EP4003380A1 - Faecalibacterium prausnitzii and christensenella bacterial strains for the treatment and prevention of bowel inflammation - Google Patents

Faecalibacterium prausnitzii and christensenella bacterial strains for the treatment and prevention of bowel inflammation

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Publication number
EP4003380A1
EP4003380A1 EP20742750.1A EP20742750A EP4003380A1 EP 4003380 A1 EP4003380 A1 EP 4003380A1 EP 20742750 A EP20742750 A EP 20742750A EP 4003380 A1 EP4003380 A1 EP 4003380A1
Authority
EP
European Patent Office
Prior art keywords
composition
bacterial strain
christensenella
group
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP20742750.1A
Other languages
German (de)
French (fr)
Inventor
Philippe Langella
Patrizia Brigidi
Rebeca MARTIN ROSIQUE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Universita di Bologna
Original Assignee
Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Universita di Bologna
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Filing date
Publication date
Application filed by Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement, Universita di Bologna filed Critical Institut National de Recherche pour lAgriculture lAlimentation et lEnvironnement
Publication of EP4003380A1 publication Critical patent/EP4003380A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K2035/11—Medicinal preparations comprising living procariotic cells
    • A61K2035/115—Probiotics

Definitions

  • the present invention relates to a composition for its use in the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel conditions.
  • composition comprising particular bacterial strains, and / or their supernatants, for its use in the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel disorders.
  • Inflammation is a natural biological process, which is a normal part of the response to injury or infection and helps protect the body against internal or external damage.
  • An inflammatory bowel disease is a group of disorders characterized by chronic and recurrent inflammation of the gastrointestinal tract. The most common form of this group is Crohn's disease.
  • the pathogenesis involves an inappropriate and continuous activation of the mucosal immune system brought about by the presence of the intestinal microbiota in a genetically predisposed patient.
  • the ability to modulate the immune response of Christensenella, and in particular of the bacterial strains Christensenella minuta and Christensenella timonensis was tested in vitro.
  • the inventors have determined the synergistic anti-inflammatory properties resulting from the implementation of association between a strain of Christensenella with a strain of Faecalibacterium prausnitzii, a well-known new generation probiotic (NGP).
  • NTP new generation probiotic
  • the present invention aims to provide a composition for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least a first bacterial strain of the Faecalibacterium prausnitzii species, and a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis, and / or their supernatants.
  • a pharmaceutical composition comprising, in a physiologically acceptable medium, these two strains and / or their supernatants is also targeted.
  • the objective of the present invention is to describe new substances, in particular probiotics and / or probiotic culture supernatants, and compositions for the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, by particularly inflammatory bowel disease in an individual.
  • prevention denote the reduction to a lesser degree of the risk or the probability of occurrence of a given phenomenon, that is to say, in the present invention.
  • invention gastrointestinal inflammation, in particular intestinal inflammation.
  • the terms “treating” and “treatment” associated with an inflammatory gastrointestinal disease denote a reduction, or even an interruption, of said inflammatory gastrointestinal disease.
  • the present invention is based on the discovery by the inventors of the capacity of certain Christensenella bacteria to improve the immunomodulatory properties of a strain of the species Faecalibacterium prausnitzii.
  • the simultaneous use of a first bacterial strain Faecalibacterium prausnitzii, or of a supernatant thereof, and of a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and their mixtures, or a supernatant thereof makes it possible to obtain anti-inflammatory results superior to the simple sum of the combined effects of these strains, or of their supernatant (s), used separately.
  • the present invention relates to a composition for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least:
  • the first bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form.
  • the second bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form.
  • the composition comprises at least:
  • the first bacterial of the Faecalibacterium prausnitzii species is strain A2-165, deposited in the German Collection of Microorganisms and Cell Cultures under number DSM-17677 in 1996.
  • the second bacterial strain is chosen from the group consisting of Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 and mixtures thereof.
  • An individual according to the present invention can in particular be a mammal, more particularly a human being.
  • the composition is used in an individual whose genus Christensenella represents at least 0.01% by number of the total of the bacterial genera of his intestinal microbiota.
  • inflammatory gastrointestinal disease may be inflammatory bowel disease, more particularly colonic inflammatory bowel disease.
  • Said colonic inflammatory bowel disease can in particular be selected from the group consisting of Crohn's disease, ulcerative colitis and pouchitis, in particular from the group consisting of Crohn's disease and ulcerative colitis. hemorrhagic.
  • the composition according to the invention is suitable for administration by the oral route.
  • the composition according to the invention can thus be in the form of powder or granules, of a food product, of a drink, of a pharmaceutical product, of a nutraceutical, of a food additive, of a food supplement. , a dairy product, a capsule or a capsule. More particularly, the composition according to the invention can be included in a food supplement.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, in a physiologically acceptable medium, at least:
  • FIG 1 shows the production of interleukin-8 (IL-8) (in pg / mL) (ordinate) in HT-29 cells stimulated by (from left to right) TNF- ⁇ alone (YBHI mucin) or in the presence of the strains C. minuta DSMZ 22607 (C. minuta), C. timonensis DSMZ 102800 (C. timonensis), F. prausnitzii A2-165 (F. prausnitzii), C. minuta DSMZ 22607 + F. prausnitzii A2-165 (C. minuta + F. prausnitzii) and C. timonensis DSMZ 102800 + F. prausnitzii A2-165 (C. timonensis + F. prausnitzii) (abscissa).
  • IL-8 interleukin-8
  • the inventors have carried out in-depth work in order to identify the capacity of a composition
  • a composition comprising a first bacterial strain of the species Faecalibacterium prausnitzii, and / or a culture supernatant of this first strain, and a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and their mixtures, and / or a culture supernatant of this second strain, to treat and / or prevent inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel diseases.
  • the inventors have unexpectedly determined that a composition according to the invention has the capacity to reduce gastrointestinal inflammation, in particular intestinal inflammation, in an individual.
  • the composition according to the invention can, in particular, reduce the concentration of pro-inflammatory molecules, such as interleukin 8 (IL-8).
  • IL-8 interleukin 8
  • a bacterial strain of Christensenella in particular one or more of the Christensenella timonensis and Christensenella minuta strain (s), or their supernatant
  • Faecalibacterium prausnitzii in particular the reference strain A2-165, or with its supernatant
  • Faecalibacterium prausnitzii makes up about 5% of the fecal microbiota in healthy adults (Hold, Schwiertz et al., Appl Environ Microbiol. 2003 Jul; 69 (7): 4320-4).
  • the importance of this bacterium is recognized around the world, especially as a player in intestinal health in humans.
  • the relative abundance of F. prausnitzii may also serve as an indicator or biomarker of gut health in adults.
