EP3937913A1

EP3937913A1 - Composition for use in the prevention and/or treatment of dysbiosis

Info

Publication number: EP3937913A1
Application number: EP20707456.8A
Authority: EP
Inventors: Hélène DUMINY; Alain Verneau; Luc HEITZ; Joël DORÉ
Original assignee: Mativa Tech; Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Current assignee: Mativa Tech; Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Priority date: 2019-03-05
Filing date: 2020-03-05
Publication date: 2022-01-19
Also published as: US20220143070A1; MX2021010219A; MA55274A; FR3093427A1; WO2020178391A1; FR3093427B1

Abstract

The present invention relates to a nutraceutical composition comprising one or more sources of fibres, 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. The present invention also relates to a method for the prevention and/or treatment of dysbiosis comprising a step of administration to a patient in need of the composition according to the invention. The present invention also relates to a three-part kit for use in the prevention and/or treatment of dysbiosis of the intestinal microbiota.

Description

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

FIELD OF THE INVENTION The present invention relates to a nutraceutical or pharmaceutical composition comprising one or more sources of fiber, glutamine, one or more probiotics, one or more sources of Omega-3, and one or more antioxidants, for its use. in the prevention and / or treatment of dysbiosis of the intestinal microbiota. The present invention also relates to a method for the prevention and / or treatment of dysbiosis comprising a step of administering to a patient in need the composition according to the invention.

The present invention also relates to a three-part kit for its use in the prevention and / or treatment of dysbiosis of the intestinal microbiota.

STATE OF THE ART

The intestinal microbiota is made up of billions of bacteria that live in symbiosis with our body. It is estimated that the microbiota is made up of around 200 species of bacteria. This microbiota has several functions: - It contributes to the degradation of digestible compounds, dietary fibers and polyphenols in particular. It thus contributes to an essential supply of vitamins from groups B and K, participates in the elimination of carcinogenic compounds and provides the body with short-chain fatty acids (acetate, propionate and butyrate), products resulting from fermentation, which are sources of energy for body tissues.

It also exerts a competitive exclusion function vis-à-vis microorganisms from the environment whose implantation and propagation it prohibits. proliferation by the occupation of metabolic and ecological niches and by the direct action of antimicrobial molecules.

It also interacts with the intestinal epithelium and beyond with immunity and all organs, thereby modulating trophic development of the intestinal wall and mucus production, immune system tone, liver metabolism, and functioning of distal organs such as adipose tissue, muscles and the brain.

For a given individual, the microbiota normally drifts little over time, apart from dietary changes or treatments. The homeostasis of the symbiosis is a guarantee for the maintenance of health and well-being.

Many chronic non-communicable diseases whose incidence has steadily increased since the end of World War II may be associated with impaired microbiota. These include Crohn's disease, obesity, type 1 and 2 diabetes, asthma and multiple sclerosis. Likewise, psychic or psychological stress can also influence the quality of the microbiota.

Alterations in the microbiota (dysbiosis) can be of different types: decrease in bacterial diversity,

change in intestinal permeability,

- increased oxidative stress,

inflammation.

Current therapeutic approaches aim to treat alterations in the microbiota by acting on an ad hoc basis and on only one of the alterations indicated above.

However, the drawback of these approaches is that they do not allow an optimal return to the symbiosis of the microbiota since it is disturbed by several factors which act, in a detrimental way, in parallel. There is therefore a need to develop innovative approaches which, by activating several levers in parallel, would ensure the preservation and / or restoration of the symbiosis of the microbiota.

The Applicant has developed an original approach consisting in combining in the same composition at least one source of dietary fiber, glutamine, at least one probiotic, at least one source of Omega-3, and at least one antioxidant. This global approach makes it possible to act on the various levers of dysbiosis and therefore gradually to restore the symbiosis.

In addition, the original approach developed by the Applicant should make it possible to limit the worsening of chronic diseases, and therefore should allow the reduction or non-increase in the intake of pharmaceutical products and the associated side effects.

The composition according to the invention makes it possible in particular to prevent and / or treat dysbiosis of the intestinal microbiota, and thus to preserve and / or restore the symbiosis of the intestinal microbiota.

ABSTRACT

The invention therefore relates to a nutraceutical or pharmaceutical composition comprising: a. one or more sources of dietary fiber,

b. glutamine,

vs. 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.

In one embodiment, the source or sources of dietary fiber in the composition according to the invention are chosen from sources of plant fibers. In a mode of embodiment, the source or sources of dietary fiber of the composition according to the invention are chosen from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds.

In one embodiment, the probiotic (s) of the composition according to the invention are chosen from lactic acid bacteria. In one embodiment, the probiotic (s) of the composition according to the invention are chosen from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture of these. In one embodiment, the probiotic or probiotics of the composition according to the invention are chosen from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture thereof.

In one embodiment, the source or sources of omega-3 of the composition according to the invention are chosen 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. In one embodiment, the source or sources of omega-3 of the composition according to the invention are chosen from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds.

In one embodiment, the antioxidant (s) of the composition according to the invention are chosen from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds. In one embodiment, the antioxidant (s) of the composition according to the invention are chosen from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds. In one embodiment, the composition according to the invention is in three parts, a first part comprising the source (s) of dietary fiber 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 In one embodiment, the antioxidant (s) are included in the first part and in the third part of the composition.

In one embodiment, the first part of the composition according to the invention has a total content of fiber sources ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition. In one embodiment, the first part of the composition according to the invention has a total content of fiber sources ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition.

In one embodiment, the first part of the composition according to the invention has a total glutamine content ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition. In one embodiment, the first part of the composition according to the invention has a total glutamine content ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition.

