Bacterial strain belonging to the genus Christensenella and compositions

Abstract

The present invention relates to a bacterial strain belonging to the genus Christensenella and the bacteria derived from it, a composition comprising it or them and its uses in particular in the treatment and / or prevention of diseases such as obesity, metabolic diseases, inflammatory bowel diseases, cancers, and diseases associated with dysbiosis of the microbiota.

Description

Title of the invention: Bacterial strain belonging to the genus Christensenella and compositions Technical field

[0001] The invention relates to a novel bacterial strain belonging to the genus Christensenella, to a composition comprising it and its uses, in particular as a medicament in the treatment and / or prevention of diseases such as metabolic diseases, inflammatory diseases, cancers or diseases associated with dysbiosis of the microbiota.

[0002] State of the art

[0003] Our intestinal microbiota or "intestinal flora" is made up of a set of non-pathogenic bacteria, viruses, parasites and fungi, or 1012 to 1014 microorganisms present in the digestive tract of each individual, which represents 2 to 10 times more than the number of cells present in our body. Therefore, its role has been increasingly studied in recent years. In 2012, a microbiologist identified and cultivated from human feces a new species: Christensenella minuta , belonging to the gram-negative Clostridiales. (Morotomi et al., Description of Christensenella minuta gen. nov.,sp. nov., isolated from human faeces, whichforms a distinct branch in the order Clostridiales , and proposai of Christensenellaceae fam. nov., International Journal of Systematic and Evolutionary Microbiology (2012), 62, 144-149).

[0004] In 2014, Goodrich et al. identified C hristensenella minuta as the most heritable bacterial taxon in humans and also suggested its therapeutic potential.

[0005] To date, it is accepted by the scientific community that the human intestinal microbiota is linked to the appearance of certain so-called "non-transmissible" pathologies associated with dysbiosis of the microbiota, such as obesity, diabetes, metabolic diseases, inflammatory intestinal diseases, or even depression. However, the prevalence of these diseases continues to increase, without any satisfactory treatment.

[0006] Globally, the number of obesity cases has almost tripled since 1975. Thus, 39% of adults are considered overweight and 13% suffer from obesity. The associated complications are well known such as metabolic diseases, in particular type 2 diabetes of which 44% of cases are attributable to overweight / obesity, heart disease of which 23% of cases are attributable, cancers which represent between 7% and 41% of cases attributable to overweight / obesity and inflammatory bowel diseases. Overweight / obesity thus causes the death of at least 2.8 million people each year, making it the fifth leading cause of death according to i'oms.

[0007] Despite progress in understanding and caring for patients, modern medicine lacks satisfactory solutions, causing major public health problems. Once confined to high-income countries, obesity is now present in low- and middle-income countries.

[0008] Drug treatments are very limited and surgical treatments are reserved for the most severe forms associated with complications and resulting in heavy constraints for the patient.

[0009] Microbial ecology has thus been increasingly studied in recent years as a regulator of metabolic functions and its central role in establishing a healthy ecosystem.

[0010] Certain bacteria of the genus Christensenella have been repeatedly associated with low body mass index in numerous human cohorts and other studies have suggested a protective role in regulating inflammation.

[0011] An absence or deficiency of bacteria of the genus Christensenella would be involved in particular in obesity, metabolic diseases, heart and vascular diseases, liver and bile duct diseases, kidney diseases, joint diseases linked to overweight, cancers in particular cancers linked to metabolism and / or dysbiosis of the microbiota, autoimmune diseases, atopic dermatological diseases, chronic inflammatory bowel diseases, pneumonia, infectious diarrhea, food allergies, inflammatory nephrology and neurological diseases including degenerative diseases or neuropsychiatric diseases such as anxiety-related disorders or eating disorders (e.g. bulimia).

[0012] However, currently, no satisfactory solution is available to patients.

[0013] There is therefore a strong medical need for a product capable of acting on the microbiota. intestinal, in particular on dysbiosis of the intestinal microbiota in order to prevent and / or treat diseases associated with dysbiosis of the intestinal microbiota.

[0014]

[0015] An objective of the present invention is therefore to provide a solution that is simple, effective and economical for restoring the intestinal microbiota, treating microbiota dysbiosis and reducing the prevalence of diseases associated with an imbalance of the intestinal microbiota in the world, such as obesity / overweight, inflammatory diseases, metabolic diseases and cancers and other diseases associated with intestinal microbiota dysbiosis. Summary of the invention

[0016] To meet this objective, the invention proposes a new specific bacterial strain of Christensenella minuta deposited with the Leibniz Institute DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, in French German Collection of Microorganisms and Cell Cultures GmbH) under the number DSM 33407.

[0017] Among the multitude of bacteria present in the intestinal microbiota, the inventors were able to identify this specific bacterial strain of Christensenella minuta particularly suited to the prevention and / or treatment of so-called "non-transmissible" pathologies associated with dysbiosis of the intestinal microbiota, in particular diseases such as obesity and metabolic diseases, inflammatory diseases, cancers, and others which will be detailed in the description which follows.

[0018] Thus, the invention relates to a bacterial strain of Christensenella minuta deposited under the number DSM 33407.

[0019] The invention also relates to the culture supernatant of the bacterial strain according to the invention.

[0020] The invention also relates to a composition comprising at least said bacterial strain according to the invention and / or the culture supernatant, in a physiologically acceptable medium.

[0021] Finally, the invention is particularly suitable for using said bacterial strain, said supernatant or said composition according to the invention as a medicament, in particular in the prevention and / or treatment of dysbiosis of the microbiota or diseases associated with dysbiosis of the intestinal microbiota.

[0022] Preferably, the invention aims to prevent and / or treat obesity and metabolic diseases, and / or chronic inflammatory bowel diseases.

[0023] Finally, the invention also relates to a non-therapeutic use of the bacterial strain according to the invention, and / or of the supernatant according to the invention, and / or of the composition according to the invention for maintaining and / or strengthening the intestinal microbiota and / or supporting the diversity of the intestinal microbiota and / or promoting the increase of beneficial bacteria in the intestinal microbiota in a healthy subject.

[0024] Other characteristics and advantages will emerge from the detailed description of the invention, the examples and the figures which follow. Brief description of the Figures

[0025] [Fig.l] [Fig.l] is an image of a Christensenella minuta bacterium according to the invention corresponding to the strain DSM 33407 produced by transmission electron microscopy in negative staining (magnification: 36kX).

[0026] [Fig.2] [Fig.2] represents the immunomodulatory effect of DSM 33 407 supernatant on the IL-8-producing HT-29 colon adenocarcinoma cell line after TNF-a stimulation. 6 independent experiments were performed in duplicate.

[0027] [Fig.3] [Fig.3] represents fasting plasma resistin levels measured after 12 weeks of exposure to either a standard diet or a high-fat diet with or without treatment with DSM 33407. Resistin is a cytokine also produced by adipose tissue in mice, and it accelerates the differentiation of preadipocytes into adipocytes.

[0028] [Fig.4] [Fig.4] represents the effect of the DSM 33407 strain on the integrity of the intestinal barrier measured by the TEER (Transepithelial Electrical Resistance) method on Caco2 cells (human colon carcinoma). The TEER method is based on the measurement of transmembrane electrical resistance as an indicator of tight junction cohesion. The membrane is destabilized by the addition of a pro-inflammatory agent (TNF-a) in the presence or absence of DSM 33407 bacteria. The control (Ctrl) + / - TNF-a corresponds to PBS IX / Glycerol 10%, a resuspension medium for DSM 33407 strain bacteria.

[0029] [Fig.5A] [Fig.5A] represents the effectiveness on weight loss. When exposed to an obesogenic diet of the HFD45 type (rich diet providing 45% of calories in the form of fat), daily treatment with DSM 33407 protects against weight gain.

[0030] [Fig.5B] [Fig.5B] represents feed efficiency. When exposed to an obesogenic diet of the HFD45 type (rich diet providing 45% of calories in the form of fat), daily treatment with DSM 33407 limits feed efficiency (i.e., the weight gain per gram of food ingested).

[0031] [Fig.ôA] [Fig.ôA] represents the efficacy on weight loss at different doses. When exposed to an obesogenic diet of the HFD45 type (45% of calories provided by fat), all doses of DSM 33407 tested between 1.107 and 1.1010 CFU / mL protected the animals from weight gain.

[0032] [Fig.ôB] [Fig.ôB] represents the feed efficiency (FE) at different doses. When exposed to an obesogenic diet of the HFD45 type (45% of calories provided by fat), all doses of DSM 33407 tested between 1.107 and 1.1010 CFU / mL limited feed efficiency.

[0033] [Fig.7A] [Fig.7A] represents the persistence of the effect of DSM 33407 treatment after treatment cessation. When exposed to an obesogenic diet such as HFD45, daily treatment with Orlistat (used here as a control) or DSM 33407 protects against weight gain.

[0034] [Fig.7B] [Fig.7B] represents the persistence of the effect of DSM 33407 treatment after treatment cessation. When exposed to an obesogenic diet of the HFD45, daily treatment with Orlistat (used here as control) or DSM 33407 protects against weight gain.

[0035] [Fig.7C] [Fig.7C] represents the persistence of the effect of DSM 33407 treatment after treatment discontinuation. Upon discontinuation of treatment, animals receiving Orlistat rapidly gained weight, unlike animals treated with DSM 33407. ND: Standard maintenance diet of the animals.

[0036] [Fig.8A] [Fig.8A] represents the efficacy on weight loss after a change to a lower-fat diet in obese mice. Animals treated with DSM 33407 exhibit greater weight loss compared to the placebo-treated group.