  • F. prausnitzii have been shown to be lower in the faeces of individuals suffering from intestinal and metabolic disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), cancer. colorectal (CRC), obesity and celiac disease (Balamurugan, Rajendiran et al. J Gastroenterol Hepatol. 2008 Aug; 23 (8 Pt 1): 1298-1303, Sokol, Pigneur et al. Proc Natl Acad Sci US A. 2008 Oct 28; 105 (43): 16731-6; Neish Gastroenterology. 2009 Jan; 136 (l): 65-80; De Palma, Nadal et al. BMC Microbiol.
  • F. prausnitzii implemented in a live form, exhibits anti-inflammatory effects in vitro and in vivo, which suggests that this bacterium could contribute to homeostasis in a healthy intestine.
  • Sokol, Pigneur et al. Proc Natl Acad Sci US A. 2008 Oct 28; 105 (43): 16731-6 Christensenella is an anaerobic bacterium and its culture requires special equipment and know-how.
  • applications WO2018 / 162738 and WO2018 / 162726 teach that the use of particular bacteria of Christensenella, belonging to species defined as being specifically distant from those of the genera Christensenella minuta and Christensenella timonensis, make it possible in particular to fight against overweight and obesity, by intervening for example on the presence of visceral fat and on intestinal permeability.
  • the inventors have surprisingly determined the ability of strains of Christensenella, and in particular of their supernatant, to increase the anti-inflammatory properties of a strain of Faecalibacterium prausnitzii, and in particular of its supernatant.
  • the inventors have demonstrated the existence of a synergistic effect of a combination of a strain of Christensenella minuta and / or of Christensenella timonensis (or of a culture supernatant of such strains) and of a strain of Faecalibacterium prausnitzii (or a supernatant of this strain) for the prevention and / or treatment of gastrointestinal inflammation.
  • the term “individual” as used in the present text preferably designates a mammal, including a non-human mammal, and more particularly a human being.
  • physiologically acceptable medium denote a medium which is compatible with the organism of the individual to which said composition is to be administered. It could be, for example, a non-toxic solvent such as water. In particular, said medium is compatible with oral administration.
  • a composition according to the invention is preferably suitable for administration by the oral route.
  • microbiota is meant all the microorganisms that have colonized an individual and with which he cohabits: bacteria for the most part, but also viruses, fungi, yeasts and protozoa.
  • the composition of the microbiota differs depending on the colonized surfaces: we thus distinguish the skin microbiota, the vaginal microbiota, the urinary microbiota, the respiratory microbiota, the ENT microbiota (otorhinolaryngology) and the intestinal microbiota, formerly called the intestinal flora, by far the most important with its 100,000 billion germs.
  • intestinal microbiota is meant all the microorganisms, in particular bacteria, which inhabit the intestine of a given individual.
  • BMI Body Mass Index
  • WHO World Health Organization
  • composition according to the invention relates to a composition for its use in the treatment and / or prevention of inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least:
  • the individual defined according to the invention is not overweight, i.e. has a body mass index (BMI) of less than 25.
  • BMI body mass index
  • BMI less than 25 denotes a BMI strictly less than 25, more particularly a BMI less than or equal to 24.99.
  • said individual may have a BMI of less than 25 and greater than or equal to 18.5.
  • the composition is used in an individual who is not deficient in Christensenella in the intestinal microbiota.
  • non-deficient in Christensenella in the intestinal microbiota, within the meaning of the present invention, is meant an individual whose bacteria of the genus Christensenella in his intestinal microbiota represent at least 0.01% by number of the total of the bacterial genera detected in his. intestinal microbiota, in particular at least 0.1% by number, and in particular at least 0.5% by number of the total bacterial genera detected in its intestinal microbiota.
  • the abundance of Christensenella can, for example, be measured by a Fish sequencing test, or by qPCR or by meta-analysis, well known to those skilled in the art.
  • the first bacterial strain of the species Faecalibacterium prausnitzii and / or the second bacterial strain as defined according to the invention can be independently implemented in a living, semi-active, inactivated or dead form.
  • a bacterial strain in a semi-active form is a microorganism whose ability to proliferate is reduced, temporarily or permanently.
  • the term “semi-active” thus designates a bacterium with low physiological activity. This activity can be measured by an exponential growth phase or a longer generation time, a slowed metabolism or an incomplete physiological response to changes in the environment, for example. In some extreme cases, the number of bacteria may be reduced since they can no longer resist changes in the environment.
  • an “inactivated” bacterial strain is a bacterial strain which is no longer capable, temporarily or permanently, of proliferating.
  • a “dead” bacterial strain is a bacterial strain which is no longer capable, definitively, of proliferating.
  • Dead or inactivated bacterial strains may have intact or ruptured cell membranes.
  • the term “inactivated” also designates the extracts and lysates of bacterial strains obtained as detailed above.
  • Obtaining dead or inactivated bacterial strains can be carried out by any method known to those skilled in the art.
  • An inactivated bacterial strain suitable for the invention can be prepared by irradiation, thermal inactivation or lyophilization of a preparation of bacterial strain. These methods are known to those skilled in the art.
  • the inactivation of bacterial strains by irradiation can include the use of gamma rays, X-rays or UV exposure.
  • the type of radiation, the intensity, the dose and the exposure time are adjusted by those skilled in the art depending on the quantity and nature of the bacterial strains to be inactivated.
  • Inactivation by lyophilization can be carried out by any method known in the field.
  • bacterial strains inactivated by lyophilization can be returned to culture.
  • a bacterial strain according to the invention can be used in whole form, that is to say essentially in its native form, or in the form of extracts or lysates comprising fractions and / or metabolites of this microorganism. Such a lysate can in particular be prepared as indicated below.
  • a lysate in accordance with the invention can comprise all or part of the fractionated elements and / or of the metabolites resulting from the lysis of the bacterial strain.
  • a lysate within the meaning of the invention denotes the product obtained at the end of the destruction or dissolution of biological cells by a phenomenon of cell lysis causing the release of the intracellular biological constituents naturally contained in the cells of the bacterial strain considered.
  • lysate is used interchangeably to denote the whole of the lysate obtained by lysis of the bacterial strain concerned or only a fraction thereof.
  • the terms “entire lysate” are used to designate more precisely the entire lysate obtained by lysis of the bacterial strain concerned.
  • the lysate used is therefore formed in all or part of the intracellular biological constituents and of the constituents of the cell walls and membranes.
  • a lysate used for the invention is the entire lysate obtained by lysis of the bacterial strain concerned.
  • This cell lysis can be carried out using different technologies, such as, for example, thermal shock, ultrasound, osmotic shock, or under mechanical stress, such as by centrifugation.
  • a culture supernatant of the first bacterial strain as defined above and / or a culture supernatant of the second bacterial strain as defined above can be used in a composition according to the invention.
  • the term “culture supernatant” denotes the culture medium in which the bacterial strains have resided during their culture, or extracellular medium.
