weight of glutamine, and from 0 to 40% by weight, preferably from 0 to 20% by weight, more preferably from 0 to 10% by weight, even more preferably from 1 to 5% by weight of antioxidants, relative to the total weight of the first part, [0227] a second part comprising from 80 to 100% by weight, preferably from 90 to 100% by weight, more preferably 100% by weight of probiotics, relative to the total weight of the second part, and [0228] a third part comprising from 10 to 50% by weight, preferably from 20 to 40% by weight of omega-3, from 50 to 90% by weight, preferably from 60 to 80% by weight of antioxidants relative to the total weight of the third part.

[0229] In one embodiment, the first part of the composition represents from 70 to 90% by weight of the composition relative to the total weight of the composition.

[0230] In one embodiment, the first part of the composition represents from 80 to 90% by weight of the composition relative to the total weight of the composition.

[0231] In one embodiment, the second part of the composition represents from 10 to 19.999% by weight of the composition relative to the total weight of the composition.

[0232] In one embodiment, the second part of the composition represents from 12 to 18% by weight of the composition relative to the total weight of the composition.

[0233] In one embodiment, the third part of the composition represents from 0.001 to 1% by weight of the composition relative to the total weight of the composition.

[0234] In one embodiment, the third part of the composition represents from 0.01 to 1% by weight of the composition relative to the total weight of the composition.

[0235] In one embodiment, the third part of the composition represents from 0.1 to 1% by weight of the composition relative to the total weight of the composition.

[0236] In one embodiment, the first part/second part weight ratio ranges from 1 to 10. In one embodiment, the first part/second part weight ratio ranges from 3 to 8.

[0237] In one embodiment, the first part/second part weight ratio ranges from 5 to 8. In one embodiment, the second part/third part weight ratio varies from 10 to 50. In one embodiment, the second part/third part weight ratio varies from 20 to 40. In one embodiment, the second part/third part weight ratio varies from 30 to 40. In one embodiment, the first part/third part weight ratio varies from 100 to 300.

[0238] In one embodiment, the first part/third part weight ratio varies from 150 to 250. In one embodiment, the first part/third part weight ratio varies from 180 to 220.

[0239] According to one embodiment, the first part comprises: [0240] glutamine, [0241] vitamin E, preferably natural vitamin E, [0242] silybin or a dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin, [0243] beta-glucans, preferably oat beta-glucans, [0244] pectins, and [0245] cellulose.

[0246] Optionally, the first part can also comprise turmeric, or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin, and quercetin.

[0247] According to a preferred embodiment, the first part comprises: [0248] less than 30 g, preferably less than 15 g, more preferably less than 8 g of glutamine, [0249] less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU of vitamin E, preferably natural vitamin E, [0250] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated at 80% by weight of silybin, [0251] less than 10 g, preferably less than 10 g, more preferably less than 2.5 g of beta-glucans, preferably oat beta-glucans, [0252] less than 10 g, preferably less than 5 g, more preferably less than 2.5 g of pectins, and [0253] less than 10 g, preferably less than 5 g, more preferably less than 2.5 g of cellulose.

[0254] Optionally, the first part can also comprise: [0255] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight of curcumin, and [0256] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin.

[0257] According to a more preferred embodiment, the first part comprises: [0258] about 5 g of glutamine, [0259] about 18 IU (12 mg) of vitamin E, preferably natural vitamin E, [0260] about 200 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated at 80% by weight of silybin, [0261] about 1.666 g of oat beta-glucans, [0262] about 1.666 g of pectins, and [0263] about 1.666 g of cellulose.

[0264] Optionally, the first part can also comprise: [0265] about 1 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight in curcumin, and [0266] about 100 mg of quercetin.

[0267] Advantageously, the first part is presented in the form of a sachet.

[0268] According to one embodiment, the second part comprises: [0269] a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021), and [0270] acacia fibers.

[0271] According to a preferred embodiment, the second part comprises: [0272] less than 100 g, preferably less than 75 g, more preferably less than 55 g of a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021), and [0273] less than 500 mg, preferably less than 400 mg, more preferably less than 300 mg of acacia fibers.

[0274] According to a more preferred embodiment, the second part comprises: [0275] about 50 mg (i.e., about 5 billion CFU) of a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021), and [0276] about 200 mg of acacia fiber.