[0037] [Fig.8B] [Fig.8B] represents the efficacy on weight loss after a change to a lower-fat diet in obese mice. Animals treated with DSM 33407 show greater weight loss compared to the placebo-treated group.

[0038] [Fig.8C] [Fig.8C] represents the feed efficiency after a change to a lower-fat diet in obese mice. Feed efficiency was reduced in animals treated with DSM 33407 compared to placebo.

[0039] [Fig.9A] [Fig.9A] represents the effect of treatment on weight gain and fat accumulation. When exposed to an obesogenic diet such as HFD45, DSM 33407 protects against weight gain.

[0040] [Fig.9B] [Fig.9B] represents the effect of treatment on weight gain and fat accumulation. When exposed to an obesogenic diet such as HFD45, DSM 33407 limits the accumulation of fat mass.

[0041] [Fig.9C] [Fig.9C] represents the effect of treatment on weight gain and fat accumulation. When exposed to an obesogenic diet of the HFD45 type, DSM 33407 shows a tendency to limit the loss of lean mass associated with weight gain.

[0042] [Fig.9D] [Fig.9D] represents the effect of treatment on adipocyte hypertrophy. Treatment with DSM 33407 shows a strong tendency to prevent visceral adipocyte hypertrophy induced by exposure to a HFD diet45.

[0043] [Fig. 10] [Fig. 10] represents the effect of treatment on leptin levels. DSM 33407 prevented the increase in circulating leptin (A) levels typically observed after 12 weeks of exposure to HFD45. Leptin is notably a hormone produced by adipose tissue (adipocytes), depending on the volume of fat tissue and is a marker of adiposity.

[0044] [Fig. 1 IA] [Fig. 1 IA] represents the effect on compulsive eating behaviors. DSM 33407 induces a strong tendency to reduce body weight regain ([Fig. 11 A]).

[0045] [Fig. 1 IB] [Fig. 1 IB] represents the effect on compulsive eating behaviors. DSM 33407 induces a strong tendency to reduce reactive hyperphagia induced following a 12-hour fast.

[0046] [Fig.l2A] [Fig.l2A] represents the effect of daily treatment with DSM 33407 on the increase in fasting plasma glucose levels classically observed during exposure to a HFD45 diet for 4 weeks.

[0047] [Fig.l2B] [Fig.l2B] represents the gene expression level of the glucokinase gene (Gck) relative to the HFD-Veh control group which did not receive treatment and therefore the effect on hepatic glycolysis.

[0048] [Fig. 13] [Fig. 13] represents the effect on bile acid balance, in particular the effect of DSM 33407 on the circulating cholic acid (CA) to taurocholic acid (TCA) ratio after 6 weeks on a control (NC) or high-fat (HFD) diet.

[0049] [Fig.l4A] [Fig.l4A] represents the beneficial effect of DSM 33407 on an obese human microbiota. DSM 33407 induces a significant and persistent increase in the synthesis of SCFAs (Short Chain Fatty Acids) (acetate, propionate, and butyrate).

[0050] [Fig.l4B] [Fig.l4B] represents the beneficial effect of DSM 33407 on an obese human microbiota. DSM 33407 induces a significant and persistent reduction in the synthesis of AGCBr (Branched Chain Fatty Acids).

[0051] [Fig.l4C] [Fig.l4C] represents the effect of DSM 33407 on the Firmicutes / Bacteroidetes ratio in the distal colon.

[0052] [Fig.l4D] [Fig.l4D] represents the effect on the relative abundance of Firmicutes and the increase in Bacteroidetes.

[0053] [Fig.l5A] [Fig.l5A] represents the composition of the metagenome in murine fecal samples (A).

[0054] [Fig.l5B] [Fig.l5B] represents the unsupervised hierarchical clustering of the mouse metagenome after 8 weeks of high-fat diet and with or without treatment with the bacterium DSM 33407.

[0055] [Fig.16A] [Fig.16A] represents the anti-proliferative effect of DSM 33407 (48h) on HCT-116 cells (colon adenocarcinoma).

[0056] [Fig.16B] [Fig.16B] represents the anti-proliferative effect of DSM 33407 (72h) on HCT-116 cells (colon adenocarcinoma).

[0057] [Fig.16C] [Fig.16C] represents the anti-proliferative effect of DSM 33407 on HepG2 cells (hepatocarcinoma). Detailed description of the invention

[0058] Definition

[0059] For the purposes of the invention, the term "bacteria" means a unicellular microorganism capable of reproducing by cell division. Bacteria are classified by family, genus, species. Each bacterial species includes a diversity of bacterial strains. The bacterial strain according to the invention belongs to the family Christensenellaceae, the genus Christensenella and the species minuta. For the purposes of the invention, the term "bacterial strain" or "strain" therefore means a specific bacterial strain but also all bacteria derived from the strain or obtained from the strain or corresponding to the bacterial strain and having the same metabolic functions, for example, at least one bacterium taken from a colony derived from the strain. For the purposes of the invention, the term "bacteria(s) according to the invention" means a bacterial strain according to the invention.

[0060] By "derived bacterial strain" or "mutant strain" or "derived strain" within the meaning of the invention, is meant a bacterial strain having a strong similarity with the bacterial strain deposited under the number DSM 33407. By way of example, the strain may comprise at least 99% homology of the 16S rRNA sequence with the strain DSM 33407. By "derived bacteria", within the meaning of the invention, is also meant a "derived bacterial strain".

[0061] By "supernatant" within the meaning of the invention, is meant the culture supernatant of the bacterial strain according to the invention optionally comprising compounds and / or cellular debris of said strain, and / or metabolites and / or molecules secreted by said strain.

[0062] By "prevention" within the meaning of the invention, is meant the reduction to a lesser degree of the risk or probability of occurrence of a given phenomenon, that is to say, in the context of the present invention, a dysbiosis of the intestinal microbiota and the associated diseases, for example obesity.

[0063] By "treatment" within the meaning of the invention, is meant a reduction in the progression of the disease, a stabilization, a reversal or regression, or even an interruption or inhibition of the progression of a dysbiosis of the intestinal microbiota, and / or of a disease such as a metabolic disease, for example obesity, or an inflammatory disease or cancer. In the context of the invention, these terms also apply to one or more symptoms of said diseases of the present invention.

[0064] For the purposes of the invention, the term "physiologically acceptable medium" means a medium which is compatible with the organism of the individual to whom said composition is to be administered. This may be, for example, a non-toxic solvent such as water. In particular, said medium is compatible with oral administration.

[0065] For the purposes of the invention, the term "pharmaceutically acceptable excipient" means any compound that facilitates the shaping of the composition and does not modify the nature of the biological activity of the active ingredient. A pharmaceutically acceptable excipient may be a solvent, plasticizer, lubricant, dispersion medium, absorption-delaying agents, flow agent, etc.

[0066] By "disease associated with a dysbiosis of the intestinal microbiota" within the meaning of the invention, we mean diseases originating from a dysbiosis of the intestinal microbiota such as certain metabolic diseases, for example diseases linked to obesity including obesity, diabetes, NASH, hepatic or pancreatic steatosis; inflammatory diseases such as chronic inflammatory bowel diseases, for example Crohn's disease, gastritis, pancreatitis, or irritable bowel syndrome; chronic diseases associated with dysbiosis, cardiac and vascular diseases, cancers, for example cancers linked to metabolism.

[0067] Bacterial strain or supernatant according to the invention

[0068] The present invention therefore relates to a bacterial strain of Christensenella minuta deposited under the number DSM 33407 hereinafter referred to as strain DSM 33407 or strain according to the invention or bacterial strain according to the invention.

[0069] The inventors discovered a bacterial strain of Christensenella minuta deposited under the number DSM 33407 and isolated from the feces of a healthy human donor. The inventors thus demonstrated in preclinical models of obesity that the administration of such a strain makes it possible to prevent weight gain and associated metabolic diseases, including in the context of a high-calorie diet. Surprisingly, a prolonged effect of the treatment on weight loss was demonstrated, including after treatment discontinuation and in the context of a high-calorie diet.

[0070] The inventors have also demonstrated in various models that the bacterial strain DSM 33407 allows: - to limit compulsive eating behaviors suggesting an anorexigenic effect, - to inhibit hepatic glycolysis and thus act on hepatic metabolism and therefore prevent the accumulation of lipids, - to obtain an immunomodulatory and anti-inflammatory effect and thus, to prevent and treat inflammatory diseases, - to restore the balance of bile acids and thus prevent and / or treat diseases linked to a disorder of bile production such as biliary stones and other pathologies of the bile ducts such as primary sclerosing cholangitis, - to obtain an anti-proliferative effect suggesting an effect in the prevention and treatment of cancers, - to promote beneficial bacteria in the microbiota such as Ruminococcaceae and Bifidobacteriaceae and maintain the diversity of the intestinal microbiota.

[0071] The said bacterial strain of Christensenella minuta was thus deposited with the Leibniz Institute DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, in French German Collection of Microorganisms and Cell Cultures GmbH) under the number DSM 33407, on 09 / 09 / 2020.

[0072] The scientific classification of the bacterial strain DSM 33407 is as follows: Domain: Bacteria; Phylum: Firmicutes; Class: Clostridia; Order: Clostridiales; Family: Christensenellaceae; Genus: Christensenella; Species: C. minuta.