  • the composition according to the invention comprises at least one culture supernatant of a bacterial strain of the species Faecalibacterium prausnitzii. According to one embodiment, the composition according to the invention comprises at least one bacterial strain of the species Faecalibacterium prausnitzii.
  • the composition according to the invention comprises at least one bacterial strain of the species Faecalibacterium prausnitzii and at least one culture supernatant of a bacterial strain of the species Faecalibacterium prausnitzii.
  • the bacterial strain of the species Faecalibacterium prausnitzii is a strain of the species F. prausnitzii having anti-inflammatory properties.
  • the bacterial strain of the species Faecalibacterium prausnitzii is the reference strain A2-165.
  • the composition according to the invention comprises a culture supernatant of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or mixtures thereof.
  • the composition according to the invention comprises at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or their mixtures and a culture supernatant of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or mixtures thereof.
  • the composition comprises at least:
  • a composition of the invention is suitable for the administration of a daily dose representing from 10 7 to 10 11 colony-forming units (cfu) of at least one bacterial strain of the species Faecalibacterium prausnitzii, preferably a daily dose equivalent to 10 9 cfu.
  • a composition of the invention is suitable for the administration of a daily dose representing from 10 7 to 10 11 colony-forming units (cfu) of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or their mixtures, preferably a daily dose equivalent to 10 9 cfu.
  • a daily dose representing from 10 7 to 10 11 colony-forming units (cfu) of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or their mixtures, preferably a daily dose equivalent to 10 9 cfu.
  • a composition according to the invention can in particular comprise, independently, a content of between 0.1% and 99.0%. in weight, in particular between 5.0% and 90.0% by weight, in particular from 25 to 70% by weight and more particularly from 30 to 50% by weight, relative to the total weight of the composition.
  • a composition according to any one of the aforementioned embodiments can independently comprise a content of between 0.1% and 99.0% by weight, in particular between 5.0% and 90.0% by weight, for example between 10.0% and 90.0% by weight; in particular from 25 to 70% by weight and more particularly from 30 to 50% by weight, of supernatant of a first bacterial strain or of a second bacterial strain as defined above, relative to the total weight of the composition.
  • composition according to the invention is a pharmaceutical composition.
  • composition according to the invention is used in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, more particularly a human being.
  • an inflammatory gastrointestinal disease is, in particular, an inflammatory bowel disease, more particularly an inflammatory bowel disease of the colon.
  • Said colonic inflammatory bowel disease can, in particular, be chosen from the group consisting of Crohn's disease (CD), ulcerative colitis (UC) and pouchitis, in particular Crohn's disease and ulcerative colitis.
  • CD Crohn's disease
  • UC ulcerative colitis
  • pouchitis in particular Crohn's disease and ulcerative colitis.
  • Crohn's disease and ulcerative colitis are two diseases characterized by inflammation of the lining of part of the digestive tract, linked to an overactive digestive immune system.
  • inflammatory bowel disorders in particular colic, more particularly Crohn's disease (CD), ulcerative colitis (UC) and pouchitis, are diseases predominantly affecting young adults, ie between 20 and 30 years old, and which evolve in spurts interspersed with periods of remission. These diseases can affect the entire digestive tract, from the mouth to the anus.
  • Crohn's disease is meant an inflammatory gastrointestinal disease which can affect the entire digestive tract. Crohn's disease, of unknown cause, is characterized by inflammation most often found in the ileum, colon and anus, which is of multifactorial origin, involving among other things a genetic component and the microbiome. Crohn's disease typically progresses in flare-ups spaced by so-called remission phases, asymptomatic. Digestive signs are most often diarrhea, abdominal pain or proctological lesion. Diagnosis of Crohn's disease requires esogastric fibroscopy and colonoscopy with biopsies. Crohn's disease can also be detected thanks to a video-capsule, this one allowing to visualize the intestines and more particularly the small intestine.
  • ulcerative colitis is meant a chronic inflammatory disease of the intestine which affects the distal end of the digestive tract, i.e. the colon and the rectum. It is characterized by continuous lesions, most often superficial, which begin in the rectum and can extend over the entire colon without ever reaching other segments of the digestive tract. It evolves in spurts interspersed with periods of remissions (calm periods without symptoms).
  • ileal reservoir obtained after a surgeon has performed an anastomosis between two parts of the intestines, i.e. the ileum and the anus. It primarily concerns patients suffering from ulcerative colitis, and having undergone total coloprotectomy.
  • a composition according to the present invention is in particular intended for the digestive tract, in particular the intestine.
  • composition according to the invention may be suitable for oral or rectal administration.
  • a composition of the invention is an oral composition, that is, it is suitable for oral administration to an individual.
  • Such a composition can be in the form of a suspension, a tablet, a pill, a capsule, a granule or a powder.
  • composition according to the invention for the oral route can be chosen from the group consisting of a food product, a drink, a pharmaceutical product, a nutraceutical, a food additive, a food supplement or a dairy product, and is, in particular , a food supplement.
  • a composition according to the present invention is a food supplement.
  • a dietary supplement for oral administration may be present in capsules, hard capsules, soft capsules, tablets, sugar-coated tablets, pills, pastes, lozenges, gums, drinkable solutions or emulsions, syrup or gel.
  • a composition according to the present invention intended for oral administration, can be provided with a coating resistant to gastric juice, in order to ensure that the bacterial strain of the present invention included in said composition can pass through the damaged stomach. The release of the bacterial strain may thus occur for the first time in the upper intestinal tract.
  • 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 colorant.
  • the formulation thereof is carried out by means of the usual processes for producing sugar-coated tablets, hard capsules, gels, controlled release hydrogels, emulsions, tablets or capsules.
  • a composition according to the present invention can also be in the form of a nutritional composition.
  • a nutritional composition according to the present invention is in the form of yogurt, cereal bar, breakfast cereal, dessert, frozen food, soup, pet food, liquid suspension, a powder, tablet, gum or candy.
  • composition containing the bacterial strain of the invention is administered intrarectally.
  • composition according to the invention administered rectally can be in the form of a suppository, an enema or a foam.
  • a composition according to the invention can also comprise at least one ingredient chosen from: antioxidants, fish oils, DHA, EPA, vitamins, minerals, phytonutrients, a protein, a lipid, probiotics and combinations of these.
  • the HT-29 (ATCC HTB-38) cell line (LGC-Standars) is cultured in Dulbecco's Modified Eagle's Minimal Essential Medium (DMEM) (Sigma-Aldrich) supplemented with 10% (w / v) serum heat-inactivated fetal bovine (FBS) (GibcoBRL, Eragny, France) and penicillin G / streptomycin (5000 IU / mL, 5000 pg / ml) (Sigma-Aldrich).