[0277] Advantageously, the second part is presented in the form of a capsule, preferably a capsule consisting of hydroxypropylmethylcellulose, more preferably a capsule consisting of 75 mg of hydroxypropylmethylcellulose.

[0278] According to one embodiment, the third part comprises fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

[0279] Advantageously, the third part also comprises turmeric, or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin, and quercetin.

[0280] Thus, the third part can for example comprise: [0281] fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0282] turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin; and [0283] quercetin.

[0284] According to a preferred embodiment, the third part comprises less than 2000 mg, preferably less than 1500 mg, more preferably less than 1250 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

[0285] Advantageously, the third part also comprises: [0286] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight of curcumin, and [0287] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin.

[0288] Thus, the third part can comprise: [0289] less than 2000 mg, preferably less than 1500 mg, more preferably less than 1250 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 may comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0290] less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight of curcumin; and [0291] less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin.

[0292] According to a more preferred embodiment, the third part comprises about 1000 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

[0293] Advantageously, the third part also comprises: [0294] about 1 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight in curcumin, and [0295] about 100 mg of quercetin.

[0296] According to an even more preferred embodiment, the third part comprises: [0297] about 1000 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); [0298] about 1 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight in curcumin; and [0299] about 100 mg of quercetin.

[0300] Advantageously, the fish oil of the composition according to the invention comprises 60% by weight of omega-3, in particular about 30% by weight of docosahexaenoic acid (DHA) relative to the weight of the fish oil, about 20% by weight of eicosapentaenoic acid (EPA) relative to the weight of fish oil and about 10% by weight of omega-3 other than DHA and EPA relative to the weight of fish oil.

[0301] Advantageously, the third part further comprises glycerol, preferably about 182 mg of glycerol. Glycerol is an excipient used as a humectant.

[0302] Optionally, the third part also comprises at least one additive aimed at preventing the deterioration of fish oil, for example selected from: an extract of rosemary and a mixture of tocopherols; this at least one additive aimed at preventing the deterioration of the fish oil is present in a small amount (less than 5%, preferably less than 3%, more preferably less than or equal to 1% by weight relative to the weight of the third part) and is not intended to induce an antioxidant effect in the subject in whom the third part of the composition according to the invention is administered.

[0303] Advantageously, the third part is presented in the form of at least one soft capsule, preferably at least one soft capsule consisting of fish gelatin, more preferably at least one soft capsule whose structure consists of 182 mg of fish gelatin. The third part can for example also be presented in the form of 2 soft capsules.

[0304] According to an advantageous feature, when the first part of the composition comprises turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight of curcumin and quercetin, the third part of the composition does not comprise any; and conversely, when the third part of the composition comprises turmeric, or a turmeric rhizome extract titrated from 80% to 95% by weight of curcumin, and quercetin, the first part of the composition does not comprise any.

[0305] The invention relates in particular to said first, second and third parts of the composition according to the invention as described above, for their use in the treatment of non-alcoholic fatty liver disease (NAFLD). Advantageously, these three parts of the composition according to the invention are administered daily at the rate of a first, a second and two third parts per day.

[0306] Excipient

[0307] In one embodiment, the nutraceutical or pharmaceutical composition of the invention further comprises, in one or more of its parts where appropriate, at least one pharmaceutically or nutraceutically acceptable excipient.

[0308] The pharmaceutical or nutraceutical composition can typically comprise carriers or vehicles. The term “carriers” or “vehicles” refers to materials suitable for administration and includes any such material known in the art, such as, for example, any liquid, gel, solvent, liquid diluent, solubilizing agent or the like, non-toxic and which does not interact with any component of the composition in a detrimental way. Examples of pharmaceutically or nutraceutically acceptable carriers include, for example, water, saline solutions, alcohol, silicone, waxes, petrolatum, vegetable oils, polyethylene glycols, propylene glycol, liposomes, sugars, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, esters of fatty acids, hydroxymethylcellulose, hydroxypropylmethylcellulose polyvinylpyrrolidone, etc.

[0309] Thus, the nutraceutical or pharmaceutical composition may further comprise a texturing agent, preferably a gelling agent, even more preferably a modified starch.

[0310] The nutraceutical or pharmaceutical composition may further comprise an anti-sticking agent in order to improve the rheological properties of the pharmaceutical or nutraceutical composition.

[0311] In one embodiment, the anti-sticking agent is magnesium stearate.