[0073] Another subject of the invention relates to a bacterial strain of Christensenella minuta derived from the bacterial strain deposited under number DSM 33407. Said strain maintains or improves the capacities described in the context of the present invention. Said derived strain can thus be produced naturally or intentionally, by mutagenesis methods known in the state of the art. By way of example, the mutagenesis methods which can be implemented in the context of the present invention are the growth of the original microorganism in the presence of mutagenic or stress-producing agents, or by genetic engineering aimed at modifying specific or non-specific genes such as site-directed mutagenesis or random mutagenesis. According to a preferred embodiment, the strain derived from the DSM 33407 strain of C. minuta is a genetically modified mutant.

[0074] Preferably, said derived strain comprises a 16S rRNA sequence having at least 99% identity with the 16S rRNA sequence of the bacterial strain DSM 33407.

[0075] 16S ribosomal RNA (16S rRNA) is the ribosomal RNA constituting the small subunit of ribosomes in prokaryotes. The genes encoding this RNA are called 16S rDNA. The 16S rRNA or 16S rDNA sequence is widely used in phylogeny because of its highly conserved structure, which makes it possible to reconstruct the evolutionary history of organisms, particularly prokaryotes and bacteria.

[0076] According to a variant, said derived strain comprises a nucleotide sequence having at least 96% ANI (Average Nucleotide Identity) identity with the nucleotide sequence of the bacterial strain DSM 33407. For the purposes of the invention, the term "ANI" means the average percentage of nucleotide identity calculated from the two-by-two comparison of all the genome sequences shared between the two bacterial strains.

[0077] According to one embodiment, the bacterial strain DSM 33407 and / or the strain derived therefrom, can be used in any form producing the desired effects and the efficacy described in the present application. In particular, the strain can be in live (cultivable or not), dead, semi-live, attenuated or inactivated form. The dead, semi-living, attenuated or inactivated form can be obtained by various techniques known to those skilled in the art. Examples include: irradiation, thermal inactivation or freeze-drying, in particular by heat, exposure to an appropriate pH, UV, gamma rays, X-rays or high pressure.

[0078] The term "semi-active" thus designates a bacterium with low physiological activity whose capacity to proliferate is reduced, temporarily or permanently. The term "inactivated" designates a bacterium which is no longer capable, temporarily or permanently, of proliferating. The term "dead" designates a bacterium which is no longer capable, permanently, of proliferating. Dead or inactivated bacteria may have intact or ruptured cell membranes. Thus the term "inactivated" also designates the extracts and lysates of bacteria obtained.

[0079] Another subject of the invention relates to the culture supernatant obtained from the bacterial strain DSM 33407 and / or the derived strain. Preferably, the culture supernatant comprises at least one of the constituents chosen from a bacterial cellular compound, bacterial cellular debris, a metabolite and / or one or more molecules secreted by the strain and / or the derived strain, or a combination thereof.

[0080] Thus, the cellular compounds and / or cellular debris may be wall components, nucleic acids, membrane components, proteins, lipids, etc. The secreted metabolites or molecules may be any molecule produced or modified by the bacterium due to its metabolic activity during its growth, its use in technological processes (for example, but not limited to, food or drug production processes). For example, the metabolites or molecules may be proteins, amino acids, enzymes, lipids, nucleic acids, etc. By "metabolite and / or molecule(s) secreted by the strain and / or the derived strain" is meant a molecule produced and exported or released outside the bacterium by the bacterium.

[0081] Composition according to the invention

[0082] The strain(s) according to the invention or derived strain(s) and / or the culture supernatant described above and the bacteria derived from said strains are advantageously administered in a composition. Said composition comprising, in a physiologically acceptable medium, at least the strain(s), useful bacteria and / or their supernatant.

[0083] Thus, another aspect of the invention relates to a composition comprising at least one bacterial strain deposited under the number DSM 33407 and / or at least one bacterial strain derived from the bacterial strain deposited under the number DSM 33407, and / or at least one culture supernatant obtained from the strain DSM 33407 and / or the derived strain, hereinafter referred to as the composition according to the invention.

[0084] Preferably, the composition according to the invention comprises a physiologically acceptable medium.

[0085] According to a preferred embodiment, the composition according to the invention further comprises at least one additional compound. An additional compound may be an ingredient, a molecule, an active principle, a microorganism, a bacterium or a mixture of bacteria.

[0086] Preferably, the additional compound is a microorganism different from the bacterial strain according to the invention or from the derived strain. More preferably, the microorganism is a bacterium of the genus Christensenella. By way of example, mention may be made of a bacterium belonging to the species C. minuta, C. timonensis, C. massiliensis and their mixtures.

[0087] According to one variant, the additional compound is a probiotic and / or a prebiotic. The prebiotic may be, for example, at least one prebiotic chosen from galactooligosaccharides, fructooligosaccharides, inulins, arabinoxylans, beta-glucans, lactoglobulins and / or beta-caseins.

[0088] According to another variant, the additional compound can be: - at least one lactic acid-producing bacterium which makes it possible to create an anaerobic environment favorable to Christensenellaceae such as at least one bacterium chosen from bacteria of the genus Lactobacillus spp., Bifidobacterium spp., Streptococcus spp. and / or - at least one bacterium producing butyric acid which creates an environment favourable to Christensenellaceae such as a bacterium of the genus Ruminococcaceae, - at least one other organism promoting the anaerobic conditions necessary for the survival of Christensenellaceae such as at least one yeast chosen from Saccharomyces spp. or microorganisms of the Methanobacteriaceae family, and / or - at least one bacterium associated with the Christensenellaceae ecosystem because they facilitate their survival in the intestine such as at least one bacterium chosen from the bacteria of the phylum Firmicutes, Bacteroidetes, Actinobacteria, Tenericutes, and Verrucomicrobia, and / or - at least one polyphenol such as, for example, at least one polyphenol chosen from quercetin, kaempferol, resveratrol, flavones (such as luteolin), flavan-3-ols or catechins, flavanones (such as naringinin), isoflavones, anthocyanidins, oligo-proanthocyanidins, and / or - at least one mineral and / or at least one vitamin and / or at least one nutritional agent, and / or - at least one pharmaceutical active ingredient preferably chosen from non-steroidal anti-inflammatory drugs, antibodies directed against pro-inflammatory targets (such as anti-TNFalpha or anti-IL6), antirheumatics, analgesics, antimicrobials, corticosteroids, steroidal anabolics, antidiabetics, thyroid agents, antidiarrheals, cough suppressants, antiemetics, antiulcers, laxatives, anticoagulants, erythropoietin, immunoglobulins, immunosuppressants, growth hormones, hormonal drugs, estrogen receptor modulators, alkylating agents, antimetabolites, mitotic inhibitors, radiopharmaceuticals, antidepressants, antipsychotics, anxiolytics, hypnotics, sympathomimetics, stimulants, donepezil, tacrine, asthma medications, beta-agonists, inhaled steroids, leukotriene inhibitors,cromoglycates or cromoglycidic acids, epinephrine, dornase alpha, cytokines, cytokine antagonists, Janus Kinase inhibitors, immunomodulators, lipid-lowering agents, cholesterol-lowering agents, antihypertensive agents.

[0089] According to a preferred object, the composition according to the invention is in any form acceptable for administration to a subject, preferably a human subject or non-human animal. Preferably, the composition according to the invention is in solid, liquid or lyophilized form.

[0090] When the composition is in liquid form, it may in particular comprise bacterial strains according to the invention and / or the derived strain and / or a culture medium for said bacteria which allows them to be preserved, such as, for example, preferably the anaerobic Columbia agar medium enriched with sheep blood, or an equivalent medium not containing any derived product of animal origin.

[0091] When the composition according to the invention is in solid form, the bacterial strains according to the invention and / or the derived strain may be present in lyophilized form, and may also comprise excipients such as, for example, microcrystalline cellulose, lactose, sucrose, fructose, levulose, starches, stachyose, raffinose, ramylum, calcium lactate, magnesium sulfate, sodium citrate, calcium stearate, polyvinylpyrrolidone, maltodextrin, galactooligosaccharides, fructooligosaccharides, pectins, beta-glucans, lactoglobulins, isomaltooligosaccharides, polydextroses, mannitol, sorbitol and / or glycerol.

[0092] According to another embodiment, the composition according to the invention is in a form suitable for administration by oral, nasal, parenteral, rectal, sublingual, ocular, auricular, inhaled or cutaneous route.

[0093] The composition may be in any suitable form. Thus, the composition according to the invention may be in a form chosen from a powder, microencapsulated powder, capsule, capsule, tablet, lozenge, granules, emulsion, suspension, suppository and a syrup.

[0094] According to a particularly suitable embodiment, the composition according to the invention may be in a gastro-resistant form, for example a coated tablet containing microencapsulated bacteria. Said composition may thus be provided with a gastro-resistant coating that is resistant to gastric juice, in order to ensure that the bacterium(s) included in said composition can pass through the stomach. The release of the bacterium(s) may thus occur for the first time in the upper intestinal tract.

[0095] The composition according to the invention may also be presented in the form of a food product, a drink, a nutraceutical, a food additive, a food supplement or a dairy product.

[0096] When the composition according to the invention is included in a food supplement for oral administration, it may be present in capsules, gel capsules, soft capsules, tablets, coated tablets, pills, pastes, lozenges, gums, drinkable solutions or emulsions, a syrup or a gel.

[0097] A food supplement according to the present invention may further comprise a sweetener, a stabilizer, an antioxidant, an additive, a flavoring agent and / or a coloring agent. The formulation thereof is carried out by means of the usual methods for producing coated tablets, capsules, gels, hydrogels for controlled release, emulsions, tablets or capsules.