In one embodiment, the third part of the composition according to the invention has a total content of omega-3 sources ranging from 10 to 50% by weight, relative to the total weight of the third part of the composition. In one embodiment, the third part of the composition according to the invention has a total content of omega-3 sources ranging from 20 to 40% by weight, relative to the total weight of the third part of the composition.

In one embodiment, the composition according to the invention is used in the prevention and / or treatment of dysbiosis of the intestinal microbiota associated with Irritable Bowel Syndrome (ER), type I diabetes, type I diabetes. II, obesity, non-alcoholic fatty liver disease (NASH) and Crohn's disease. In one embodiment, the composition according to the invention is used in the prevention and / or treatment of dysbiosis of the intestinal microbiota associated with Irritable Bowel Syndrome (ER), type I diabetes, type I diabetes. II, obesity and non-alcoholic fatty liver disease (NASH). In one embodiment, the composition according to the invention is used in the prevention and / or treatment of dysbiosis of the intestinal microbiota associated with Irritable Bowel Syndrome (ER). DEFINITIONS

In the present invention, the terms below are defined as follows:

“Antioxidant capacity” designates a biological parameter which reports on the antioxidant protection system and constitutes a method of detecting oxidative stress. The antioxidant capacity is lower as the production of free radicals is high.

"About" when it precedes a number, means plus or minus 10% of the value of that number.

“Gut microbiota dysbiosis” refers to a microbial imbalance or poor adaptation of the gut microbiota. It can be manifested in particular by one or more of the following events: decrease in bacterial diversity, modification of intestinal permeability, increase in oxidative stress and inflammation. In one embodiment, dysbiosis is manifested by at least two of the following events: decrease in bacterial diversity, change in intestinal permeability, increase in oxidative stress, and low grade inflammation (as distinguished from acute inflammation). In one embodiment, the dysbiosis is manifested by at least three of the following events: decrease in bacterial diversity, change in gut permeability, increase in oxidative stress, and low grade inflammation. In one embodiment, dysbiosis is manifested by all of the following: decreased bacterial diversity, altered gut permeability, increased oxidative stress, and low grade inflammation.

“Nutraceutical composition” or “Alicament” or “Foods with nutritional purposes” or “Food supplements” are interchangeable terms and designate any substance containing nutrients, whether intended for human or animal consumption, whether composed of a single ingredient or of a mixture of ingredients, whether liquid, semi-liquid or solid, whether it mainly comprises carbohydrates, fats, proteins or any mixture of these, which 'it is edible in itself or requires processing such as baking, mixing, cooling, mechanical processing, etc.

“Pharmaceutical composition” denotes a composition comprising an active principle in association with a pharmaceutically acceptable vehicle or excipient. A pharmaceutical composition is for therapeutic use and relates to health. In particular, a pharmaceutical composition may be indicated for treating or preventing a disease. According to the invention, the term "treatment of a disease" denotes the reduction or alleviation of at least one side effect or a symptom of a disease, disorder or condition associated with a deficiency of. the function of an organ, tissue or cell. The term "preventing disease" or "inhibiting the development of disease" refers to the prevention or avoidance of the onset of a symptom.

“Adverse reaction” means any adverse reaction occurring in a patient, living donor or recipient, related or likely to be related to a drug. - “Serious side effect” means any side effect that is lethal or potentially life-threatening, or leading to significant or lasting disability or incapacity, or causing or prolonging hospitalization, or manifesting as a congenital anomaly or malformation.

“Adverse event” means any harmful event occurring in a person who is amenable to biomedical research, whether or not such event is related to the research or the product to which this research relates.

“Serious adverse event” means any adverse event which: results in death; endangers the life of the person who submits the search; requires hospitalization or prolongation of hospitalization; causes significant or lasting disability or handicap; results in a congenital anomaly or malformation; or any event considered medically serious, and with regard to the drug, regardless of the dose administered.

“Dietary fiber” means the parts of an element of plant origin made up of complex mixtures of carbohydrates from the cell wall or cytoplasm of plant cells, and which cannot be completely. broken down by human digestive enzymes. In one embodiment, the dietary fibers, soluble or insoluble, are chosen from pectins, celluloses, hemicelluloses, starches, in particular resistant starches, beta-glucans and a mixture of these compounds. dietary ”means foods or nutrients comprising dietary fiber. These include plant foods such as fruits, vegetables, legumes and grains. By way of fruits as sources of dietary fiber, mention may in particular be made of almonds, currants, prunes, walnuts and bananas. By way of vegetables as sources of dietary fiber, mention may in particular be made of artichokes, carrots, potatoes, green cabbage and cauliflower. By way of legumes as a source of dietary fiber, mention may in particular be made of white beans, split peas, chickpeas, lentils and peas. By way of cereals as sources of dietary fiber, mention may in particular be made of wheat bran, oat bran, oat flakes and rice. In one embodiment, sources of dietary fiber will denote foods or nutrients comprising at least 3 g of fiber per 100 g of food or nutrient, preferably comprising at least 6 g of fiber per 100 g of food. or nutrient.

"Inflammation" refers to a response of living tissue to an attack the etiology of which may, for example, be infectious, physical, chemical, vascular, dysimmunitary. It involves cells, vessels, changes in the extracellular matrix and many chemical mediators of inflammation. “Acute inflammation” means the immediate response to an aggressive agent, of short duration (a few days or weeks), of often sudden onset and characterized by intense vasculo-exudative phenomena. “Low-grade inflammation” or “chronic inflammation” designates inflammation that is opposed to acute inflammation in that its onset is slower, in that the biological and clinical signs are less intense and in that it progresses by persisting or worsening for several months or more years.