  • DMEM Dulbecco's Modified Eagle's Minimal Essential Medium
  • FBS serum heat-inactivated fetal bovine
  • penicillin G / streptomycin 5000 IU / mL, 5000 pg / ml
  • the single cultures and the co-cultures composed of the combinations between the listed strains are prepared at time 0. At 24 hours, the bacterial samples are centrifuged for 10 minutes at 6000 rpm. The supernatants thus obtained are stored at -80 ° C. in order to continue the analysis of their immunomodulatory properties in vitro.
  • Anti-inflammatory tests are carried out according to the procedure described by Kechaou et al. , 2012 (Kechaou N et a /.: Appl Environ Microbiol 2012, 79: 1491-1499). Specifically, 50,000 HeLa or HT-29 cells per well are seeded in 24-well culture plates (Nunc). Twenty-four hours before the bacterial contact, the culture medium is replaced by a medium containing 5% FBS. The experiments are undertaken on the 7th day after seeding, while the cells are at confluence (1.83 ⁇ 10 6 cells / well). Twenty-four hours before the bacterial co-culture (day 6), the culture medium is replaced with a medium containing 5% heat inactivated FBS and 1% glutamine.
  • the reference strain F. prausnitzii A2-165 is well known for its immunomodulatory properties and more particularly for its anti-inflammatory effects.
  • IL-8 a pro-inflammatory cytokine induced by TNF- ⁇ stimulation in HT-29 epithelial cells.
  • the inventors observed that the two strains are capable of blocking the production of IL-8 in the same way as the positive control (F. prausnitzii A2-165) (FIG. 1).
  • C. minuta DSMZ 22607 and C. timonensis DSMZ 102800 increase the anti-inflammatory properties of the F. prausnitzii A2-165 strain in vitro.
  • co-cultures with F. prausnitzii A2-165 were performed.
  • C. minuta DSMZ 22607 and C. timonensis DSMZ 102800 advantageously, and quite unexpectedly, synergistically increase the anti-inflammatory properties of the strain F. prausnitzii A2-165 in a manner statistically significant.

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Abstract

The present invention relates to a composition for use thereof in the treatment and/or prevention of an inflammatory bowel disease in an individual, the composition comprising, in a physiologically acceptable medium, at least (I) (a) a first bacterial strain of the Faecalibacterium prausnitzii species, and/or (b) a culture supernatant of a first bacterial strain of the Faecalibacterium prausnitzii species; and (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta and Christensenella timonensis, and mixtures thereof, and/or (b) a culture supernatant of a second bacterial strain chosen from the group consisting of Christensenella minuta and Christensenella timonensis, and mixtures thereof.

Description

Description Description
SOUCHES BACTERIENNES DE FAECALIBACTERIUM PRAUSNITZII ET DE CHRISTENSENELLA POUR LE TRAITEMENT ET LA PREVENTION D UNE INFLAMMATION GASTRO-INTESTINALE BACTERIAL STRAINS OF FAECALIBACTERIUM PRAUSNITZII AND CHRISTENSENELLA FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL INFLAMMATION
Domaine technique Technical area
La présente invention concerne une composition pour son utilisation dans le traitement et/ou la prévention de maladies gastro-intestinales inflammatoires chez un individu, en particulier d’affections intestinales inflammatoires. The present invention relates to a composition for its use in the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel conditions.
Elle concerne en particulier une composition comprenant des souches bactériennes particulières, et/ou leurs surnageants, pour son utilisation dans le traitement et/ou la prévention de maladies gastro-intestinales inflammatoires chez un individu, en particulier d’affections intestinales inflammatoires. It relates in particular to a composition comprising particular bacterial strains, and / or their supernatants, for its use in the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel disorders.
Technique antérieure Prior art
L’inflammation est un processus biologique naturel, qui constitue une partie normale de la réponse à des lésions ou des infections et contribue à la protection de l’organisme contre les agressions internes ou externes. Inflammation is a natural biological process, which is a normal part of the response to injury or infection and helps protect the body against internal or external damage.
Cependant, un dysfonctionnement des mécanismes de l’inflammation, en particulier une inflammation persistante ou trop abondante, peut causer des maladies douloureuses et mettant en danger la vie du patient. De telles maladies comprennent, par exemple, des troubles cutanés, des troubles intestinaux, des troubles neurologiques, l’arthrite et des maladies auto-immunes. Plusieurs de ces maladies inflammatoires restent sans traitement ou sans traitement adéquat. However, dysfunction of the mechanisms of inflammation, especially persistent or too abundant inflammation, can cause painful and life-threatening illnesses. Such diseases include, for example, skin disorders, intestinal disorders, neurological disorders, arthritis and autoimmune diseases. Many of these inflammatory diseases go untreated or without adequate treatment.
Par conséquent, l’étude et la recherche de nouvelles stratégies de traitement anti- inflammatoire constituent un sujet majeur en médecine et en recherche biomédicale. Therefore, the study and research of new anti-inflammatory treatment strategies is a major topic in medicine and biomedical research.
Une affection intestinale inflammatoire est un groupe de troubles caractérisés par une inflammation chronique et récurrente du tractus gastro-intestinal. La forme la plus courante de ce groupe est la maladie de Crohn. La pathogenèse met en œuvre une activation inappropriée et continue du système immunitaire muqueux entraînée par la présence du microbiote intestinal chez un patient génétiquement prédisposé. Il existe un besoin constant de nouvelles substances, en particulier de probiotiques, ou de compositions pour le traitement et/ou la prévention de maladies gastro-intestinales inflammatoires, en particulier des affections intestinales inflammatoires, chez un individu. Ainsi, la capacité à moduler la réponse immunitaire de Christensenella, et en particulier des souches bactériennes Christensenella minuta et Christensenella timonensis, a été testée in vitro. De plus, les inventeurs ont déterminé les propriétés anti-inflammatoires synergiques issues de la mise en œuvre d’association entre une souche de Christensenella avec une souche de Faecalibacterium prausnitzii, un probiotique de nouvelle génération (NGP) bien connu. An inflammatory bowel disease is a group of disorders characterized by chronic and recurrent inflammation of the gastrointestinal tract. The most common form of this group is Crohn's disease. The pathogenesis involves an inappropriate and continuous activation of the mucosal immune system brought about by the presence of the intestinal microbiota in a genetically predisposed patient. There is a constant need for new substances, in particular probiotics, or compositions for the treatment and / or prevention of inflammatory gastrointestinal diseases, particularly inflammatory bowel conditions, in an individual. Thus, the ability to modulate the immune response of Christensenella, and in particular of the bacterial strains Christensenella minuta and Christensenella timonensis, was tested in vitro. In addition, the inventors have determined the synergistic anti-inflammatory properties resulting from the implementation of association between a strain of Christensenella with a strain of Faecalibacterium prausnitzii, a well-known new generation probiotic (NGP).
Exposé de l’invention Disclosure of the invention
La présente invention vise à proposer une composition pour son utilisation dans le traitement et/ou la prévention d’une maladie gastro-intestinale inflammatoire chez un individu, la composition comprenant, dans un milieu physiologiquement acceptable, au moins une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis, et/ou leurs surnageants. The present invention aims to provide a composition for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least a first bacterial strain of the Faecalibacterium prausnitzii species, and a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis, and / or their supernatants.