[0312] In one embodiment, the nutraceutical or pharmaceutical composition further comprises minerals and micronutrients such as nutrient minerals and vitamins in accordance with recommendations from government bodies such as the USRDA. For example, the composition may contain per daily dose one or more of the following micronutrients: zinc, chromium, calcium, magnesium, phosphorus, iron, copper, iodine, selenium, beta-carotene, vitamin C, vitamin B1, vitamin B6, vitamin B2, niacin, vitamin B12, folic acid, biotin, vitamin D or vitamin E.

[0313] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0314] a. one or more sources of dietary fibers selected from sources of vegetable fibers, preferably selected from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds, [0315] b. glutamine, [0316] c. one or more probiotics, [0317] d. one or more sources of omega-3, and [0318] e. one or more antioxidants, [0319] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0320] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0321] a. one or more sources of dietary fibers, [0322] b. glutamine, [0323] c. one or more probiotics selected from lactic acid bacteria, preferably selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof, more preferably selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof, [0324] d. one or more sources of omega-3, and [0325] e. one or more antioxidants, [0326] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0327] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0328] a. one or more sources of dietary fibers, [0329] b. glutamine, [0330] c. one or more probiotics, [0331] d. one or more sources of omega-3 selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds, and preferably selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds, and [0332] e. one or more antioxidants, [0333] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0334] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0335] a. one or more sources of dietary fibers, [0336] b. glutamine, [0337] c. one or more probiotics, [0338] d. one or more sources of omega-3, and [0339] e. one or more antioxidants selected from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds, [0340] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0341] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0342] a. one or more sources of dietary fibers selected from sources of vegetable fibers, preferably selected from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds, [0343] b. glutamine, [0344] c. one or more probiotics selected from lactic acid bacteria, preferably selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof, more preferably selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof, [0345] d. one or more sources of omega-3, and [0346] e. one or more antioxidants, [0347] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0348] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0349] a. one or more sources of dietary fibers, [0350] b. glutamine, [0351] c. one or more probiotics, [0352] d. one or more sources of omega-3 selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds, and preferably selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds, and [0353] e. one or more antioxidants selected from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds, [0354] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0355] In one embodiment, the nutraceutical or pharmaceutical composition comprises: [0356] a. one or more sources of dietary fibers selected from sources of vegetable fibers, preferably selected from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds, [0357] b. glutamine, [0358] c. one or more probiotics selected from lactic acid bacteria, preferably selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof, more preferably selected from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof, [0359] d. one or more sources of omega-3 selected from docosahexaenoic acid, eicosatetraenoic acid, hexadecatrienoic acid, α-linolenic acid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid, docosapentaenoic acid, tetracosapentaenoic acid, tetracosahexaenoic acid, and mixtures of these compounds, and preferably selected from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds, and [0360] e. one or more antioxidants selected from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably selected from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds, [0361] for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0362] Administration Route

[0363] In one embodiment, the composition according to the invention is orally administered.

[0364] In one embodiment, the composition according to the invention is presented in one or more of the following forms: capsules (hard capsules), soft capsules, tablets, drinkable solutions, powders to be dissolved and/or dispersed, concentrated solutions to be diluted, sachets (sealed bags).

[0365] In one embodiment, the composition according to the invention is presented in the form of capsules.

[0366] In one embodiment, the composition according to the invention is presented in the form of soft capsules.

[0367] In one embodiment, the composition according to the invention is presented in the form of a sachet.

[0368] In one embodiment, the first part of the composition according to the invention as defined hereinabove is presented in the form of a sachet.

[0369] In one embodiment, the second part of the composition according to the invention as defined hereinabove is presented in the form of a soft capsule. In another embodiment, the second part of the composition according to the invention as defined hereinabove is in the form of a hard capsule.

[0370] In one embodiment, the third part of the composition according to the invention as defined hereinabove is presented in the form of a hard capsule. In another embodiment, the third part of the composition according to the invention as defined hereinabove is presented in the form of a soft capsule.

[0371] Use of the Composition

[0372] The features of the composition according to the invention as described above apply for the uses of the composition, the composition for uses and for the methods of prevention and/or treatment comprising a step of administration to a patient in need of the composition according to the invention.