“Probiotic” designates living microorganisms (bacteria or yeasts) added exogenously to an organism, for example via food, which exert a beneficial effect on the organism which ingests them. "Omega-3" refers to fatty acids omega-3 which are polyunsaturated fatty acids that comprise at least one double carbon-carbon bond between the 3 ^rd and the 4 ^th carbon of the carbon chain of the acid starting with last carbon in the carbon chain (omega carbon).

- "Antioxidant" refers to a molecule that slows down or prevents the oxidation process, that is to say the oxidation of other chemicals in particular due to the presence of free radicals by neutralizing them. For the purposes of the present invention, the term "antioxidant" is aimed in particular at a molecule which slows down or prevents the oxidation process of human cells.

- "Glutamine" refers to the amino acid of the formula:

[Chem 1]

“FIB4 score” or “Fibrosis-4 score” designates a score used to assess fibrosis, integrating the following parameters: patient age, serum concentrations of AS AT and AL AT, venous blood platelet concentration.

“NAFLD Score” or “Non-Alcoholic Fatty Liver Disease Fibrosis Score” or “score

NFS ”designates a score used to assess fibrosis, integrating the following parameters: patient age, hyperglycemia / diabetes, body mass index (BMI), serum concentrations of ASAT, ALT and albumin, venous blood platelet concentration.

“SAF score” (Steatosis Activity Fibrosis) designates a composite histological score taking into account steatosis, histological activity and hepatic fibrosis, as defined in Bedossa P. et al., “Histopathological algorithm and scoring System for evaluation of liver lesions in morbidly obese patients ”, Hepatology, 2012 Nov; 56 (5): 1751-9.

"Oxidative stress" or "oxidative stress" refers to an attack on cells by free radicals, also called "reactive oxygen species" (ROS), by nitrogen monoxide NO, by hydrogen peroxide H2O2 or by the hydroxyl radical HO ". These compounds attacking cells lead to peroxidation of proteins and lipids, even to an alteration of nucleic acids (DNA breaks, etc. For the purposes of the present invention, the cells attacked during oxidative stress are in particular human cells.

“Subject” means an animal, including a human being. For the purposes of the present invention, a subject may be a patient, namely a person receiving medical care, undergoing or having undergone medical treatment, or being monitored for the development of a disease. Said disease can for example be non-alcoholic fatty liver disease (NASH), Irritable Bowel Syndrome (AD), type I diabetes, type II diabetes, obesity, Crohn's disease, preferably an non-alcoholic fatty liver disease (NASH).

“Symbiosis of the intestinal microbiota” means, unlike dysbiosis, a balance between the intestinal microbiota and the body.

DETAILED DESCRIPTION

The present invention relates to a nutraceutical or pharmaceutical composition comprising: a. one or more sources of dietary fiber,

b. glutamine,

vs. one or more probiotics,

d. one or more sources of Omega-3, and

e. one or more antioxidants,

The Applicant has observed that the composition according to the invention makes it possible to prevent and / or treat dysbiosis of the intestinal microbiota. By acting on the four axes identified in parallel: increasing bacterial diversity,

decrease in intestinal permeability,

decrease in oxidative stress, and

- reduction in low-grade inflammation,

the composition according to the invention makes it possible to restore the symbiosis of the intestinal microbiota and the body.

Sources of dietary fiber

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 thus constitute an ingredient of choice for opening up ecological niches and enabling a great diversity of microorganisms equipped to hydrolyze various complex polysaccharide structures to dominate. In one embodiment, the sources of dietary fiber are chosen from sources of plant fibers.

In one embodiment, the sources of dietary fiber are selected from sources of soluble dietary fiber.

In one embodiment, the sources of dietary fiber are selected from sources of insoluble dietary fiber.

In one embodiment, the sources of dietary fiber are selected from sources of celluloses, hemicelluloses, starches, pectins, beta-glucans, and a mixture of these compounds.

In one embodiment, the sources of fiber can be selected from fruits, vegetables, legumes, grains or a mixture of these sources. In one embodiment, the fruits are selected from almonds, currants, prunes, walnuts, bananas and a mixture of these sources.

In one embodiment, the vegetables are chosen from artichokes, carrots, potatoes, green cabbage, cauliflower, and a mixture of these sources. In one embodiment, the legumes are selected from white beans, split peas, chickpeas, lentils, peas, and a mixture of these sources.

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

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

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

In one embodiment, the sources of dietary fiber are celluloses. In one embodiment, the sources of dietary fiber are hemicelluloses.

In one embodiment, the sources of dietary fiber are starches. In one embodiment, the sources of dietary fiber are resistant starches.

In one embodiment, the sources of dietary fiber are pectins.

In one embodiment, the sources of dietary fiber are beta-glucans. In one embodiment, the sources of dietary fiber are a mixture of celluloses, pectins, and beta-glucans.

In one embodiment, the sources of dietary fiber comprise at least 3 g of fiber per 100 g of sources of dietary fiber. In one embodiment, the sources of dietary fiber comprise at least 6 g of fiber per 100 g of sources of dietary fiber.

In one embodiment, the sources of dietary fiber are dietary fiber directly and include 100 g of fiber per 100 g of sources of dietary fiber. Glutamine

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

[Chem 2]

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

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

Glutamine is commercially available in different pack sizes and in different amounts.

Probiotics

The composition according to the invention comprises one or more probiotics. In one embodiment, the probiotics help decrease 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 make it possible to increase the diversity of the composition of the microbiota.

In one embodiment, the probiotic (s) are chosen from lactic acid bacteria. In one embodiment, the probiotic (s) is (are) selected from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof.

In one embodiment, the probiotic (s) of the composition according to the invention are chosen 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.