Une composition pharmaceutique comprenant, dans un milieu physiologiquement acceptable, ces deux souches et/ou leurs surnageants est également visée. A pharmaceutical composition comprising, in a physiologically acceptable medium, these two strains and / or their supernatants is also targeted.
Résumé de l’invention Summary of the invention
L’objectif de la présente invention est de décrire de nouvelles substances, en particulier des probiotiques et/ou des surnageants de culture de probiotiques, et des compositions pour le traitement et/ou la prévention de maladies gastro-intestinales inflammatoires chez un individu, en particulier des affections intestinales inflammatoires chez un individu. The objective of the present invention is to describe new substances, in particular probiotics and / or probiotic culture supernatants, and compositions for the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, by particularly inflammatory bowel disease in an individual.
Dans le contexte de la présente invention, les termes « prévenir » et « prévention » désignent la réduction à un degré moindre du risque ou de la probabilité d’occurrence d’un phénomène donné, c’est-à-dire, dans la présente invention, une inflammation gastro-intestinale, en particulier une inflammation intestinale. In the context of the present invention, the terms "prevent" and "prevention" denote the reduction to a lesser degree of the risk or the probability of occurrence of a given phenomenon, that is to say, in the present invention. invention, gastrointestinal inflammation, in particular intestinal inflammation.
Dans le contexte de la présente demande, les termes « traiter » et « traitement » associés à une maladie gastro-intestinale inflammatoire désignent une diminution, voire une interruption, de ladite maladie gastro-intestinale inflammatoire. La présente invention est basée sur la découverte par les inventeurs de la capacité de certaines bactéries Christensenella à améliorer les propriétés immunomodulatrices d’une souche de l’espèce Faecalibacterium prausnitzii. In the context of the present application, the terms “treating” and “treatment” associated with an inflammatory gastrointestinal disease denote a reduction, or even an interruption, of said inflammatory gastrointestinal disease. The present invention is based on the discovery by the inventors of the capacity of certain Christensenella bacteria to improve the immunomodulatory properties of a strain of the species Faecalibacterium prausnitzii.
Comme le démontrent les résultats des inventeurs, l’utilisation simultanée d’une première souche bactérienne Faecalibacterium prausnitzii, ou d’un surnageant de celle-ci, et d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, ou d’un surnageant de celles-ci, permet d’obtenir des résultats anti-inflammatoires supérieurs à la simple somme des effets combinées de ces souches, ou de leur(s) sumageant(s), mis en œuvre séparément. As demonstrated by the results of the inventors, the simultaneous use of a first bacterial strain Faecalibacterium prausnitzii, or of a supernatant thereof, and of a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and their mixtures, or a supernatant thereof, makes it possible to obtain anti-inflammatory results superior to the simple sum of the combined effects of these strains, or of their supernatant (s), used separately.
Cela est notamment matérialisé par la démonstration de la capacité de cette association de souches et/ou de surnageants, à réduire significativement la production de molécules pro inflammatoires, notamment de l’interleukine 8 (IL-8). This is materialized in particular by demonstrating the ability of this combination of strains and / or supernatants to significantly reduce the production of pro-inflammatory molecules, in particular interleukin 8 (IL-8).
Ainsi, selon un premier objet, la présente invention concerne une composition pour son utilisation dans le traitement et/ou la prévention d’une maladie gastro-intestinale inflammatoire chez un individu, la composition comprenant, dans un milieu physiologiquement acceptable, au moins : Thus, according to a first object, the present invention relates to a composition for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least:
(I) (a) une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou (I) (a) a first bacterial strain of the species Faecalibacterium prausnitzii, and / or
(b) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; (b) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii;
et and
(II) (a) une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof,
et/ou and or
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
Selon un mode de réalisation particulier, la première souche bactérienne est présente dans la composition sous une forme vivante, inactive et/ou morte, de préférence sous une forme vivante. Selon un mode de réalisation particulier, la seconde souche bactérienne est présente dans la composition sous une forme vivante, inactive et/ou morte, de préférence sous une forme vivante. According to a particular embodiment, the first bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form. According to a particular embodiment, the second bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form.
Selon un mode de réalisation particulier, la composition comprend au moins : According to a particular embodiment, the composition comprises at least:
(a) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; et (a) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii; and
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
En particulier, la première bactérienne de l’espèce Faecalibacterium prausnitzii est la souche A2-165, déposée à la German Collection of Microorganisms and Cell Cultures sous le numéro DSM-17677 en 1996. In particular, the first bacterial of the Faecalibacterium prausnitzii species is strain A2-165, deposited in the German Collection of Microorganisms and Cell Cultures under number DSM-17677 in 1996.
En particulier, la seconde souche bactérienne est choisie dans le groupe constitué de Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 et leurs mélanges. In particular, the second bacterial strain is chosen from the group consisting of Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 and mixtures thereof.
Un individu selon la présente invention peut en particulier être un mammifère, plus particulièrement un être humain. An individual according to the present invention can in particular be a mammal, more particularly a human being.
Selon un mode de réalisation particulier, la composition est utilisée chez un individu dont le genre Christensenella représente au moins 0,01 % en nombre du total des genres bactériens de son microbiote intestinal. According to a particular embodiment, the composition is used in an individual whose genus Christensenella represents at least 0.01% by number of the total of the bacterial genera of his intestinal microbiota.
Une maladie gastro-intestinale inflammatoire peut en particulier être une affection intestinale inflammatoire, plus particulièrement une affection intestinale inflammatoire colique. In particular, inflammatory gastrointestinal disease may be inflammatory bowel disease, more particularly colonic inflammatory bowel disease.
Ladite affection intestinale inflammatoire colique peut, en particulier, être choisie dans le groupe constitué de la maladie de Crohn, de la recto-colite hémorragique et de la pochite, en particulier dans le groupe constitué de la maladie de Crohn et de la recto-colite hémorragique. Said colonic inflammatory bowel disease can in particular be selected from the group consisting of Crohn's disease, ulcerative colitis and pouchitis, in particular from the group consisting of Crohn's disease and ulcerative colitis. hemorrhagic.
Selon un autre mode de réalisation, la composition selon l’invention est adaptée à une administration par la voie orale. La composition selon l’invention peut ainsi être sous la forme de poudre ou granulés, d’un produit alimentaire, d’une boisson, d’un produit pharmaceutique, d’un nutraceutique, d’un additif alimentaire, d’un complément alimentaire, d’un produit laitier, d’une capsule ou d’une gélule. Plus particulièrement, la composition selon l’invention peut être comprise dans un complément alimentaire. According to another embodiment, the composition according to the invention is suitable for administration by the oral route. The composition according to the invention can thus be in the form of powder or granules, of a food product, of a drink, of a pharmaceutical product, of a nutraceutical, of a food additive, of a food supplement. , a dairy product, a capsule or a capsule. More particularly, the composition according to the invention can be included in a food supplement.