[0098] A composition according to the present invention may also be in the form of a nutritional composition. Such a nutritional composition according to the present invention may be in the form of a yogurt, a cereal bar, a breakfast cereal, a dessert, a frozen food, a soup, a pet food, a liquid suspension, a powder, a tablet, a gum or a candy.

[0099] A nutritional composition according to the present invention may further comprise at least one ingredient selected from: antioxidants, fish oils, DHA, EPA, vitamins, minerals, phytonutrients, a protein, a lipid, probiotics, prebiotics and combinations thereof.

[0100] According to another object of the invention, the composition comprises 104 to 1012 colony forming units (CFU) of bacteria per daily dose of composition to be administered, preferably 106 to 1012 colony forming units (CFU) of bacteria per daily dose of composition to be administered.

[0101] Preferably this corresponds to a daily dose of bacteria to be administered, regardless of the weight of the person or animal. Preferably, this dose is administered in a single dose. More preferably, the useful composition comprises 107 to 1011 CFU of bacteria per daily dose to be administered, even more preferably 109 CFU. The bacteria are a mixture of bacteria corresponding to or derived from the bacterial strain DSM 33407 and / or corresponding to the derived strain.

[0102] The term CFU (Colony Forming Unit) or CFU (Colony Forming Unit) is a unit for counting the number of bacteria capable of giving rise to a colony during propagation, i.e. viable bacteria. It should be understood that non-viable bacteria may also be present in the compositions and that in general, they should not have a negative effect on the properties of the live bacteria in the composition, and on the contrary, they may exert an effect on themselves.

[0103] Preferably, the daily dose is measured per gram or milliliter of the composition according to the final invention.

[0104] According to another preferred subject, when the composition according to the invention comprises a mixture of bacteria, said mixture comprising at least live bacteria, the composition preferably comprises at least 10% of live bacteria (by number), more preferably at least 50% (by number).

[0105] The live bacteria are a mixture of bacteria corresponding to the bacterial strain DSM 33407 and / or corresponding to the strain derived or originating from said strains.

[0106] In the case of the use of a supernatant of any one of the aforementioned bacterial strains, the composition according to the invention including it may in particular comprise a content of between 0.1 and 99% by weight, in particular from 5 to 95% by weight, in particular from 10 to 90% by weight and more particularly from 15 to 85% by weight, relative to the total weight of the composition.

[0107] Thus, a composition according to the invention may comprise a content of between 0.1 and 99% by weight, in particular from 5 to 95%, in particular from 10 to 90% by weight, more particularly from 15 to 85% by weight, of supernatant relative to the total weight of the composition.

[0108] According to a particular embodiment, the composition according to the invention also comprises at least one pharmaceutically acceptable excipient.

[0109] When the composition comprises such a pharmaceutically acceptable excipient, the composition according to the invention is advantageously a pharmaceutical composition.

[0110] Thus, according to another object, the invention also relates to a pharmaceutical composition comprising the ingredient(s) included in the composition according to the invention and according to any one of the embodiments described above.

[0111] Said pharmaceutical composition according to the invention has at least one application in improving the physical, physiological or psychological well-being of a sick subject, which results in an improvement in the general state of health of said subject or a reduction in the risk of disease. Said pharmaceutical composition may be a medicament.

[0112] Therapeutic and non-therapeutic use

[0113] Thus, another aspect of the invention relates to the bacterial strain according to the invention and / or the derived strain, the supernatant according to the invention, or the composition according to the invention, or the pharmaceutical composition according to the invention for its use as a medicament.

[0114] In particular, the invention makes it possible to provide an effective quantity of bacterial strains according to the invention or of the derived strain, for use as a medicament.

[0115] Such use as a medicine necessarily has a preventive and / or therapeutic effect, that is to say reducing to a lesser degree the risk of being ill and / or reducing or stabilizing or reversing or interrupting the progression of the disease.

[0116] Use as a medicament in the context of the present invention refers to human or veterinary use, said medicament is then administered to a human subject or a non-human animal subject.

[0117] By human subject is also meant an adult or a child or a baby, including a newborn or an infant.

[0118] Preferably, the invention relates to the bacterial strain according to the invention and / or the derived strain, or the bacteria derived from said strains according to the invention, the supernatant according to the invention, or the composition according to the invention, or the pharmaceutical composition according to the invention for its use as a medicament, in particular in the prevention and / or treatment of dysbiosis of the microbiota, in particular of the intestinal microbiota and / or diseases associated with dysbiosis of the intestinal microbiota and / or chronic diseases and / or obesity and / or metabolic diseases and / or inflammatory diseases and / or cancers.

[0119] According to one embodiment, the invention also relates to the bacterial strain according to the invention and / or the derived strain, the supernatant according to the invention, or the composition according to the invention, or the pharmaceutical composition according to the invention. for its use as a medicament, in the prevention and / or treatment of chronic diseases associated with dysbiosis of the microbiota and / or metabolic diseases, preferably metabolic diseases associated with dysbiosis of the microbiota and / or obesity and / or inflammatory diseases, preferably inflammatory diseases associated with dysbiosis of the microbiota and / or cancers, preferably cancers linked to metabolism.

[0120] Preferably, the invention relates to the bacterial strain according to the invention and / or the derived strain, the supernatant according to the invention, or the composition according to the invention, or the pharmaceutical composition according to the invention for its use as a medicament, in the prevention and / or treatment of at least one disease chosen from: - Metabolic diseases, selected from non-insulin-dependent diabetes, gestational diabetes, NASH, hepatic steatosis, pancreatic steatosis, hyperlipidemia, hypercholesterolemia, infertility linked to overweight, urinary incontinence linked to overweight, - Other chronic metabolic diseases, including thyroiditis, - cardiac and vascular diseases, selected from atherosclerosis, thrombopathies, acute pericarditis and chronic constrictive pericarditis, arterial hypertension, vasculitis - liver and bile duct diseases, selected from hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cirrhosis, hepatic encephalopathy, gallstones - joint diseases related to overweight, chosen from osteopenia, osteoporosis, osteoarthritis, inflammation of the vertebral discs - neurodegenerative diseases, selected from Alzheimer's disease, Parkinson's disease, motor neuron diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and Kennedy's disease - cancers linked to metabolism and / or dysbiosis of the microbiota, chosen from hepatocarcinomas, cancers of the digestive tract such as esophagus, stomach and colorectal cancer, pancreatic carcinoma, neuroendocrine tumors (NETs) of the gastroenteropancreatic system, liver tumors, tumors of the gallbladder and biliary tract, renal tumors, glioblastomas, lymphomas, multiple myelomas, chronic myeloid leukemia, chronic myeloproliferative diseases, lung carcinomas - autoimmune diseases, chosen from insulin-dependent diabetes, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, polyendocrine autoimmune syndrome - atopic dermatological diseases, chosen from eczema and psoriasis - chronic inflammatory bowel diseases, selected from Crohn's disease, ulcerative colitis, diverticulitis, esophagitis, gastritis, pancreatitis, peptic ulcer, irritable bowel syndrome - respiratory function disorders, chosen from asthma, cystic fibrosis, chronic obstructive pulmonary diseases and chronic bronchitis, interstitial lung diseases and pulmonary fibrosis, sleep apnea syndrome (SAOS) - pneumonias, chosen from infectious pneumonias, influenza pneumonia and avian flu, severe acute respiratory syndrome (SARS), pneumocystis pneumonia - Infectious diarrhea, selected from Clostridium difficile infection, EHEC infection, salmonella gastroenteritis, campylobacter enteritis, food poisoning by enterotoxin-producing bacteria, cholera, yersiniosis, shigellosis, cryptosporidiosis, listeriosis - Food allergies, chosen from celiac disease, lactose intolerance, bile salt malabsorption syndrome - Inflammatory nephrologies or those linked to microbiota dysbiosis, chosen from urethritis, chronic renal failure, urolithiasis - Other inflammatory disorders, selected from multiple sclerosis, lymphangitis - Neurological diseases linked to microbiota dysbiosis, selected from anorexia, bulimia, depression, bipolar syndrome, autism, schizophrenia, Tourette's syndrome.

[0121] According to a particularly advantageous embodiment, the invention relates to the prevention and / or treatment of at least two diseases chosen from the preceding list, preferably at least three, more preferably at least four and even more preferably at least five.

[0122] According to a final object, the invention also relates to a non-therapeutic use of a bacterial strain according to the invention, and / or a supernatant according to the invention, and / or composition according to the invention for maintaining and / or strengthening the intestinal microbiota and / or supporting the diversity of the intestinal microbiota and / or promoting the increase of beneficial bacteria in the intestinal microbiota and / or promoting weight loss in a healthy subject.