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.

In one embodiment, the probiotic of the composition according to the invention is Lactobacillus rhamnosus, preferably Lactobacillus rhamnosus GG. In one embodiment, the number of colony-forming unit (or CFU or “Colony-forming unit”) of probiotics is greater than or equal to 10 ⁶ cells per gram of probiotics. In one embodiment, the number of probiotic colony-forming units is greater than or equal to 5.10 ⁶ cells per gram of probiotics. In one embodiment, the number of probiotic colony forming units is greater than or equal to 10 ⁷ cells per gram of probiotics. In one embodiment, the number of probiotic colony-forming units is greater than or equal to 5.10 ⁷ cells per gram of probiotics. In one embodiment, the number of probiotic colony forming units is greater than or equal to 10 ⁸ cells per gram of probiotics. In one embodiment, the number of probiotic colony-forming units is greater than or equal to 5.10 ⁸ cells per gram of probiotics. In one embodiment, the number of probiotic colony forming units is greater than or equal to 10 ⁹ cells per gram of probiotics. In one embodiment, the number of probiotic colony forming units is between 10 ⁶ and 10 ¹⁰ cells per gram of probiotics.

Sources of omega-3

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

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

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

In one embodiment, the source (s) of omega-3 is selected from algae. In one embodiment, the source (s) of omega-3 is directly omega-3.

In one embodiment, the source (s) of omega-3 are chosen 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.

In one embodiment, 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.

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

Antioxidants

The composition according to the invention also comprises one or more antioxidants. In one embodiment, the antioxidant (s) helps decrease inflammation. In one embodiment, the antioxidant (s) make it possible to reduce oxidative stress. In one embodiment, the antioxidant or antioxidants reduce inflammation and oxidative stress. In one embodiment, the antioxidant (s) participate in 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.

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.

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

In one embodiment, boswellia is used as the source of the boswellic acid.

In one embodiment, green tea is used as a source of catechins. In one embodiment, milk thistle is used as a source of silybin.

In one embodiment, turmeric is used as a source of curcumin. In one embodiment, sophorajaponica is used as a source of quercetin.

According to one embodiment, the antioxidant (s) is a mixture, administered to the subject in need thereof via a single galenic form or administered by distributing the antioxidants in at least two galenical forms, comprising at least two compounds chosen from: silybin, or extract dry aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin,

quercetin,

curcumin, or extract of turmeric rhizome preferably titrated from 80% to 95% by weight in curcumin, and / or

Vitamin E.

According to a preferred embodiment, the antioxidant (s) is a mixture, administered to the subject in need thereof via a single galenic form or administered by distributing the antioxidants in at least two galenical forms, consisting of at least two compounds chosen from: silybin , or dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin,

quercetin,

Vitamin E.

In the prior art, certain antioxidants have been tested individually and at high doses in the treatment of NASH; the interest of the specific mixture consisting of at least two compounds from 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 a synergistic action of said antioxidants in improving NASH. Indeed, the antioxidants are used individually at lower doses than the individual doses used in the 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 NASH as the effect of each individual antioxidant tested at high dose in the prior art.

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: - less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of dry extract of aerial parts of milk thistle titrated at 80% by weight of silybin (Silybum marianum ),

less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin,

- 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 in curcumin, and

less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU of vitamin E. In one embodiment, the antioxidant (s) is a mixture administered in one or more pharmaceutical forms, for example for use within the body. 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:

200 mg of dry extract of aerial parts of milk thistle titrated at 80% by weight of silybin (Silybum marianum),

100 mg of quercetin,

1 g of turmeric rhizome extract titrated at least 80% by weight in curcumin, preferably titrated from 80% to 95% by weight in curcumin, and 12 mg (18IU) of vitamin E. 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: less than 5000 mg, preferably less than 1000 mg, more preferably less than 500 mg, even more preferably about 200 mg of berberine, less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably approximately 100 mg of quercetin, less than 1.75 g, preferentially less than 1.5 g, more preferably less than 1.35 g, even more preferably approximately 1 g of extract of turmeric rhizome titrated to at least 80%, preferably 80% to 95% by weight of curcumin,

less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU, even more preferably around 12 mg (18IU) of vitamin E.

Alternatively, the antioxidant (s) is (are) 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: less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably approximately 200 mg of dry extract of aerial parts of milk thistle titrated at 80% by weight of silybin (Silybum marianum),

less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably around 100 mg of quercetin, less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g , even more preferably approximately 1 g of turmeric rhizome extract titrated from 80% to 95% by weight in curcumin, and of

less than 600 IU, preferably less than 100 IU, more preferentially less than 20 IU, even more preferably around 18 IU of vitamin E. Formulation

In one embodiment, the composition according to the invention comprises or consists of: glutamine;

silybin or a dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin;

beta-glucans, for example oat beta-glucans;

pectins;

cellulose;

a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021); fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA);

turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin; and

quercetin.

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

In one embodiment, the composition according to the invention comprises or consists of: - glutamine;

vitamin E, preferably natural;

beta-glucans, for example oat beta-glucans;

- pectins;

cellulose;

a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021); acacia fibers; fish oil, preferably titrated to at least 60% by weight in omega-3, for example said omega-3 can comprise docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA);

turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin;

quercetin.

In one embodiment, the composition according to the invention comprises or consists of: less than 30 g, preferably less than 15 g, more preferably less than 8 g, even more preferably approximately 5 g of glutamine;

- 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;

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;

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;

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;

less than 100 g, preferably less than 75 g, more preferably less than 55 g, even more preferentially approximately 50 mg (i.e. approximately 5 billion CFU) of a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021);

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-3 3 may include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); less than 1.75 g, preferably less than 1.5 g, more preferentially less than 1.35 g, even more preferably approximately 1 g of extract of turmeric rhizome (Curcuma longa) titrated at 80% by weight of curcumin; and

less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg, even more preferably about 100 mg of quercetin.