Selon un second objet, la présente invention concerne une composition pharmaceutique comprenant, dans un milieu physiologiquement acceptable, au moins : According to a second object, the present invention relates to a pharmaceutical composition comprising, in a physiologically acceptable medium, at least:
(I) (a) une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou (I) (a) a first bacterial strain of the species Faecalibacterium prausnitzii, and / or
(b) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; (b) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii;
et and
(II) (a) une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof,
et/ou and or
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
Brève description des dessins Brief description of the drawings
[Fig 1] représente la production d’interleukine- 8 (IL-8) (en pg/mL) (ordonnée) dans des cellules HT-29 stimulées par (de gauche à droite) du TNF-a seul (YBHI mucin) ou en présence des souches C. minuta DSMZ 22607 (C. minuta), C. timonensis DSMZ 102800 (C. timonensis), F. prausnitzii A2-165 (F. prausnitzii), C. minuta DSMZ 22607 + F. prausnitzii A2-165 ( C. minuta + F. prausnitzii) et C. timonensis DSMZ 102800 + F. prausnitzii A2-165 (C. timonensis + F. prausnitzii) (abscisse). [Fig 1] shows the production of interleukin-8 (IL-8) (in pg / mL) (ordinate) in HT-29 cells stimulated by (from left to right) TNF-α alone (YBHI mucin) or in the presence of the strains C. minuta DSMZ 22607 (C. minuta), C. timonensis DSMZ 102800 (C. timonensis), F. prausnitzii A2-165 (F. prausnitzii), C. minuta DSMZ 22607 + F. prausnitzii A2-165 (C. minuta + F. prausnitzii) and C. timonensis DSMZ 102800 + F. prausnitzii A2-165 (C. timonensis + F. prausnitzii) (abscissa).
Description détaillée detailed description
Les inventeurs ont conduit des travaux approfondis afin d’identifier la capacité d’une composition comprenant une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou un surnageant de culture de cette première souche, et une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, et/ou un surnageant de culture de cette seconde souche, à traiter et/ou prévenir des maladies gastro-intestinales inflammatoires chez un individu, en particulier des affections intestinales inflammatoires. En effet, les inventeurs ont déterminé de façon inattendue qu’une composition selon l’invention possède la capacité de réduire une inflammation gastro-intestinale, en particulier une inflammation intestinale, chez un individu. The inventors have carried out in-depth work in order to identify the capacity of a composition comprising a first bacterial strain of the species Faecalibacterium prausnitzii, and / or a culture supernatant of this first strain, and a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and their mixtures, and / or a culture supernatant of this second strain, to treat and / or prevent inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel diseases. Indeed, the inventors have unexpectedly determined that a composition according to the invention has the capacity to reduce gastrointestinal inflammation, in particular intestinal inflammation, in an individual.
En effet, il est présentement décrit que la composition selon l’invention peut, en particulier, réduire la concentration de molécules pro-inflammatoires, telle que l’interleukine 8 (IL-8). Il est par ailleurs démontré que l’association d’une souche bactérienne de Christensenella, en particulier de l’une ou des souche(s) Christensenella timonensis et Christensenella minuta, ou de leur surnageant, avec une souche bactérienne de l’espèce Faecalibacterium prausnitzii, en particulier la souche de référence A2-165, ou avec son surnageant, possèdent des propriétés anti-inflammatoires supérieures à celles attendues par la simple addition des effets de ces souches et/ou surnageant mis en œuvre séparément. Indeed, it is presently described that the composition according to the invention can, in particular, reduce the concentration of pro-inflammatory molecules, such as interleukin 8 (IL-8). It has also been demonstrated that the association of a bacterial strain of Christensenella, in particular one or more of the Christensenella timonensis and Christensenella minuta strain (s), or their supernatant, with a bacterial strain of the species Faecalibacterium prausnitzii , in particular the reference strain A2-165, or with its supernatant, have anti-inflammatory properties superior to those expected by the simple addition of the effects of these strains and / or the supernatant used separately.
De nos jours, il est reconnu que la bactérie commensale probiotique Faecalibacterium prausnitzii représente environ 5 % du microbiote fécale chez les adultes sains (Hold, Schwiertz et al., Appl Environ Microbiol. 2003 Jul; 69(7):4320-4). L’importance de cette bactérie est reconnue à travers le monde, notamment en tant qu’ acteur de la santé intestinale chez l’Homme. L’abondance relative de F. prausnitzii peut d’ailleurs servir comme indicateur ou biomarqueur de la santé intestinale chez les adultes. Nowadays, it is recognized that the probiotic commensal bacterium Faecalibacterium prausnitzii makes up about 5% of the fecal microbiota in healthy adults (Hold, Schwiertz et al., Appl Environ Microbiol. 2003 Jul; 69 (7): 4320-4). The importance of this bacterium is recognized around the world, especially as a player in intestinal health in humans. The relative abundance of F. prausnitzii may also serve as an indicator or biomarker of gut health in adults.
En ce sens, il a été démontré que les niveaux de F. prausnitzii sont moins importants dans les fèces des individus souffrant de désordres intestinaux et métaboliques tels que les affections intestinales inflammatoires (IBD), le syndrome du côlon irritable (IBS), le cancer colorectal (CRC), l’obésité et la maladie cœliaque (Balamurugan, Rajendiran et al. J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1): 1298- 1303, Sokol, Pigneur et al. Proc Natl Acad Sci U S A. 2008 Oct 28; 105(43): 16731-6; Neish Gastroenterology. 2009 Jan; 136(l):65-80 ; De Palma, Nadal et al. BMC Microbiol. 2010 Feb 24; 10:63 ; Furet, Kong et al. Diabètes. 2010 Dec; 59(12):3049-57; Rajilic-Stojanovic, Biagi et al. Gastroenterology. 2011 Nov; 141(5): 1792-801) ainsi que chez les personnes âgées (van Tongeren, Slaets et al. Appl Environ Microbiol. 2005 Oct; 71(10):6438-42). In this sense, the levels of F. prausnitzii have been shown to be lower in the faeces of individuals suffering from intestinal and metabolic disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), cancer. colorectal (CRC), obesity and celiac disease (Balamurugan, Rajendiran et al. J Gastroenterol Hepatol. 2008 Aug; 23 (8 Pt 1): 1298-1303, Sokol, Pigneur et al. Proc Natl Acad Sci US A. 2008 Oct 28; 105 (43): 16731-6; Neish Gastroenterology. 2009 Jan; 136 (l): 65-80; De Palma, Nadal et al. BMC Microbiol. 2010 Feb 24; 10:63; Ferret, Kong et al. al. Diabetes. 2010 Dec; 59 (12): 3049-57; Rajilic-Stojanovic, Biagi et al. Gastroenterology. 2011 Nov; 141 (5): 1792-801) as well as in the elderly (van Tongeren, Slaets et al. al. Appl Environ Microbiol. 2005 Oct; 71 (10): 6438-42).