[0373] The composition according to the invention is used in the prevention and/or treatment of dysbiosis of the intestinal microbiota. An object of the present invention is therefore the composition according to the invention, for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota. As mentioned above, dysbiosis includes a change in the intestinal flora (intestinal microbiota), increased intestinal permeability, oxidative stress, and low-grade inflammation. The composition according to the invention has the advantage of acting on these four axes of dysbiosis. Thus, the present invention also relates to the composition according to the invention for use for improving the intestinal microbiota, in particular by increasing intestinal bacterial diversity, for reducing intestinal permeability, for reducing oxidative stress and for reducing low-grade inflammation.

[0374] The composition according to the invention is thus also used in the preservation and/or restoration of the symbiosis of the intestinal microbiota. An object of the present invention is therefore the composition according to the invention, for use in the preservation and/or restoration of the symbiosis of the intestinal microbiota. Indeed, the composition according to the invention allows the preservation and/or restoration of the symbiosis through the prevention and/or treatment of dysbiosis of the intestinal microbiota.

[0375] In one embodiment, the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome (IBS).

[0376] In one embodiment, the dysbiosis of the intestinal microbiota is associated with type I diabetes.

[0377] In one embodiment, the dysbiosis of the intestinal microbiota is associated with type II diabetes.

[0378] In one embodiment, the dysbiosis of the intestinal microbiota is associated with obesity.

[0379] In one embodiment, the dysbiosis of the intestinal microbiota is associated with non-alcoholic fatty liver disease (NAFLD).

[0380] In one embodiment, the dysbiosis of the intestinal microbiota is associated with Crohn's disease.

[0381] In one embodiment, the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome, type I diabetes, type II diabetes, obesity, non-alcoholic fatty liver disease, and Crohn's disease.

[0382] In one embodiment, the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome, type I diabetes, type II diabetes, obesity, non-alcoholic fatty liver disease.

[0383] In one embodiment, the dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome (IBS)

[0384] In one embodiment, the dysbiosis of the intestinal microbiota is associated with allergies.

[0385] In one embodiment, dysbiosis of the intestinal microbiota is associated with food-type allergies.

[0386] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of Irritable Bowel Syndrome (IBS). An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of Irritable Bowel Syndrome (IBS).

[0387] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of type I diabetes. An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of type I diabetes.

[0388] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of type II diabetes. An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of type II diabetes.

[0389] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of obesity. An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of obesity.

[0390] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of non-alcoholic fatty liver disease (NAFLD). An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of non-alcoholic fatty liver disease (NAFLD). Indeed, currently, the only effective treatment for NAFLD is to reduce the weight of the patient by at least 10%. However, this loss of weight objective is difficult to maintain over the long term and other actions should be considered. Dysbiosis as well as insulin resistance are implicated in the pathophysiology of NAFLD. Thus, the present invention also relates to the composition according to the invention for use in the prevention and/or treatment of NAFLD.

[0391] In one embodiment, the composition according to the invention is used in the prevention and/or treatment of Crohn's disease. An object of the present invention is thus the composition according to the invention in the prevention and/or treatment of Crohn's disease.

[0392] The invention also relates to a method of preventing and/or treating dysbiosis comprising a step of administering to a patient in need thereof the composition according to the invention.

[0393] In one embodiment, the invention also relates to a method of preventing and/or treating Irritable Bowel Syndrome (IBS) comprising a step of administering to a patient in need thereof the composition according to the invention.

[0394] In one embodiment, the invention also relates to a method of preventing and/or treating type I diabetes comprising a step of administering to a patient in need thereof the composition according to the invention.

[0395] In one embodiment, the invention also relates to a method of preventing and/or treating type II diabetes comprising a step of administering to a patient in need thereof the composition according to the invention.

[0396] In one embodiment, the invention also relates to a method of preventing and/or treating obesity comprising a step of administering to a patient in need thereof the composition according to the invention.

[0397] In one embodiment, the invention also relates to a method of preventing and/or treating non-alcoholic fatty liver disease comprising a step of administering to a patient in need thereof the composition according to the invention.

[0398] In one embodiment, the invention also relates to a method of preventing and/or treating Crohn's disease comprising a step of administering to a patient in need thereof the composition according to the invention.

[0399] In one embodiment, the composition according to the invention is administered once daily.

[0400] In one embodiment, the composition according to the invention is administered twice daily.

[0401] In one embodiment, the composition according to the invention is administered daily over a period of between 1 and 3 months.

[0402] In one embodiment, the composition according to the invention is administered daily over a period of more than 3 months, in particular over a period of at least 12 months.