According to one embodiment, the composition according to the invention also comprises: less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU, even more preferably approximately 18 IU (12 mg) of vitamin E, preferably of natural vitamin E; and or

- less than 500 mg, preferably less than 400 mg, more preferably less than 300 mg, even more preferably around 200 mg of acacia fibers.

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

The composition according to the invention can in particular be administered once a day to a subject in need thereof. The various compounds 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 a part being packaged in two soft capsules.

In one embodiment, the composition according to the invention is in three parts. In one embodiment, the composition according to the invention is in three parts: a first part comprising one or more sources of dietary fiber, preferably as defined above, glutamine, preferably as defined above ,

- a second part comprising one or more probiotics, preferably as defined above,

a third part comprising one or more sources of omega-3, preferably as defined above,

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.

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

In one embodiment, only the first part of the composition according to the invention comprises one or more antioxidants.

In one embodiment, only the third part of the composition according to the invention comprises one or more antioxidants.

In one embodiment, the second part of the composition according to the invention does not include antioxidants. In one embodiment, the first part of the composition according to the invention has a total content of fiber sources ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition according to the invention.

In one embodiment, the first part of the composition according to the invention has a total content of fiber sources ranging from 40 to 60% by weight, relative to the total weight of the first part of the composition according to the invention. In one embodiment, the first part of the composition according to the invention has a total glutamine content ranging from 30 to 70% by weight, relative to the total weight of the first part of the composition according to the invention.

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

In one embodiment, the first part of the composition according to the invention has a total antioxidant content ranging from 0 to 40% by weight, relative to the total weight of the first part of the composition according to the invention. In one embodiment, the first part of the composition according to the invention has a total antioxidant content ranging from 0 to 20% by weight, relative to the total weight of the first part of the composition according to the invention.

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

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

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.

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. In one embodiment, the second part of the composition according to the invention has a total probiotic content of 100% by weight, relative to the total weight of the second part of the composition according to the invention. In one embodiment, the third part of the composition according to the invention has a total content of omega-3 sources ranging from 10 to 50% by weight, relative to the total weight of the third part of the composition according to 'invention.

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

In one embodiment, the third part of the composition according to the invention has a total antioxidant content ranging from 50 to 90% by weight, relative to the total weight of the third part of the composition according to the invention. In one embodiment, the third part of the composition according to the invention has a total antioxidant content ranging from 60 to 80% by weight, relative to the total weight of the third part of the composition according to the invention.

In one embodiment, the composition according to the invention comprises: 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 of 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, 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 part two and

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. 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.

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. 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.

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. 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.

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.

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.

In one embodiment, the first part / second part weight ratio varies from 1 to 10.

In one embodiment, the first part / second part weight ratio varies from 3 to 8. In one embodiment, the first part / second part weight ratio varies 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. 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. According to one embodiment, the first part comprises: glutamine,

vitamin E, preferably natural,

silybin or a dry extract of aerial parts of milk thistle (Silybum marianum) preferably titrated at 80% by weight of silybin,

- beta-glucans, preferably oat beta-glucans,

pectins, and

cellulose.

Optionally, the first part can also comprise turmeric or a turmeric rhizome extract titrated from 80% to 95% by weight in curcumin and quercetin. According to a preferred embodiment, the first part comprises: less than 30 g, preferably less than 15 g, more preferably less than 8 g of glutamine,

less than 600 IU, preferably less than 100 IU, more preferably less than 20 IU of vitamin E, preferably natural vitamin E,

- 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,

less than 10 g, preferably less than 10 g, more preferably less than 2.5 g of beta-glucans, preferably oat beta-glucans,

- less than 10 g, preferably less than 5 g, more preferably less than

2.5 g of pectins, and

less than 10 g, preferably less than 5 g, more preferably less than 2.5 g of cellulose. Optionally, the first part can also comprise: less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of extract of turmeric rhizome (Curcuma longa) titrated at 80% by weight in curcumin, and

- less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin.

According to a more preferred embodiment, the first part comprises: approximately 5 g of glutamine,

about 18IU (12 mg) of vitamin E, preferably natural vitamin E, - about 200 mg of dry extract of aerial parts of milk thistle (Silybum marianum) titrated at 80% by weight of silybin,

approximately 1.666 g of oat beta-glucans,

approximately 1.666 g of pectins, and

about 1.666 g of cellulose. Optionally, the first part can also include: approximately 1 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight in curcumin, and

about 100 mg of quercetin.

Advantageously, the first part is in the form of a sachet. According to one embodiment, the second part comprises: a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021), and acacia fibers.

According to a preferred embodiment, the second part comprises: 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

less than 500 mg, preferably less than 400 mg, more preferably less than 300 mg of acacia fibers. According to a more preferred embodiment, the second part comprises: approximately 50 mg (i.e. approximately 5 billion CFU) of a mixture of three probiotics: Lactobacillus rhamnosus GG, Bifidobacterium breve BR03 (DSM 16604), Lactobacillus plantarum LP01 (LMG P-21021), and

about 200 mg of acacia fiber. Advantageously, the second part is in the form of a capsule, preferably a capsule consisting of hydroxypropylmethylcellulose, more preferably a capsule consisting of 75 mg of hydroxypropylmethylcellulose.

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).

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

Thus, the third part can for example comprise: - 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);

- quercetin.

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 oil of fish, 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).