[0123] For the purposes of the invention, the term "healthy subject" means a subject who is not ill and not suffering from any illness, in particular not suffering from a disease chosen from: - Metabolic diseases, chosen from non-insulin-dependent diabetes, gestational diabetes, NASH, hepatic steatosis, pancreatic steatosis, hyperlipidemia, hypercholesterolemia, infertility linked to being overweight, urinary incontinence linked to being overweight, - Other chronic metabolic diseases, including thyroiditis, - cardiac and vascular diseases, selected from atherosclerosis, thrombopathies, acute pericarditis and chronic constrictive pericarditis, arterial hypertension, vasculitis - liver and bile duct diseases, selected from hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cirrhosis, hepatic encephalopathy, gallstones - joint diseases related to overweight, chosen from osteopenia, osteoporosis, osteoarthritis, inflammation of the vertebral discs - neurodegenerative diseases, selected from Alzheimer's disease, Parkinson's disease, motor neuron diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and Kennedy's disease - cancers linked to metabolism and / or dysbiosis of the microbiota, chosen from hepatocarcinomas, cancers of the digestive tract such as esophagus, stomach and colorectal cancer, pancreatic carcinoma, neuroendocrine tumors (NETs) of the gastroenteropancreatic system, liver tumors, tumors of the gallbladder and biliary tract, renal tumors, glioblastomas, lymphomas, multiple myelomas, chronic myeloid leukemia, chronic myeloproliferative diseases, lung carcinomas - autoimmune diseases, chosen from insulin-dependent diabetes, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, polyendocrine autoimmune syndrome - atopic dermatological diseases, chosen from eczema and psoriasis - chronic inflammatory bowel diseases, selected from Crohn's disease, ulcerative colitis, diverticulitis, esophagitis, gastritis, pancreatitis, peptic ulcer, irritable bowel syndrome - respiratory function disorders, chosen from asthma, cystic fibrosis, chronic obstructive pulmonary diseases and chronic bronchitis, interstitial lung diseases and pulmonary fibrosis, sleep apnea syndrome (SAOS) - pneumonias, chosen from infectious pneumonias, influenza pneumonia and avian flu, severe acute respiratory syndrome (SARS), pneumocystis pneumonia - Infectious diarrhea, selected from Clostridium difficile infection, EHEC infection, salmonella gastroenteritis, campylobacter enteritis, food poisoning by enterotoxin-producing bacteria, cholera, yersiniosis, shigellosis, cryptosporidiosis, listeriosis - Food allergies, chosen from celiac disease, lactose intolerance, bile salt malabsorption syndrome - Inflammatory nephrologies or those linked to microbiota dysbiosis, chosen from urethritis, chronic renal failure, urolithiasis - Other inflammatory disorders, selected from multiple sclerosis, lymphangitis - Neurological diseases linked to microbiota dysbiosis, selected from anorexia, bulimia, depression, bipolar syndrome, autism, schizophrenia, Tourette's syndrome.

[0124] The invention is now illustrated by examples of bacteria useful according to the invention, methods of culturing these bacteria, examples of compositions containing them and results of tests demonstrating the effectiveness of the invention which are presented for illustration purposes only. Examples

[0125] Example 1: Characterization of C. minuta according to the invention filed under number DSM 33407,

[0126] The bacterial strain C. minuta DSM 33407 can be characterized by the following method.

[0127] Native bacteria of strain DSM 33407 (10 pL of culture medium dosed at 109 CFU / mL) were deposited on ionized carbon grids (Delta Microscopy, Toulouse, France) and negative staining was performed with Nano-Tungsten (Nano-W, Nanoprobes, LFG Distribution, France).

[0128] Observation of the grid-mounted bacteria was carried out with a transmission electron microscope (Talos F200S G2 - Thermofisher - Eindhoven) at 200kV, equipped with a 4K*4K One View camera (Gatan, Paris, France). Sample preparation and acquisitions were carried out at the Bordeaux Imaging Center (member of France-Biolmaging, ANR-10-INBS-04). Gram staining was carried out following the Classical procedure. The bacterium according to the invention has the following characteristics: gram negative, strict anaerobic, non-spore forming and resistant to bile acids. From the strain DSM 33407, the generation time (G) is 9.2 hours and the growth rate (K) is 0.11 G / hours.

[0129] [Fig.l] represents the image of a Christensenella minuta bacterium according to the invention produced by negative staining transmission electron microscopy (magnification: 36kX). The average dimensions of a bacterium of the DSM 33407 strain are: length = 1.77 +- 0.34 mm; width = 1.52 +- 0.03 mm; with a membrane thickness = 35 nm (average produced from 40 bacteria).

[0130] Example 2: Anti-inflammatory effect of the strain according to the invention.

[0131] In the present study, the inventors investigated the immunomodulatory and anti-inflammatory effect of the strain DSM 33407.

[0132] The study protocol is as follows. HT-29 cells (ECACC) were seeded in 24-well plates at 3x105 cells per well in McCoy's 5A medium (Gibco) supplemented with 10% fetal calf serum (FCS, Gibco) and incubated at 37°C / 5% CO2 for 24 hours. The cells were washed with PBS-1X (Gibco) and cultured for an additional 24 hours in McCoy's 5A medium with 2% FCS. The cells were then stimulated for 6 hours with 5 ng / ml TNF-a in the presence of 10% DSM 33407 stationary phase supernatant or bacterial culture medium as a control (ctrl). After 6 h, cell culture supernatants were collected and stored at -80°C until IL-8 quantification by ELISA. IL-8 assay was performed by BioLegend specific ELISA, according to the manufacturer's instructions. Absorbance at 460 nm was read using FluoStar Omega microplate reader, BMG Labtech.

[0133] To evaluate the immunomodulatory effect of the DSM 33407 strain, HT-29 cells were stimulated with the pro-inflammatory cytokine TNF-a and DSM 33407 supernatant in stationary phase for 6H. The chemokine IL-8 is secreted by HT-29 in a TNF-a-induced inflammatory state (Ctrl). The values ​​represent the mean normalized in percentage relative to the control + TNF-a, representing the IL-8 secretion induced by TNF-a stimulation, i.e. 100%.

[0134] [Fig.2] shows that in the presence of the supernatant of the DSM 33407 strain, the secretion of IL-8 is reduced by 50% compared to the control (p<0.0001, Dunnett's multiple comparisons test). The supernatant of the DSM 33407 strain therefore has an immunomodulatory and anti-inflammatory effect.

[0135] Example 3: Anti-inflammatory effect of the strain according to the invention,

[0136] In the present study, the inventors investigated the anti-inflammatory effect of the DSM 33407 strain on a total of 30 male mice.

[0137] The study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a standard diet (ND for normal diet) or a high-fat diet (HFD45: 45% of caloric intake comes from fat) for 12 consecutive weeks. During this time, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). During the study, weight and food intake were monitored. Each group consisted of 10 mice. Blood levels of an adipokyne considered an indirect inflammatory marker, resistin, were measured. Quantification was performed using custom-built BIORAD plates (Biorad, Marnes la Coquette, France). All samples were evaluated in duplicate.

[0138] The results were analyzed by one-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test) using Prism8 software (Graphpad). All results are expressed as mean ± standard deviation of the mean (SEM) and the significance threshold is set at p < 0.05 for all analyses.

[0139] [Fig.3] shows that fasting plasma resistin levels measured after 12 weeks of exposure to HFD45 were significantly reduced in the group of animals treated with DSM 33407. Thus, in association with a limitation of weight gain, daily administration of DSM 33407 significantly reduced circulating (fasting blood) resistin levels.

[0140] Example 4: Effect of the strain according to the invention on the integrity of the intestinal barrier.

[0141] In the present study, the inventors investigated the protective effect on the intestinal epithelium of the strain DSM 33407.

[0142] The study protocol is as follows. Caco-2 cells (ECACC) were seeded at 2x104 cells per well in 24-well plates containing inserts with a permeable polyester membrane Transwell (Corning Life Science). The cells were cultured in DMEM medium supplemented with 20% fetal calf serum (FCS, Gibco) and incubated at 37 °C / 5% CO2. Transepithelial electrical resistance (TEER) was checked daily from the seventh day of culture using an EV0M3 ohmmeter (WPI). The medium was replaced every 2 days for 8 to 10 days, until the optimal TEER was reached (2000 Q.cm2). Upon reaching the reference TEER, cells were treated in the apical compartment with DSM 33407 at an MOI of 50 or 1X PBS / 10% Glycerol (control) for 3 h, then 100 ng / ml of TNF-a was added or not in the basal compartment.TEER was measured just before the addition of TNF-a (T0) and 6 h (T6H) after the addition of TNF-a.

[0143] To assess the ability of strain DSM 33407 to restore or strengthen the intestinal barrier, polarized monolayer Caco-2 cells were pretreated with DSM 33407 and then sensitized to TNF-a. TEER was compared at T0 (before addition of TNF) and T6H. Values ​​represent the mean normalized to the -TNF-a control, representing basal TEER.

[0144] The results in [Fig.4] indicate that treatment of Caco-2 with TNF-a induces an increase in permeability (Ctrl + TNF-a). The DSM 33407 strain is thus able to restore the epithelial barrier, with a return to the basal level (Ctrl - TNF-a).

[0145] Example 5: Effect on weight gain and feed efficiency of the strain according to the invention.

[0146] In the present study, the inventors investigated the effect of strain DSM 33407 on weight gain.

[0147] The study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a normal diet (ND; 10 mice) or a high-fat diet (HFD45, 45% of caloric intake comes from fat) for 4 consecutive weeks (20 mice). During this time, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). Each group consisted of 10 mice. During the study, weight and food intake were monitored, thus allowing the estimation of feed efficiency (FE; in g / kcal). To compare the impact of treatments on FE, the area under the curve (AUC) was measured between D0 and D27.Results were analyzed by two-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test or Dunett test) using Prism8 software (Graphpad). All results are expressed as mean ± standard deviation of the mean (SEM) and the significance level is set at p<0.05 for all analyses. (Statistical symbols on graphs: *p<0.05, **p<0.01, ***p<0.001).

[0148] Animals on HFD45 all gained significantly more weight than animals remaining on ND. Treatment with DSM 33407 significantly prevented weight gain induced by exposure to the obesogenic HFD45 diet (Figure 5). The first significant effects on weight gain appeared from the 11th day of treatment. In the group treated with DMS 33407, feed efficiency was significantly reduced compared to the group of animals on placebo.