Par ailleurs, il a également été démontré que F. prausnitzii, mis en œuvre sous une forme vivante, présente des effets anti-inflammatoires in vitro et in vivo , ce qui laisse présager que cette bactérie pourrait contribuer à l’homéostasie dans un intestin sain (Sokol, Pigneur et al. Proc Natl Acad Sci U S A. 2008 Oct 28; 105(43): 16731-6). Christensenella est une bactérie anaérobie et sa culture nécessite un équipement et un savoir- faire particulier. Bien qu'elle ne soit pas considérée comme un membre dominant du microbiote intestinal chez les adultes en bonne santé, elle représente 8,6% des bactéries identifiées dans les selles de la mère au moment de la naissance chez l’homme et représente 20% des bactéries présentes dans des échantillons de méconium du nourrisson (Koenig JE, et al. : Proc Natl Acad Sci U S A 2011, 108 Suppl 1:4578-4585). Il a par ailleurs été observé que les membres de Christensenellaceae présents dans les échantillons fécaux de volontaires sains sont plus nombreux que dans ceux de patients atteints d’une maladie gastro-intestinale inflammatoire dans des échantillons pédiatriques et jeunes (Papa E et al. : PLoS One 2012, 7:e39242.). Ces observations ont suggéré l'hypothèse que cette bactérie est corrélée à un vieillissement en bonne santé. In addition, it has also been shown that F. prausnitzii, implemented in a live form, exhibits anti-inflammatory effects in vitro and in vivo, which suggests that this bacterium could contribute to homeostasis in a healthy intestine. (Sokol, Pigneur et al. Proc Natl Acad Sci US A. 2008 Oct 28; 105 (43): 16731-6). Christensenella is an anaerobic bacterium and its culture requires special equipment and know-how. Although it is not considered a dominant member of the gut microbiota in healthy adults, it accounts for 8.6% of bacteria identified in the mother's stool at the time of birth in humans and accounts for 20% bacteria present in infant meconium samples (Koenig JE, et al: Proc Natl Acad Sci USA 2011, 108 Suppl 1: 4578-4585). It has also been observed that the members of Christensenellaceae present in fecal samples from healthy volunteers are more numerous than those from patients with inflammatory gastrointestinal disease in pediatric and young samples (Papa E et al .: PLoS One 2012, 7: e39242.). These observations suggested the hypothesis that this bacterium is correlated with healthy aging.
Il a été décrit dans la demande WO2016156527 l’intérêt de rétablir une population minimale en Christensenella chez des individus présentant une maladie inflammatoire intestinale liée à une déficience en Christensenella dans le microbiote intestinal. It has been described in application WO2016156527 the interest of re-establishing a minimum population of Christensenella in individuals exhibiting an inflammatory bowel disease linked to a deficiency of Christensenella in the intestinal microbiota.
Par ailleurs, les demandes WO2018/162738 et WO2018/162726 enseignent que l’utilisation de bactéries particulières de Christensenella , appartenant à des espèces définies comme étant spécifiquement éloignées de celles des genres Christensenella minuta et Christensenella timonensis, permettent de lutter notamment contre le surpoids et l’obésité, en intervenant par exemple sur la présence de graisse viscérale et sur la perméabilité intestinale. Furthermore, applications WO2018 / 162738 and WO2018 / 162726 teach that the use of particular bacteria of Christensenella, belonging to species defined as being specifically distant from those of the genera Christensenella minuta and Christensenella timonensis, make it possible in particular to fight against overweight and obesity, by intervening for example on the presence of visceral fat and on intestinal permeability.
Les inventeurs ont cependant déterminé, de manière surprenante, la capacité de souches de Christensenella , et en particulier de leurs surnageant, à augmenter les propriétés anti inflammatoires d’une souche de Faecalibacterium prausnitzii, et notamment de son surnageant. Ainsi, les inventeurs ont mis en évidence l’existence d’un effet synergique d’une association d’une souche de Christensenella minuta et/ou de Christensenella timonensis (ou d’un surnageant de culture de telles souches) et d’une souche de Faecalibacterium prausnitzii (ou d’un surnageant de cette souche) sur la prévention et/ou le traitement d’une inflammation gastro-intestinale. However, the inventors have surprisingly determined the ability of strains of Christensenella, and in particular of their supernatant, to increase the anti-inflammatory properties of a strain of Faecalibacterium prausnitzii, and in particular of its supernatant. Thus, the inventors have demonstrated the existence of a synergistic effect of a combination of a strain of Christensenella minuta and / or of Christensenella timonensis (or of a culture supernatant of such strains) and of a strain of Faecalibacterium prausnitzii (or a supernatant of this strain) for the prevention and / or treatment of gastrointestinal inflammation.
Le terme « individu » tel qu’utilisé dans le présent texte désigne de préférence un mammifère, y compris un mammifère non-humain, et plus particulièrement un être humain. Les termes « milieu physiologiquement acceptable » désignent un milieu qui est compatible avec l’organisme de l’individu auquel ladite composition doit être administrée. Il peut s’agir, par exemple, d’un solvant non toxique tel que l’eau. En particulier, ledit milieu est compatible avec une administration orale. Une composition selon l’invention est de préférence adaptée à une administration par la voie orale. The term “individual” as used in the present text preferably designates a mammal, including a non-human mammal, and more particularly a human being. The terms “physiologically acceptable medium” denote a medium which is compatible with the organism of the individual to which said composition is to be administered. It could be, for example, a non-toxic solvent such as water. In particular, said medium is compatible with oral administration. A composition according to the invention is preferably suitable for administration by the oral route.
Par « microbiote », on entend l'ensemble des micro-organismes ayant colonisé un individu et avec lesquels il cohabite : des bactéries pour l'essentiel, mais également des virus, des champignons, des levures et des protozoaires. La composition du microbiote diffère selon les surfaces colonisées : on distingue ainsi le microbiote cutané, le microbiote vaginal, le microbiote urinaire, le microbiote respiratoire, le microbiote ORL (otorhinolaryngologie) et le microbiote intestinal, autrefois appelé flore intestinale, de loin le plus important avec ses 100 000 milliards de germes. Ainsi, on entend par « microbiote intestinal » l’ensemble des micro-organismes, notamment des bactéries, qui peuplent l’intestin d’un individu donné. Par « Indice de masse corporel » (IMC), on désigne, selon une définition officielle de l’Organisme Mondiale de la Santé (OMS), l’indicateur des risques pour la santé associé à un poids excessif et à un poids insuffisant. By "microbiota" is meant all the microorganisms that have colonized an individual and with which he cohabits: bacteria for the most part, but also viruses, fungi, yeasts and protozoa. The composition of the microbiota differs depending on the colonized surfaces: we thus distinguish the skin microbiota, the vaginal microbiota, the urinary microbiota, the respiratory microbiota, the ENT microbiota (otorhinolaryngology) and the intestinal microbiota, formerly called the intestinal flora, by far the most important with its 100,000 billion germs. Thus, by "intestinal microbiota" is meant all the microorganisms, in particular bacteria, which inhabit the intestine of a given individual. By "Body Mass Index" (BMI), according to an official definition of the World Health Organization (WHO), is meant the indicator of the health risks associated with overweight and underweight.