Advantageously, the third part also comprises: - less than 1.75 g, preferably less than 1.5 g, more preferably less than 1.35 g of extract of turmeric rhizome (Curcuma longa) titrated at 80% by weight in curcumin, and

less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin. Thus, the third part can comprise: 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-3s can include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA);

- 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

less than 1000 mg, preferably less than 500 mg, more preferably less than 300 mg of quercetin. According to a more preferred embodiment, the third part comprises approximately 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).

Advantageously, the third part also comprises: - approximately 1 g of extract of turmeric rhizome (Curcuma longa) titrated at 80% by weight of curcumin, and

about 100 mg of quercetin. According to an even more preferred embodiment, the third part comprises: approximately 1000 mg of fish oil, preferably titrated to at least 60% by weight of omega-3, for example said omega-3 can comprise the acid docosahexaenoic (DHA) and eicosapentaenoic acid (EPA);

- approximately 1 g of turmeric rhizome extract (Curcuma longa) titrated at 80% by weight in curcumin; and

about 100 mg of quercetin.

Advantageously, the third part further comprises glycerol, preferably approximately 182 mg of glycerol. Glycerol is an excipient used as a humectant. Optionally, the third part also comprises at least one additive aimed at preventing the deterioration of fish oil, for example chosen 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 have an antioxidant effect in the subject in whom the third part of the composition according to the invention is administered.

Advantageously, the third part is 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, the structure of which consists of 182 mg of fish gelatin. The third part can for example also be in the form of 2 soft capsules.

According to an advantageous characteristic, when the first part of the composition comprises turmeric or an extract of turmeric rhizome titrated from 80% to 95% by weight in curcumin and quercetin, the third part of the composition does not include any. not ; 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 include any.

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 (NASH). 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.

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

The pharmaceutical or nutraceutical composition can typically include 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. Thus, the nutraceutical or pharmaceutical composition may further comprise a texturing agent, preferably a gelling agent, even more preferably a modified starch. The nutraceutical or pharmaceutical composition may further comprise an anti-stick agent in order to improve the rheological properties of the pharmaceutical or nutraceutical composition.

In one embodiment, the anti-stick agent is magnesium stearate. In one embodiment, the nutraceutical or pharmaceutical composition further comprises minerals and micronutrients such as trace elements 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 B 12, folic acid, biotin, vitamin D or vitamin E.

In one embodiment, the nutraceutical or pharmaceutical composition comprises: a. one or more sources of dietary fiber chosen from sources of plant fibers, preferably are chosen from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds,

b. glutamine,

vs. one or more probiotics,

d. one or more sources of omega-3, and

e. one or more antioxidants,

In one embodiment, the nutraceutical or pharmaceutical composition comprises: a. one or more sources of dietary fiber,

b. glutamine, vs. one or more probiotics chosen from lactic acid bacteria, preferably chosen from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture of these, more preferably are chosen from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture of these this,

d. one or more sources of omega-3, and

e. one or more antioxidants,

b. glutamine,

vs. one or more probiotics,

d. one or more sources of omega-3 chosen 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 e. one or more antioxidants,

for use in the prevention and / or treatment of dysbiosis of the intestinal microbiota. In one embodiment, the nutraceutical or pharmaceutical composition comprises: a. one or more sources of dietary fiber,

b. glutamine,

vs. one or more probiotics, d. one or more sources of omega-3, and

e. one or more antioxidants chosen from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably chosen from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds,

In one embodiment, the nutraceutical or pharmaceutical composition comprises: a. one or more sources of dietary fiber chosen from sources of plant fibers, preferably are chosen from sources of hemicellulose celluloses, pectins, starch, beta-glucans, and a mixture of these compounds,

b. glutamine,

vs. one or more probiotics chosen from lactic acid bacteria, preferably chosen from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture of these, more preferably are chosen from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture of these this,

d. one or more sources of omega-3, and

e. one or more antioxidants,

b. glutamine,

vs. one or more probiotics, 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 e. one or more antioxidants chosen from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably chosen from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds,

b. glutamine,

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 chosen from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds, and e. one or more antioxidants chosen from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably chosen from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds,

for its use in the prevention and / or treatment of dysbiosis of the intestinal microbiota.

Administration mode

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

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

In one embodiment, the composition according to the invention is in the form of capsules.

In one embodiment, the composition according to the invention is in the form of soft capsules. In one embodiment, the composition according to the invention is in the form of a sachet.

In one embodiment, the first part of the composition according to the invention as defined above is in the form of a sachet.

In one embodiment, the second part of the composition according to the invention as defined above is in the form of a soft capsule. In another embodiment, the second part of the composition according to the invention as defined above is in the form of a capsule. In one embodiment, the third part of the composition according to the invention as defined above is in the form of a capsule. In another embodiment, the third part of the composition according to the invention as defined above is in the form of a soft capsule. Use of composition

The characteristics of the composition according to the invention as described above apply for the uses of the composition, the composition for its 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. 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 its use in the prevention and / or treatment of dysbiosis of the intestinal microbiota. As mentioned above, dysbiosis includes a change in the intestinal flora (gut 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 its 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. .

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 its 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.

In one embodiment, dysbiosis of the gut microbiota is associated with Irritable Bowel Syndrome (ER). In one embodiment, dysbiosis of the gut microbiota is associated with type I diabetes.

In one embodiment, dysbiosis of the gut microbiota is associated with type II diabetes. In one embodiment, dysbiosis of the gut microbiota is associated with obesity.

In one embodiment, dysbiosis of the gut microbiota is associated with non-alcoholic fatty liver disease (NASH).

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

In one embodiment, gut microbiota dysbiosis is associated with Irritable Bowel Syndrome, type I diabetes, type II diabetes, obesity, nonalcoholic fatty liver disease.