[0403] Kit

[0404] The present invention also relates to a kit in three parts: [0405] a first part comprising one or more sources of dietary fibers, preferably as defined above, glutamine, preferably as defined above, [0406] a second part comprising one or more probiotics, preferably as defined above, [0407] a third part comprising one or more sources of omega-3, preferably as defined above, [0408] one or more antioxidants, preferably as defined above, the antioxidant(s) being comprised in the first part of the kit and/or in the second part of the kit.

[0409] The different parts of the kit can have embodiments corresponding to the different embodiments defined for the first, second and third parts of the composition according to the invention, as defined hereinabove.

EXAMPLES

[0410] The present invention will be better understood in view of the following examples which illustrate without limitation the invention.

[0411] Examples of compositions according to the invention were prepared according to Tables 1 to 4 below.

Example 1: Composition for Use in the Prevention and/or Treatment of Irritable Bowel Syndrome (IBS)

[0412]

TABLE-US-00001 TABLE 1 Purity/source of Amount Part Ingredient the ingredient (mg*) 1 (sachet) Beta-glucan 100% 1666 Cellulose 100% 1666 Pectin 100% 1666 Glutamine 100% 5000 Resveratrol 100% 200 Boswellic acid From Boswellia titrated at 160 80% by weight of boswellic acid 2 (capsule) Lactobacillus Each strain is dosed at 100 50 rhamnosus GG + billion CFU per gram. The Bifidobacterium proportion of each strain is breve BR03 + equal. The product contains Lactobacillus 5 billion CFU LP01 plantarum 3 (soft Omega-3 From fish oil titrated to 60% 600 capsule) by weight of omega-3 (33% EPA and 22% DHA) Curcumin From turmeric titrated at 950 95% by weight in curcumin Quercetin From Sophora Japonica 100 titrated to 98% by weight of quercetin *relative to the pure ingredient EPA: Eicosapentaenoic acid DHA: Docosahexaenoic acid

[0413] The three-part composition according to Table 1 above can be used in the treatment and/or prevention of Irritable Bowel Syndrome (IBS). The composition is administered orally in a single dose, daily, for a period of between 1 and 3 months, to patients with IBS.

[0414] The three-part composition according to Table 1 is expected to treat IBS.

Example 2: Composition for Use in the Prevention and/or Treatment of Obesity

[0415]

TABLE-US-00002 TABLE 2 Purity/source of Amount Part Ingredient the ingredient (mg*) 1 (sachet) Beta-glucan 100% 1666 Cellulose 100% 1666 Pectin 100% 1666 Glutamine 100% 5000 Catechin From green tea titrated to 60 30% by weight of catechins 2 (capsule) Lactobacillus Each strain is dosed at 100 50 rhamnosus GG + billion CFU per gram. The Bifidobacterium proportion of each strain is breve BR03 + equal. The product contains Lactobacillus 5 billion CFU LP01 plantarum 3 (soft Omega-3 From fish oil titrated to 60% 600 capsule) by weight of omega-3 (33% EPA and 22% DHA) Curcumin From turmeric titrated at 950 95% by weight in curcumin Quercetin From Sophora Japonica 100 titrated to 98% by weight of quercetin *relative to the pure ingredient EPA: Eicosapentaenoic acid DHA: Docosahexaenoic acid

[0416] The three-part composition according to Table 2 above can be used in the treatment and/or prevention of obesity. The composition is administered orally in a single dose, daily, for a period of between 1 and 3 months, to obese patients.

[0417] The three-part composition according to Table 2 is expected to treat obesity.

Example 3: Composition for Use in the Prevention and/or Treatment of Diabetes (Type I or II)

[0418]

TABLE-US-00003 TABLE 3 Purity/source of Amount Part Ingredient the ingredient (mg*) 1 (sachet) Beta-glucan 100% 1666 Cellulose 100% 1666 Pectin 100% 1666 Glutamine 100% 5000 Berberine 100% 200 2 (capsule) Lactobacillus Each strain is dosed at 100 50 rhamnosus GG + billion CFU per gram. The Bifidobacterium proportion of each strain is breve BR03 + equal. The product contains Lactobacillus 5 billion CFU LP01 plantarum 3 (soft Omega-3 From fish oil titrated to 60% 600 capsule) by weight of omega-3 (33% EPA and 22% DHA) Curcumin From turmeric titrated at 950 95% by weight in curcumin Quercetin From Sophora Japonica 100 titrated to 98% by weight of quercetin *relative to the pure ingredient EPA: Eicosapentaenoic acid DHA: Docosahexaenoic acid

[0419] The three-part composition according to Table 3 above can be used in the treatment and/or prevention of type I or II diabetes. The composition is administered orally in a single dose, daily, for a period of between 1 and 3 months, to patients with diabetes.