[0149] Example 6 _: Effect on weight gain and feed efficiency of the strain according to the invention at different doses.

[0150] In the present study, the inventors investigated the effect of strain DSM 33407 at different doses on weight gain.

[0151] The study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a standard diet (ND for normal diet; 10 mice) or a high-fat diet (HFD45, 45% of caloric intake comes from fat; 20 mice) for 6 consecutive weeks. During this time, the animals were treated daily by oral gavage with either 4 different doses of DSM 33407 (treated group) or its vehicle (Placebo control group). The doses tested were 1.5 × 107 CFU / mL, 1.5 × 108 CFU / mL, 1.5 × 109 CFU / mL (reference dose), and 1.5 × 1010 CFU / mL. Each group consisted of 10 mice. During the study, weight, food intake were monitored, thus allowing the estimation of feed efficiency (FE; in g / kcal). To compare the impact of treatments on FE, the area under the curve (AUC) was measured between DO and D40.

[0152] The results were analyzed by two-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test or Dunett test) via Prism8 software (Graphpad). All results are expressed as mean ± standard deviation of the mean (SEM) and the significance threshold is set at p<0.05 for all analyses. (Statistical symbols on the graphs: *p<0.05, **p<0.01, ***p<0.001).

[0153] Animals on HFD45 all gained significantly more weight than animals remaining on ND. All doses of DSM 33407 tested between 1.107 and 1.1010 CFU / mL significantly prevented weight gain induced by exposure to the obesogenic HFD45 diet (Figure 6). The first significant effects on weight gain appeared as early as day 18 of treatment. All four concentrations showed similar effects. In all groups treated with DSM 33407, feed efficiency was significantly reduced compared to the group of animals on placebo.

[0154] Example 7: Effect on weight gain and persistence of the effect, including after stopping treatment.

[0155] In the present study, the inventors investigated the effect of strain DSM 33407 on weight gain and the continuation of this effect after stopping treatment.

[0156] The study protocol is as follows. A total of forty (40) 7-week-old male C57B16 mice were exposed to either a standard diet (ND for normal diet; 10 mice) or a high-fat diet (HFD45, 45% of caloric intake comes from fat; 30 mice) for 7 consecutive weeks. During this time, the animals were treated daily by oral gavage with DSM 33407 (treated group; 1,109 CFU / mL), or with its vehicle (Placebo control group), or with Orlistat (standard obesity treatment). All treatments were stopped and the animals remained on HFD45 for an additional 3 weeks. Each group consisted of 10 mice. The objective here was to test the potential persistence of the effect of DSM 33407 on weight gain. To compare the impact of treatments on weight gain, the area under the curve was measured between D0 and D48 (treatment period) and between D48 and D67 (washout period)..

[0157] Daily weight monitoring results were analyzed by two-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test), and area under the curve results were analyzed by one-way ANOVA with multiple comparisons (Tukey test). All results are expressed as mean ± standard deviation from the mean (SEM) and the significance threshold is set at p<0.05 (statistical symbols on the graphs: *p<0.05, ***p<0.001).

[0158] Again, the animals on HFD45 all gained significantly more weight than the animals remaining on ND. Treatment with DSM 33407 significantly prevented the weight gain induced by exposure to the obesogenic diet HFD45 as shown in Figure 7. The observed effect is comparable to that observed in animals treated with a standard obesity treatment (Orlistat). During the 3 weeks following the cessation of treatment, the animals that were on Orlistat had an acceleration of their weight gain, quickly bringing them closer to the group of animals that were on Placebo. Conversely, the animals on DSM 33407 showed a maintenance of protection against weight gain. These results indicate a persistence of the beneficial effects of DSM 33407 during the 3 weeks following the cessation of treatment, during exposure to an obesogenic diet.

[0159] Example 8: Effect of the strain according to the invention on weight loss during a change of diet.

[0160] In the present study, the inventors investigated the effect of strain DSM 33407 on weight loss during a change in diet in order to evaluate the impact of treatment with DSM 33407 on the weight of obese animals during a change in diet.

[0161] The study protocol is as follows. A total of thirty (30) 18-week-old obese male C57B16 mice raised on a very high fat diet (HFD60, 60% of caloric intake from fat) were gavaged with the DSM 33407 vehicle for one week. At D0, some animals were placed on a standard diet (ND for normal diet; 10 mice) for 4 weeks. The other animals were switched to a lower fat diet (HFD45, 45% of caloric intake from fat; 20 mice) for 4 weeks. These animals were treated with either DSM 33407 (1.5×109 CFU / mL; 10 mice) or its vehicle (placebo control group). During the study, weight and food intake were monitored, allowing for an estimation of feed efficiency (FE; in g / kcal).The main objective of the study was to evaluate the impact of treatment with DSM 33407 on the weight of animals during a change in diet. To compare the impact of treatments on weight and FE, the area under the curve (AUC) was measured between D0 and D28.

[0162] Daily weight monitoring results were analyzed by two-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test), and area under the curve results were analyzed by one-way ANOVA with multiple comparisons (Tukey test). All results are expressed as mean ± standard deviation from the mean (SEM) and the significance threshold is set at p<0.05 (statistical symbols on the graphs: ***p<0.001).

[0163] Treatment with DSM 33407 potentiates weight loss when switching to a lower fat diet in obese mice as shown in Figure 8. Switching from a HFD60 to ND diet induces drastic weight loss. Among animals switched from a HFD60 to HFD45 diet, animals treated with DSM 33407 exhibited greater weight loss compared to the placebo-treated group ([Fig.8A] and 8B). Feed efficiency was reduced in animals treated with DSM 33407 compared to placebo ([Fig.8C]).

[0164] The results thus confirmed that the transition from a HFD60 diet to ND induced a drastic weight loss in obese mice. In obese mice switched to a lower-fat diet (HFD45) and treated with DSM 33407, weight loss and a decrease in feed efficiency were observed. Despite the transition to the HFD45 diet, the animals receiving the placebo continued to gain weight during the 4 weeks of follow-up. These results indicate a potentiating effect of DSM 33407 on weight loss in obese animals.

[0165] Example 9: Effect of the strain according to the invention on adipogenesis in adipose tissue.

[0166] The main objective of the study was to evaluate the impact of treatment with DSM 33407 on the evolution of weight and body composition of animals during exposure to a high-fat diet for 12 weeks.

[0167] The study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a standard diet (ND for normal diet) or a high-fat diet (HFD45: 45% of caloric intake comes from fat) for 12 consecutive weeks. During this period, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). During the study, the weight of the animals was measured and body composition measurements (fat mass and lean mass) by magnetic resonance were carried out at the end of the study (D84). Each group consisted of 10 mice.

[0168] The main objective of the study was to evaluate the impact of treatment with DSM 33407 on the evolution of weight and body composition of animals during exposure to an obesogenic diet.

[0169] Daily weight monitoring results were analyzed by two-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test), and body composition results were analyzed by one-way ANOVA with multiple comparisons (Fischer LSD test). All results are expressed as mean ± standard deviation from the mean (SEM) and the significance threshold is set at p<0.05 (statistical symbols on the graphs: *p<0.05, **p<0.01, ***p<0.001).

[0170] When exposed to the obesogenic HFD45-type diet, daily treatment with DSM 33407 protects against weight gain ([Fig.9A]) and limits the accumulation of fat mass ([Fig.9B]), and shows a tendency to limit the loss of lean mass associated with weight gain ([Fig.9C]).

[0171] A very significant increase in adipocyte hypertrophy (reduction in atrophy) was also observed in animals placed under HFD45 and treated with Placebo. In contrast, treatment with DSM 33407 shows a strong tendency to prevent visceral adipocyte hypertrophy induced by exposure to a HFD45 diet ([Fig.9D]).

[0172] The animals on HFD45 all gained significantly more weight than the animals remaining on ND. Treatment with DSM 33407 significantly prevented weight gain and visceral adipocyte hypertrophy. At the end of the study, body composition analysis showed that in these animals the accumulation of fat mass was also significantly reduced compared to the animals on placebo. The DSM 33407 treatment also showed a strong tendency to limit the loss of lean mass associated with the induction of obesity by a fatty diet.

[0173] Example 10: Effect of the strain according to the invention on adipogenesis in adipose tissue (leptin).

[0174] The study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a standard diet (ND for normal diet) or a high-fat diet (HFD45: 45% of caloric intake comes from fat) for 12 consecutive weeks. During this period, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). At the end of the study, the animals were fasted and blood was collected to extract plasma and measure leptin levels. These measurements were carried out with custom-built BIORAD plates (Biorad, Marnes la Coquette, France). All samples were evaluated in duplicate. The results were analyzed by one-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test) using Prism8 software (Graphpad).All results are expressed as mean ± standard deviation of the mean (SEM) and the significance threshold is set at p < 0.05 for all analyses (statistical symbols on the graphs: *p<0.05, **p<0.01, ***p<0.001).

[0175] Daily treatment with DSM 33407 prevented the increase in circulating leptin levels (Figure 10A) typically observed after 12 weeks of exposure to HFD45%.

[0176] Exposure to a high-fat diet thus induced a very significant increase in circulating leptin levels in the placebo-treated animals. In the group of animals treated daily with DSM 33407, this increase was significantly reduced for leptin.

[0177] Example 11: Effect of the strain according to the invention on compulsive eating behaviors (anorexigenic effect).