In one embodiment, dysbiosis of the gut microbiota is associated with Irritable Bowel Syndrome (ER).

In one embodiment, dysbiosis of the gut microbiota is associated with allergies.

In one embodiment, dysbiosis of the gut microbiota is associated with food-type allergies.

In one embodiment, the composition according to the invention is used in the prevention and / or treatment of Irritable Bowel Syndrome (AD). An object of the present invention is thus the composition according to the invention in the prevention and / or treatment of Irritable Bowel Syndrome (AD). 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. type I diabetes. 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.

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.

In one embodiment, the composition according to the invention is used in the prevention and / or treatment of non-alcoholic fatty liver disease (NASH). 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 (NASH). Indeed, currently the only effective treatment for NASH is to reduce the patient's weight by at least 10%. However, this weight goal is difficult to maintain over the long term and other actions should be considered. Both dysbiosis and insulin resistance are implicated in the pathophysiology of NASH. Thus, the present invention also relates to the composition according to the invention for its use in the prevention and / or treatment of NASH.

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.

The invention also relates to a method for preventing and / or treating dysbiosis comprising a step of administering the composition according to the invention to a patient in need. In one embodiment, the invention also relates to a method for the prevention and / or treatment of Irritable Bowel Syndrome (AD) comprising a step of administering the composition according to the invention to a patient in need.

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 of the composition according to the invention.

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 of the composition according to the invention. 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 the composition according to the invention.

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 the composition according to the invention to a patient in need.

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 of the composition according to the invention.

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

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

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

Kit The present invention also relates to a kit in three parts: a first part comprising one or more sources of dietary fiber, preferably as defined above, glutamine, preferably as defined above,

a second part comprising one or more probiotics, preferably as defined above,

one or more antioxidants, preferably as defined above, the antioxidant (s) being included in the first part of the kit and / or in the second part of the kit. 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 above.

EXAMPLES The present invention will be better understood on reading the following examples which non-limitatively illustrate the invention.

Examples of composition according to the invention were prepared according to Tables 1 to 4 below. Example 1: composition for its use in the prevention and / or treatment of Irritable Bowel Syndrome (ER)

[Table 1]

* compared to the pure ingredient

EPA: Eicosapentaenoic acid

DHA: Docosahexaenoic acid

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

The three part composition according to Table 1 is expected to treat SU. Example 2: composition for its use in the prevention and / or treatment of obesity

[Table 2]

* compared to the pure ingredient

EPA: Eicosapentaenoic acid

DHA: Docosahexaenoic acid

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.

The three part composition according to Table 2 is expected to treat obesity. Example 3: composition for its use in the prevention and / or treatment of diabetes (type I or II)

[Table 3]

* compared to the pure ingredient

EPA: Eicosapentaenoic acid

DHA: Docosahexaenoic acid

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

The three part composition according to Table 3 is expected to treat type I or II diabetes. Example 4: composition for its use in the prevention and / or treatment of non-alcoholic fatty liver disease - NASH

[Table 4]

* compared to the pure ingredient

EPA: Eicosapentaenoic acid

DHA: Docosahexaenoic acid

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

The three part composition according to Table 4 is expected to treat NASH. Thus, through its four examples, it is expected that the compositions according to the examples above make it possible to restore dysbiosis by the combined action of the constituents on different 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 organism.

Example 5: Observational study of the effectiveness of a composition according to the invention in improving moderate to severe non-alcoholic fatty liver disease (NASH) The severity of NASH is linked to the extent of hepatic fibrosis; it can progress to cirrhosis (stage F4 fibrosis according to the METAVIR score), and cirrhosis can itself progress to hepatocarcinoma (primary liver cancer). Currently, the only effective treatment for NASH is to reduce the patient's weight by at least 10%. However, this weight goal 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, referred to below as "Combo", with a placebo, in improving moderate to severe NASH.

Material and method

Material Composition of the Combo capsule and the placebo capsule:

Composition of the soft capsule Combo and the soft capsule of the placebo:

Additives aimed at preventing spoilage of fish oil (mixture of tocopherols (E306) and rosemary extract (E392)) are present only as excipients and are intended only to prevent oxidation of fish oil. fish. Composition of the Combo sachet and the placebo sachet:

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

60 patients are included in the study. These patients have moderate to severe diagnosed NASH and moderate to severe fibrosis (stage F2 or F3 according to the METAVIR score) and are 18 years of age or older. They are offered inclusion in the study at the time of the announcement of their liver biopsy results. The criteria for non-inclusion of people who are suitable for research are as follows: cirrhosis (stage F4 according to the METAVIR score); hepato-cellular carcinoma; ongoing steatogenic (corticosteroid, methotrexate, amiodarone, tamoxifen) or hepatotoxic treatment (amitriptyline, imipramine, clozapine, diclofenac); viral liver damage; autoimmune liver damage; anticoagulant therapy; antibiotic treatment within two months of inclusion; allergy to soy, aspirin, fish, maltodextrin or El 10 dye; poorly balanced diabetes (HbAlc> 8%); pregnant woman ; excessive alcohol intake (> 100 g / week).

Method

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. 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.

Methods of administration: each patient is administered 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. In addition, physical activity advice and hygiene-dietetic advice are given to each patient included.

Patient monitoring methods:

Medical visits: 6 medical visits for clinical examination are carried out: on the day of inclusion (S0), 4 weeks after inclusion (S4), 12 weeks after inclusion

(S 12), 24 weeks after baseline (S24), 36 weeks after baseline (S36) and at the end of the study (at the end of the 48 ^th week: S48). The clinical parameters monitored during each of the 6 visits are as follows: weight, blood pressure, abdominal perimeter, BMI calculation. Furthermore, an elastometric measurement by FibroScan® is carried out at S0, S24 and S48.