[0420] The three-part composition according to Table 3 is expected to treat type I or II diabetes.

Example 4: Composition for Use in the Prevention and/or Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD)

[0421]

TABLE-US-00004 TABLE 4 Purity/source of Amount Part Ingredient the ingredient (mg*) 1 (sachet) Beta-glucan 100% 1666 Cellulose 100% 1666 Pectin 100% 1666 Glutamine 100% 5000 Silybin From milk thistle titrated to 200 80% by weight of silybin 2 (capsule) Lactobacillus Each strain is dosed at 100 50 rhamnosus GG + billion CFU per gram. The Bifidobacterium proportion of each strain is breve BR03 + equal. The product contains Lactobacillus 5 billion CFU LP01 plantarum 3 (soft Omega-3 From fish oil titrated to 60% 600 capsule) by weight of omega-3 (33% EPA and 22% DHA) Curcumin From turmeric titrated at 950 95% by weight in curcumin Quercetin From Sophora Japonica 100 titrated to 98% by weight of quercetin *relative to the pure ingredient EPA: Eicosapentaenoic acid DHA: Docosahexaenoic acid

[0422] The three-part composition according to Table 4 above can be used in the treatment and/or prevention of non-alcoholic fatty liver disease (NAFLD). The composition is administered orally in a single dose, daily, for a period of between 1 and 3 months, to patients with NAFLD.

[0423] The three-part composition according to Table 4 is expected to treat NAFLD.

[0424] Thus, through these four examples, it is expected that the compositions according to the examples above restore dysbiosis by the combined action of the constituents on various manifestations of dysbiosis (decrease in bacterial diversity, modification of intestinal permeability, increased oxidative stress, inflammation). The action on these different levers makes it possible to treat dysbiosis and restore the symbiosis of the microbiota and the body.

Example 5: Observational Study of the Efficacy of a Composition According to the Invention in Improving Moderate to Severe Non-Alcoholic Fatty Liver Disease (NAFLD)

[0425] The severity of NAFLD is related to the extent of the liver fibrosis; it can progress to cirrhosis (stage F4 fibrosis according to the METAVIR score), while cirrhosis can itself evolve to hepatocarcinoma (primary liver cancer). Currently, the only effective treatment for NAFLD is to reduce the weight of the patient by at least 10%. However, this weight loss objective is difficult to maintain over the long term and other actions should be considered. A double-blind observational study is thus carried out in order to compare the effectiveness of a composition according to the invention, hereinafter called “Combo”, with a placebo, in improving moderate to severe NAFLD.

[0426] Materials and Methods

[0427] Materials

[0428] Composition of the capsule of Combo and the placebo capsule:

TABLE-US-00005 Capsule Combo Placebo Probiotics: 50 mg or — Lactobacillus rhamnosus GG 5 billion Bifidobacterium breve BR03 (DSM 16604) CFU Lactobacillus plantarum LP01 (LMG P-21021) Shell: HPMC  75 mg  75 mg Acacia fibers 200 mg — Maltodextrine — 250 mg

[0429] Composition of the soft capsule of Combo and the placebo soft capsule:

TABLE-US-00006 Soft capsule Combo Placebo Fish oil titrated at 60% by weight in omega-3 500 mg — Shell: fish gelatin 182 mg 162 mg Moistening agent: glycerol  53 mg Additives to prevent spoilage of fish oil: mixture of — tocopherols (E306), rosemary extract (E392) Soy lecithin — 540 mg

[0430] The additives to prevent spoilage of fish oil (mixture of tocopherols (E306) and rosemary extract (E392)) are present only as excipients and are only intended to prevent oxidation of the fish oil.