[0178] The objective of this study was to evaluate the ability of DSM 33407 to impact the feeding behavior of animals fed an obesogenic diet. To do this, a fasting paradigm followed by re-exposure to food was used to induce reactive hyperphagia in the animals.

[0179] The study protocol is as follows. A total of twenty (20) 7-week-old male C57B16 mice were exposed to either a high-fat diet (HFD45: 45% of caloric intake from fat) for 2 consecutive weeks. During this period, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). On the 14th day, the animals were weighed and fasted for 12 hours. On the morning of the 15th day, the feeders were replaced in the cages. Then the animals' food intake was measured after 1, 2, 4, 8, 24, 48, and 72 hours. The animals were weighed once a day. Results were analyzed by two-way ANOVA with multiple comparisons (uncorrected LSD test) using Prism8 software (Graphpad).All results are expressed as mean ± standard deviation of the mean (SEM) and the significance threshold is set at p < 0.05 for all analyses (statistical symbols on graphs: *p<0.05).

[0180] In animals fed a high-fat diet (HFD45), a 12-hour fast induced weight loss. Upon re-exposure to food, the animals rapidly regained a significant amount of weight and exhibited reactive hyperphagia. Animals treated daily with DSM 33407 induced a strong tendency toward reduced body weight regain ([Fig. 11 A]) visible from 48 hours. In parallel, the amount of calories ingested (cumulatively) during the fasting-induced hyperphagia phase was reduced in the group treated ([Fig. 11 B]) with DSM 33407.

[0181] Example 1 2: Effect of the strain according to the invention on plasma glucose levels and on hepatic glycolysis.

[0182] The plasma glucose level study protocol is as follows. A total of thirty (30) 7-week-old male C57B16 mice were exposed to either a normal diet (ND; 10 mice) or a high-fat diet (HFD45, 45% of caloric intake comes from fat) for 4 consecutive weeks (20 mice). During this time, the animals were treated daily by oral gavage, either with DSM 33407 (treated group) or with its vehicle (control group). Each group consisted of 10 mice. During the study, the animals were fasted and blood was collected to extract plasma at different times (0 and 4 weeks). Circulating glucose levels were measured using custom-built BIORAD plates (Biorad, Marnes la Coquette, France). All samples were evaluated in duplicate. Results were analyzed by one-way ANOVA with multiple comparisons (Benjamini, Krieger and Yegutieli test) using Prism8 software (Graphpad). All results are expressed as mean ± standard deviation of the mean (SEM) and the significance level is set at p < 0.05 for all analyses (statistical symbols on graphs: ***p < 0.001).

[0183] Exposure to a high-fat diet for 4 weeks induced a very significant increase in fasting plasma glucose levels in the placebo-fed animals shown in [Fig.l2A]. In the group of animals treated daily with DSM 33407, this increase was completely prevented.

[0184] The protocol for studying hepatic glycolysis is identical to that previously described. In addition, the expression of glucokinase (Gck) was measured by quantitative PCR using a pair of specific primers (Bio-Rad). Briefly, RNAs were extracted from mouse livers according to and with the RNeasy Lipid tissue kit from Qiagen. The synthesis of complementary DNAs was carried out with the iScript Advanced cDNA synthesis kit from Bio-Rad, according to the instructions. Finally, from the cDNAs, a quantitative PCR was carried out using the SsoAdvanced Universal SYBR Green Supermix kit from Bio-Rad, according to the instructions with the CFX 96 Touch instrument from Bio-Rad. The primer pairs used for this study (Gck, Gapdh, Tbpl, Hrpt) are pairs designated and validated by Bio-Rad. All data used for statistical analysis were extracted using Bio-Rad's CFX Maestro software. Statistical analysis was performed using R (v. 3.6.2).An ANOVA was performed with the treatment factor followed by a Tukey post-hoc test to obtain a p-value adjusted for multiple comparison.

[0185] Animals fed a high-fat diet (HFD-Veh) developed overexpression of the glucokinase (Gck) gene, a key regulator of hepatic glycolysis, compared to the control group (NC-Veh). Treatment with C. minuta DSM 33407 (HFD-DSM 33407) completely inhibited the high-fat diet-induced Gck overexpression. Therefore, it can be concluded that C. minuta DSM 33407 acts on hepatic metabolism through the regulation of energy pathways to prevent lipid accumulation ([Fig.l2B]).

[0186] Example 1 3: Effect of the strain according to the invention on the balance of bile acids.

[0187] The study protocol is identical to that presented in Example 5. In this study, the dose of C. minuta DSM 33407 of 109 CFU was used. Bile acids were measured from a serum sample collected on day 40 (D40) by an HPLC (High Performance Liquid Chromatography) method.

[0188] Bile acids play a major role in the intestinal absorption of lipids. Bile acids are secreted by the liver into the bile in the form of conjugated acids, of which taurocholic acid (TCA) is the main component in mice. TCA is then deconjugated by bacteria in the intestinal microbiota to form cholic acid (CA). 95% of bile acids secreted by bile are reabsorbed in the small intestine during digestion, forming the enterohepatic bile acid cycle. The circulating CA / TCA ratio is therefore an indicator of the activity of the enterohepatic cycle and reflects the metabolic balance of the liver and microbiota. When animals are fed a high-fat diet for 6 weeks, the CA / TCA ratio is significantly increased ([Fig. 13]). This imbalance is completely prevented by treatment with C.minutaDSM 33407, which indicates that the treatment is effective in treating diseases related to a disorder of bile production such as gallstones and other pathologies of the bile ducts such as primary sclerosing cholangitis.

[0189] Example 1 4: Effect of the strain according to the invention on the microbiota of obese human subjects.

[0190] The study protocol is as follows. The SHIME® (Human Intestinal Microbial Ecosystem Simulator) is a validated in vitro system for studying DSM 33407 biodistribution and its impact on the microbiota. It consists of a succession of 5 reactors simulating the different parts of the human gastrointestinal tract. The microbiotas of 2 obese human subjects were isolated from the feces of donors pre-selected for their lack of Christensenellaceae and injected into the SHIME system. After 4 weeks of microbiota stabilization and controls, the DSM 33407 treatment was inoculated for 3 weeks (2,109 CFU / day). Finally, a one-week washout period (without treatment) was performed at the end of the treatment to assess the presumed persistence of the product effect.SCFA (short-chain fatty acid; acetate, propionate, butyrate) and rSCFA (branched SCFA; isobutyric acid, isovaleric acid and isocaproic acid) production were measured throughout the study ([Fig.l4A] and 14B). Results were analyzed by one-way or mixed-model ANOVA with multiple comparisons (uncorrected Fischer LSD test) using Prism8 software (Graphpad). All results ([Fig.l4A] and 14B) are expressed as mean ± standard deviation of the mean (SEM) and the significance level . is set at p<0.05 for all analyses (statistical symbols on graphs: *p<0.05, **p<0.01, **p<0.001).

[0191] Throughout the study, samples were taken from the system in order to be able to follow the evolution of the composition of the inoculated microbiota in response to treatment with DSM 33407 ([Fig.l4C] and 14D).

[0192] DNA from microbiota samples was extracted with a specific kit. All results are expressed as mean ± standard deviation of the mean (SEM) and the significance threshold is set at p<0.05 for all analyses (statistical symbols on the graphs: *p<0.05, **p<0.01, **p<0.001).

[0193] The results presented in Figure 14 show the beneficial effects of daily treatment with DSM 33407 on an obese human microbiota. Indeed, a significant, rapid, and sustained increase in the levels of the 3 main SCFAs (Short Chain Fatty Acids) (acetate, propionate, butyrate) was measured in the proximal colon ([Fig.l4A]). The production of these SCFAs reflects an increase in the beneficial saccharolytic fermentation activities in the distal colon ([Fig.l4B]). In parallel, a significant and sustained decrease in the levels of rBNCFAs (Branched Chain Fatty Acids) was measured. The production of rBNCFA indicates a reduction in proteolytic activities within the treated microbiota. It is interesting to note that during the washout period, the levels of SCFAs and rBNCFA remained at their level without returning to the initial concentrations.This suggests the establishment of beneficial effects of DSM 33407 in the long term that persist after treatment discontinuation.

[0194] The results presented in [Fig.l4C] and 14D show a significant decrease in the Firmicutes / Bacteroidetes ratio in the distal colon observed when DSM 33407 was inoculated (TRI, TR2 and TR3). This effect remained constant after one week without inoculation of the bacteria. The decrease in this ratio is explained by the decrease in the relative abundance of Firmicutes and the increase in Bacteroidetes (Figure D). These results thus show the beneficial effect of DSM 33407 in restoring the healthy microbiota of obese individuals. In fact, the Bacteroidetes / Firmicutes ratio is known to be reduced in obese individuals or those suffering from inflammatory bowel diseases.

[0195] Example 1 5: Effect _ of the strain according to the invention on the beneficial bacteria of the microbiota and on the diversity of the intestinal microbiota in animals.

[0196] The study protocol is identical to that presented in Example 5.

[0197] Study of beneficial bacteria.

[0198] The microbiota was obtained by the shot gun method. DNA extraction from mouse stool samples was performed using the Qiagen DNeasy Power Soil Pro Kit DNA extraction kit and following the manufacturer's recommended protocol. The extracted DNA samples were quantified using a Qubit 4 fluorometer and the Qubit™ dsDNA HS Kit (Thermofisher Scientific). DNA libraries were prepared using the Nextera XT DNA Library Prep Kit (Illumina) and the Nextera Index Kit (Illumina) following the manufacturer's protocol. DNA libraries were quantified using a Qubit 4 fluorometer and the Qubit™ dsDNA HS Kit. Paired-end sequencing (2X150 bp) was performed on an Illumina HiSeq4000 with an average sequencing depth of 5 million reads.