Biological controls: blood samples and stool samples are taken to verify the safety and efficacy of the Combo: on inclusion in the study (S0), 24 weeks after inclusion (S24) and on end of the study (S48).

o Blood samples: the biological parameters checked are as follows: AS AT, ALAT, alkaline phosphatase, gamma-GT, total bilirubin, triglycerides, HDL-cholesterol, LDL-cholesterol, apolipoprotein Al, ferritinemia, glycemia, glycated hemoglobin (HbAlc), insulinemia, calculation of the HOMA index (Homeostasis Model Accessment 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 Reunites" (which involves the measurement of the antioxidant capacity), lipopolysaccharides (LPS), C-reactive protein (CRP), IL6 (interleukin -6), TNF (tumor necrosis factor);

o Stool samples: the parameter analyzed is as follows: analysis of the fecal microbiota by sequencing of the 16S RNA of bacteria (“Phase IV” Luxia method); Pathology: a liver biopsy aspiration is performed at the end of the study (W48) with calculation of the SAF score, in addition to the liver biopsy performed before the inclusion of patients in the study;

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 (S48).

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

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

The objectives of taking the Combo are as follows: - main objective: reduction of NASH at W48 with reduction or stabilization of histological signs, reduction in elastometry scores and in NAFLD and FIB4 biological scores; and

secondary objectives: improvement of the symbiosis and improvement of the quality of life (physical and nutritional state) at W48. The outcomes for the study are as follows: the primary objective outcomes are:

o histological improvement in NASH after 48 weeks of taking the Combo: a liver biopsy puncture to assess the histological evolution of NASH is performed at W48. A histological improvement in NASH is expected with an arrest in the progression of NASH, 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 (S0) and it is whereas it was 3.5 at the end of the study (W48), ie an improvement in the score of 30% and a decrease in the median score of 1.0; o a reduction in elastometric parameters: an examination by FibroScan® is carried out at W48: evaluation of fibrosis by measurement of elasticity and evaluation of steatosis by measurement of CAP (Controlled

Parameter attenuation). 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 from 330 dB / m to 247 dB / m is expected, ie an improvement of 25%; and

o a decrease in biological FIB4 scores (Fibrosis-4 score) and NAFLD;

the secondary endpoints are:

o evaluation of the symbiosis at W48: a concomitant improvement of the microbiota (promotion of its richness 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 mediators of inflammation: 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 concentrations) is expected. , IL6 and / or TNF) and / or oxidative stress (increased antioxidant capacity); and

o lifestyle assessment at W48: physical activity (IPAQ questionnaire), nutritional status (3-day summary assessment). 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 freeze of databases. The comparative analysis is conducted blindly, that is to say that neither the statistician nor the coordinating investigator knows the identification of 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%.

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

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

First, the data are analyzed by intention to treat in order to meet the primary and secondary endpoints.

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 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).

Claims

1. Nutraceutical or pharmaceutical composition comprising: a. one or more sources of dietary fiber, b. glutamine, c. one or more probiotics, d. one or more sources of omega-3, and e. one or more antioxidants,

2. Composition for its use according to claim 1, in which the source or sources of dietary fiber are chosen from sources of plant fibers, preferably are chosen from sources of celluloses, hemicellulose, pectins, starch, beta-glucans, and a mixture of these compounds.

3. Composition for its use according to any one of claims 1 to 2, in which the probiotic (s) are (are) chosen from lactic acid bacteria, preferably are chosen from the family of Lactobacillaceae, Bifidobacteriaceae, and a mixture thereof. , and more preferably are chosen from Lactobacillus rhamnosus, Lactobacillus plantarum, Bifidobacterium breve, and a mixture of these.

4. Composition for its use according to any one of claims 1 to 3, wherein the source (s) of omega-3 are chosen 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 chosen from docosahexaenoic acid, eicosatetraenoic acid, α-linolenic acid, and mixtures of these compounds.

5. Composition for its use according to any one of claims 1 to 4, in which the antioxidant (s) are chosen from curcuminoids, quercetin, rutin, catechins, boswellic acid, resveratrol, berberine, silybin and a mixture of these compounds, and preferably are chosen from curcumin, quercetin, resveratrol, berberine, silybin, catechins, boswellic acid and a mixture of these compounds.

6. Composition for its use according to any one of claims 1 to 5, said composition being in three parts, a first part comprising the source (s) of dietary fiber and glutamine, a second part comprising the probiotic (s), a third part. comprising the source or sources 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 .

7. Composition for its use according to claim 6, wherein the first part of the composition has a total content of fiber sources ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to total weight of the first part of the composition.

8. Composition for its use according to claim 6 or 7, wherein the first part of the composition has a total glutamine content ranging from 30 to 70% by weight, preferably ranging from 40 to 60% by weight, relative to total weight of the first part of the composition.

9. Composition for its use according to any one of claims 6 to 8, in which the third part of the composition has a total content of omega-3 sources ranging from 10 to 50% by weight, preferably ranging from 20 at 40% by weight, relative to the total weight of the third part of the composition.

10. A composition for its use according to any one of claims 1 to 9, wherein dysbiosis of the intestinal microbiota is associated with Irritable Bowel Syndrome (ER), type I diabetes, type II diabetes, obesity, nonalcoholic fatty liver disease (NASH) and Crohn's disease, preferably associated with Irritable Bowel Syndrome (AD), type I diabetes, type II diabetes, obesity and non-alcoholic fatty liver disease (NASH), and more preferably associated with Irritable Bowel Syndrome (AD).