[0431] Composition of the sachet of Combo and the placebo sachet:

TABLE-US-00007 Sachet Combo Placebo Glutamine 5 g — Turmeric rhizome extract (Curcuma longa) 1 g — titrated at 80% by weight in curcumin Natural Vitamin E 12 mg (18 UI) — Quercetin 100 mg — Dry extract of aerial parts of milk thistle 200 mg — (Silybum marianum) titrated at 80% by weight in silybin Oat beta-glucans from oat bran (Avena saliva) 1.666 g — Pectin 1.666 g — Cellulose 1.666 g — Maltodextrine — 9 g Talc — 2 g Orange Yellow S (E110) — 10 mg

[0432] The placebo is identical in shape, color, presentation and taste compared to the Combo. The Combo and the placebo are provided to patients in one-month boxes containing 30 white sachets and 60 soft capsules and 30 capsules in blister packs.

[0433] 60 patients are included in the study. These patients have moderate to severe diagnosed NAFLD and moderate to severe fibrosis (stage F2 or F3 according to the METAVIR score) and are 18 years or older. They are offered inclusion in the study when their liver biopsy results are announced. The criteria for not including people who are willing to participate to research are as follows: cirrhosis (stage F4 according to the METAVIR score); hepato-cellular carcinoma; ongoing steatogenic treatment (corticosteroids, methotrexate, amiodarone, tamoxifen) or hepatotoxic treatment (amitriptyline, imipramine, clozapine, diclofenac); viral liver damage; autoimmune liver damage; anticoagulant therapy; antibiotic treatment in the two months preceding inclusion; allergy to soy, aspirin, fish, maltodextrin or E110; poorly balanced diabetes (HbA1c>8%); pregnant woman; excessive alcohol intake (>100 g/week).

[0434] Methods

[0435] Randomization is carried out electronically via a dedicated website. Thus, independently of the doctors and the patients, each patient is included either in the group of patients receiving the Combo or in the group of patients receiving the placebo.

[0436] 30 patients receive the Combo and 30 patients receive the placebo, for 48 weeks for each patient. Each patient receives the quantity needed for three months of Combo or placebo on a quarterly basis from the pharmacy of one of the two centers participating in the research.

[0437] Administration method: each patient administers to themselves each day, once a day, in the morning: 2 soft capsules, 1 capsule and 1 sachet diluted in a 100 mL glass of water or fruit juice or in a food product, whether it is the Combo or the placebo. This administration is carried out every day for 48 weeks for each patient.

[0438] In addition, physical activity advice and hygiene and dietetic advice are provided to each included patient.

[0439] Patient follow-up methods: [0440] Medical visits: 6 medical visits for clinical examination are carried out: the day of inclusion (W0), 4 weeks after inclusion (W4), 12 weeks after inclusion (W12), 24 weeks after inclusion (W24), 36 weeks after inclusion (W36) and at the end of the study (at the end of the 48th week: W48). The clinical parameters checked during each of the 6 visits are as follows: weight, blood pressure, abdominal perimeter, BMI calculation. In addition, an elastometric measurement by FibroScan® is carried out at W0, W24 and W48. [0441] Biological controls: blood samples and stool samples are taken to assess the safety and efficacy of the Combo: on inclusion in the study (W0), 24 weeks after inclusion (W24) and at the end of the study (W48). [0442] Blood samples: the biological parameters checked are as follows: ASAT, ALAT, alkaline phosphatase, gamma-GT, total bilirubin, triglycerides, HDL-cholesterol, LDL-cholesterol, apolipoprotein A1, ferritinemia, glycemia, glycated hemoglobin (HbA1c), insulinemia, calculation of the HOMA index (Homeostasis Model Assessment of insulin resistance), platelets, C-reactive protein (CRP), ionogram (natremia, kalaemia), serum creatinine, albuminemia, alpha2macroglobulinemia, haptoglobulinemia, calculation of the Fibrosis 4 (FIB4) score, calculation of the NAFLD score, oxidative stress measured by the analysis method of the company “Laboratoires Réunis” (which involves the measurement of antioxidant capacity), lipopolysaccharides (LPS), C-reactive protein (CRP), IL6 (interleukin-6), TNF (tumor necrosis factor); [0443] Stool samples: the parameter analyzed is as follows: analysis of the fecal microbiota by sequencing of the 16S RNA of bacteria (Luxia “Phase IV” method); [0444] Anatomic pathology: a liver biopsy puncture is performed at the end of the study (W48) with calculation of the SAF score, in addition to the liver biopsy puncture performed before the inclusion of patients in the study; [0445] Dietetic assessment and IPAQ questionnaire: a dietetic assessment and a response to an IPAQ questionnaire by each patient are scheduled three times during the study: the day of inclusion (W0), 24 weeks after inclusion (W24) and at the end of the study (W48).