[0199] Sequence processing was performed using CosmosID's online platform “Metagenomics Cloud”. Data annotated at family rank were exported, and statistical analyses were performed in Python 3.

[0200] The data were analyzed by Principal Component Analysis, in order to identify groups without a priori and presented in [Fig.l5A].

[0201] Treatment with C. minuta DSM 33407 supports the development of other bacteria such as Bifidobacteriaceae and Ruminococcaceae known for their beneficial metabolism, respectively production of lactic acid and butyric acid indicating a beneficial effect on the intestinal microbiota.

[0202] Study of the diversity of the microbiota.

[0203] Unsupervised hierarchical clustering was achieved using a Python 3 script exploiting the clustermap function from the Seabom v. 0.10.1 library. The function calculates the Euclidean distance matrix between bacterial families and then classifies them using the Voor Hees algorithm. The matrix is ​​colored according to the correlation parameter “r”.

[0204] The results are presented in [Fig.l5B] and show that mice treated for 8 weeks with a high-fat diet and supplemented or not with DSM 33407, favor beneficial bacterial families such as Ruminococcaceae, Rikenellaceae, Lactobacillaceae and Akkermansiaceae (Group B). In contrast, bacterial families rich in opportunistic pathogens such as Enterobacteriaceae, Yersiniaceae, Neisseriaceae and Xanthomonaceae (Group A) are grouped in a distinct manner away from the group supported by Christensenellaceae.

[0205] Example 1 6: Anti-proliferative effect of the strain according to the invention.

[0206] The study protocol is as follows. The HCT-116 and HepG2 cell lines were obtained from Sigma-Aldrich. HCT-116 were maintained in culture in McCoy's 5A medium (Gibco) supplemented with 10% fetal bovine serum (Gibco) and 1% penicillin / streptomycin (Sigma-Aldrich) and HepG2 were cultured in DMEM medium (Gibco) supplemented with 10% S VF (Gibco), in a humid atmosphere incubator at 37°C and 5% CO2.

[0207] Cells were seeded at a density of 10,000 cells / well in a total volume of 100 μl in a 96-well plate. After 24 h of incubation, the culture medium was removed from the adherent cells and new medium supplemented with 10% of DSM 33407 stationary phase supernatant was added and in GAM control (bacterial culture medium). Akt inhibitor VIII was used as a positive control. Each condition was done in 4 replicates. Cells were incubated for an additional 48 h or 72 h.

[0208] Cell proliferation was determined using the CellTiter-Glo 2.0 assay kit (Promega). Measurements were performed according to the manufacturer's instructions. Briefly, the plates were removed from the incubator and allowed to equilibrate at room temperature for 30 min and an equal volume of CellTiter-Glo 2.0 reagent was added directly to the wells (100 μl). The plates were shaken at 300 rpm for 2 min using a rotary shaker and then incubated at room temperature for 10 min. The reaction mixture was then transferred to a white-walled 96-well plate and the luminescent signal was measured using a microplate reader (FLUOstar Omega, BMG Labtech).

[0209] The results presented in Figure 16 allow us to observe the influence of the DSM 33407 strain on the proliferation of tumor cells, in particular the effect on a human colon adenocarcinoma cell line, the HCT-116 line, and on a human hepatocarcinoma line, the HepG2 line. The effect of the supernatant on proliferation was evaluated at 48h (A) and 72h (B) on the HCT-116 cells and at 48h (C) on the HepG2 cells. The DSM 33407 supernatant significantly reduced proliferation compared to the control, corresponding to the cells treated with the bacterial culture medium (bacterial culture medium vs. DSM 33407: p=0.0049 (A), p<0.0001 (B) and p=0.0019 (C), Dunnett's multiple comparisons test). Akt inhibitor VIII is used as a control for blocking cell proliferation.

[0210] The supernatant of strain DSM 33407 induces a decrease in the proliferation of HCT-116 and HepG2 tumor lines, suggesting a potential role in the inhibition of tumor development.

Claims

Claims

1. Bacterial strain of Christensenella minuta deposited under number DSM 33407.

2. Bacterial strain according to the preceding claim, characterized in that it is alive, dead, attenuated or inactivated.

3. Composition comprising at least one bacterial strain according to one of the preceding claims.

4. Composition according to the preceding claim further comprising at least one additional compound.

5. Composition according to the preceding claim, characterized in that the additional compound is a microorganism different from the bacterial strain according to one of claims 1 or 2.

6. Composition according to the preceding claim, characterized in that the microorganism is a bacterium of the genus Christensenella.

7. Composition according to one of claims 4 to 6, characterized in that the compound is a probiotic.

8. Composition according to one of claims 3 to 7, characterized in that it also comprises at least one pharmaceutically acceptable excipient.

9. Composition according to one of claims 3 to 8, characterized in that it is in solid, liquid or lyophilized form.

10. Composition according to one of claims 3 to 9, said composition being in a form suitable for administration by oral, nasal, parenteral, rectal, sublingual, ocular, auricular, inhaled or cutaneous route.

11. Composition according to one of claims 3 to 10, characterized in that it comprises at least 50% of bacteria according to one of claims 1 or 2, living (in number).

12. Composition according to one of claims 3 to 11, in which the composition is in the form of powder, microencapsulated powder, capsule, capsule, tablet, lozenge, granules, emulsion, suspension, suppository, syrup.

13. A composition according to any one of claims 3 to 11, wherein the composition is in the form of a food product, a beverage, a nutraceutical, a food additive, a food supplement or a dairy product.

14. Bacterial strain according to one of claims 1 or 2, or composition according to one of claims 3 to 13, for use as a medicament.

15. Bacterial strain, or composition, for its use according to claim 14, in the prevention and / or treatment of dysbiosis of the microbiota.

16. Bacterial strain, or composition, for its use according to one of claims 14 or 15, in the prevention and / or treatment of chronic diseases.

17. Bacterial strain, or composition, for its use according to one of claims 14 or 15, in the prevention and / or treatment of obesity.

18. Bacterial strain, or composition, for its use according to one of claims 14 or 15, in the prevention and / or treatment of metabolic diseases.

19. Bacterial strain, or composition, for its use according to one of claims 14 or 15, in the prevention and / or treatment of inflammatory diseases.

20. Bacterial strain, or composition, for its use according to claim 14, for its use in the prevention and / or treatment of cancers.

21. Bacterial strain, or composition, for its use according to the preceding claim, in the prevention and / or treatment of metabolism-related cancers.

22. Bacterial strain, or composition, for its use according to claim 14, in the prevention and / or treatment of at least one disease chosen from: - Metabolic diseases, chosen from non-insulin-dependent diabetes, gestational diabetes, NASH, hepatic steatosis, pancreatic steatosis, hyperlipidemia, hypercholesterolemia, infertility linked to overweight, urinary incontinence linked to overweight, - Other chronic metabolic diseases, including thyroiditis, - Cardiac and vascular diseases, chosen from atherosclerosis, thrombopathies, acute pericarditis and chronic constrictive pericarditis, arterial hypertension, vasculitis - liver and bile duct diseases, selected from hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cirrhosis, hepatic encephalopathy, gallstones - joint diseases related to overweight, chosen from osteopenia, osteoporosis, osteoarthritis, inflammation of the vertebral discs - neurodegenerative diseases, selected from Alzheimer's disease, Parkinson's disease, motor neuron diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and Kennedy's disease - cancers linked to metabolism and / or dysbiosis of the microbiota, chosen from hepatocarcinomas, cancers of the digestive tract such as esophagus, stomach and colorectal cancer, pancreatic carcinoma, neuroendocrine tumors (NETs) of the gastroenteropancreatic system, liver tumors, tumors of the gallbladder and biliary tract, renal tumors, glioblastomas, lymphomas, multiple myelomas, chronic myeloid leukemia, chronic myeloproliferative diseases, lung carcinomas - autoimmune diseases, chosen from insulin-dependent diabetes, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, polyendocrine autoimmune syndrome - atopic dermatological diseases, chosen from eczema and psoriasis - chronic inflammatory bowel diseases, selected from Crohn's disease, ulcerative colitis, diverticulitis, esophagitis, gastritis, pancreatitis, peptic ulcer, irritable bowel syndrome - respiratory function disorders, selected from asthma, cystic fibrosis, chronic obstructive pulmonary disease and chronic bronchitis, interstitial lung disease and pulmonary fibrosis, sleep apnea syndrome (SAOS) - pneumonias, selected from infectious pneumonias, influenza pneumonia and avian flu, severe acute respiratory syndrome (SARS), pneumocystis pneumonia - Infectious diarrhea, selected from Clostridium difficile infection, EHEC infection, salmonella gastroenteritis, campylobacter enteritis, food poisoning by enterotoxin-producing bacteria, cholera, yersiniosis, shigellosis, cryptosporidiosis, listeriosis - Food allergies, chosen from celiac disease, lactose intolerance, bile salt malabsorption syndrome - Inflammatory nephrologies or those linked to microbiota dysbiosis, chosen from urethritis, chronic renal failure, urolithiasis - Other inflammatory disorders, chosen from multiple sclerosis, lymphangitis - Neurological diseases linked to microbiota dysbiosis, chosen from anorexia, bulimia, depression, bipolar syndrome, autism, schizophrenia, Tourette's syndrome.

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