[0446] In some cases, treatment should be interrupted: serious side effect, worsening of liver disease justifying stopping the treatment, antibiotic therapy for more than one month, decision of the patient.

[0447] The reasons for patients leaving the study are: withdrawal of the consent of the patient (possible at any time during the study, without justification required), loss of follow-up of patients, death, antibiotic therapy for more than one month.

[0448] The objectives of administering the Combo are the following: [0449] main objective: reduction of NAFLD at W48 with reduction or stabilization of histological signs, reduction in elastometric scores and in NAFLD and FIB4 biological scores; and [0450] secondary objectives: improvement of the symbiosis and improvement of the quality of life (physical and nutritional state) at W48.

[0451] The outcomes for the study are as follows: [0452] the criteria for assessment of the main outcome are: [0453] histological improvement in NAFLD after 48 weeks of taking the Combo: a liver biopsy puncture to assess the histological evolution of NAFLD is performed at W48. A histological improvement in NAFLD is expected with an interruption in the progression of NAFLD, at least a stabilization or even a decrease in fibrosis and a decrease in fibrinogenesis. The SAF score is calculated (Steatosis Activity Fibrosis); it is estimated at 4.5 on the day of inclusion (W0) and it is expected that it will be 3.5 at the end of the study (W48), i.e., an improvement in the score of 30% and a decrease the median score of 1.0; [0454] a reduction in elastometry parameters: an examination by FibroScan® is performed at W48: evaluation of fibrosis by measuring elasticity and evaluation of steatosis by measuring the CAP (Controlled Attenuation Parameter). A decrease in elasticity of 2.5 kPa is expected (estimated elasticity before treatment: 9.5 kPa; expected elasticity after treatment: 7.0 kPa, i.e., a 26% improvement in elasticity). A decrease in CAP is expected from 330 dB/m to 247 dB/m, i.e., an improvement of 25%; and [0455] a decrease in FIB4 (Fibrosis-4 score) and NAFLD biological scores; [0456] the secondary outcomes are: [0457] evaluation of the symbiosis at W48: a concomitant improvement of the microbiota (promotion of its diversity and its anti-inflammatory potential by increasing the relative abundance of butyrate-producing bacteria) and/or intestinal permeability and/or reduction of low-grade inflammation and/or reduction of oxidative stress. The parameters evaluated are: analysis of the microbiota in the stool (sequencing of 16S RNA from bacteria), measurement of intestinal permeability (determination of LPS lipopolysaccharides from a blood sample), measurement of low-grade inflammation (determination of inflammation mediators: CRP, IL6 and TNF from a blood sample), measurement of oxidative stress (antioxidant capacity from a blood sample). A concomitant improvement in microbiota parameters (relative abundance of bacteria producing butyrate) and/or intestinal permeability (decrease in LPS concentration) and/or low-grade inflammation (decrease in CRP, IL6 and/or TNF concentrations) and/or oxidative stress (increased antioxidant capacity) is expected; and [0458] lifestyle assessment at W48: physical activity (IPAQ questionnaire), nutritional status (summary over 3 days).

[0459] Statistical Analysis Plan: Statistical analysis is performed at the end of follow-up for all patients, after a blind review for data quality issues and a database freeze. The comparative analysis is carried out blind, that is to say that neither the statistician nor the coordinating investigator can identify the placebo and Combo groups. Once the analysis is finalized and presented to the steering committee, the identification of groups is provided. Statistical analysis is performed with a bilateral alpha risk of 5%.

[0460] Quantitative data is described by means and standard deviations and medians and interquartile ranges. They are compared using non-parametric tests (Wilcoxon Mann-Withney, Kruskal-Wallis). Paired tests are used when comparing repeated measurements of the same patients (evolution of biological data, elastometry, IPAQ).

[0461] Qualitative data are expressed in numbers and percentages. The proportions of missing data are calculated. They are compared using Chi-2 tests or Fisher tests when the groups are independent and McNemar tests when the groups are paired (repeated measures).

[0462] First, the data is analyzed by intention to treat in order to meet the primary and secondary endpoints.

[0463] All patients who received at least one administration of the study product are included in the analysis for the primary endpoint (ICH standards). The number of subjects to be included takes into account possible patients lost to follow-up. For the other analyzes and in the event of missing data, the values of the last known observation are used in the intention-to-treat analysis (LOCF method, last observation carried forward).