[Table 1] [Table 1]
Table 1 : Indicateur des risques pour la santé Table 1: Health risk indicator
L’IMC se calcule en divisant le poids de l’individu (en kilogrammes) par sa taille au carré (en mètres). Composition selon l’invention La présente invention concerne une composition pour son utilisation dans le traitement et/ou la prévention d’une maladie gastro-intestinale inflammatoire chez un individu, la composition comprenant, dans un milieu physiologiquement acceptable, au moins : BMI is calculated by dividing an individual's weight (in kilograms) by their height squared (in meters). Composition according to the invention The present invention relates to a composition for its use in the treatment and / or prevention of inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least:
(I) (a) une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou (I) (a) a first bacterial strain of the species Faecalibacterium prausnitzii, and / or
(b) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; (b) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii;
et and
(II) (a) une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof,
et/ou and or
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
En particulier, l’individu défini selon l’invention n’est pas en surpoids, i.e. possède un indice de masse corporel (IMC) inférieur à 25. In particular, the individual defined according to the invention is not overweight, i.e. has a body mass index (BMI) of less than 25.
Par « IMC inférieur à 25 », on désigne un IMC strictement inférieur à 25, plus particulièrement un IMC inférieur ou égale à 24,99. The term “BMI less than 25” denotes a BMI strictly less than 25, more particularly a BMI less than or equal to 24.99.
Selon l’un quelconque de ces modes de réalisation, ledit individu peut posséder un IMC inférieur à 25 et supérieur ou égal à 18,5. According to any of these embodiments, said individual may have a BMI of less than 25 and greater than or equal to 18.5.
Selon un mode de réalisation particulier, la composition est utilisée chez un individu non déficient en Christensenella dans le microbiote intestinal. According to a particular embodiment, the composition is used in an individual who is not deficient in Christensenella in the intestinal microbiota.
Par « non-déficient en Christensenella » dans le microbiote intestinal, au sens de la présente invention, on entend désigner un individu dont les bactéries du genre Christensenella dans son microbiote intestinal représente au moins 0.01% en nombre du total des genres bactériens décelés dans son microbiote intestinal, en particulier au moins 0,1% en nombre, et notamment au moins 0,5% en nombre du total des genres bactériens décelés dans son microbiote intestinal. Recueilli dans les selles, l'abondance en Christensenella peut par exemple être mesurée par un test de séquençage Fish, ou de qPCR ou de méta analyse, bien connus de l’homme du métier. By “non-deficient in Christensenella” in the intestinal microbiota, within the meaning of the present invention, is meant an individual whose bacteria of the genus Christensenella in his intestinal microbiota represent at least 0.01% by number of the total of the bacterial genera detected in his. intestinal microbiota, in particular at least 0.1% by number, and in particular at least 0.5% by number of the total bacterial genera detected in its intestinal microbiota. Collected in the stool, the abundance of Christensenella can, for example, be measured by a Fish sequencing test, or by qPCR or by meta-analysis, well known to those skilled in the art.
Selon la présente invention, la première souche bactérienne de l’espèce Faecalibacterium prausnitzii et/ou la seconde souche bactérienne telle que définie selon l’invention peuvent être indépendamment mises en œuvre sous une forme vivante, semi-active, inactivée ou morte. According to the present invention, the first bacterial strain of the species Faecalibacterium prausnitzii and / or the second bacterial strain as defined according to the invention can be independently implemented in a living, semi-active, inactivated or dead form.
Au sens de l’invention, une souche bactérienne sous une forme semi-active est un microorganisme dont la capacité à proliférer est réduite, temporairement ou définitivement. Le terme " semi-active " désigne ainsi une bactérie à faible activité physiologique. Cette activité peut être mesurée par une phase de croissance exponentielle ou un temps de génération plus long, un métabolisme ralenti ou une réponse physiologique incomplète aux modifications de l'environnement, par exemple. Dans certains cas extrêmes, le nombre de bactéries peut être réduit puisqu'elles ne peuvent plus résister aux changements de l'environnement. For the purposes of the invention, a bacterial strain in a semi-active form is a microorganism whose ability to proliferate is reduced, temporarily or permanently. The term “semi-active” thus designates a bacterium with low physiological activity. This activity can be measured by an exponential growth phase or a longer generation time, a slowed metabolism or an incomplete physiological response to changes in the environment, for example. In some extreme cases, the number of bacteria may be reduced since they can no longer resist changes in the environment.
Ainsi, au sens de l'invention, une souche bactérienne « inactivée » est une souche bactérienne qui n'est plus capable, temporairement ou définitivement, de proliférer. Thus, within the meaning of the invention, an “inactivated” bacterial strain is a bacterial strain which is no longer capable, temporarily or permanently, of proliferating.
Au sens de l'invention, une souche bactérienne « morte » est une souche bactérienne qui n'est plus capable, définitivement, de proliférer. For the purposes of the invention, a “dead” bacterial strain is a bacterial strain which is no longer capable, definitively, of proliferating.
Les souches bactériennes mortes ou inactivées peuvent avoir les membranes cellulaires intactes ou rompues. Ainsi le terme « inactivé » désigne également les extraits et lysats de souches bactériennes obtenus comme détaillés ci-avant. L'obtention de souches bactériennes mortes ou inactivées peut être effectuée par toute méthode connue de l'homme du métier. Une souche bactérienne inactivée convenant à l'invention peut être préparée par irradiation, inactivation thermique ou lyophilisation d'une préparation de souche bactérienne. Ces méthodes sont connues de l'homme du métier. Dead or inactivated bacterial strains may have intact or ruptured cell membranes. Thus the term “inactivated” also designates the extracts and lysates of bacterial strains obtained as detailed above. Obtaining dead or inactivated bacterial strains can be carried out by any method known to those skilled in the art. An inactivated bacterial strain suitable for the invention can be prepared by irradiation, thermal inactivation or lyophilization of a preparation of bacterial strain. These methods are known to those skilled in the art.
Plus particulièrement, l’inactivation de souches bactériennes par irradiation peut comprendre la mise en œuvre de rayons gamma, de rayons X ou une exposition aux UV. Le type de rayonnement, l'intensité, la dose et le temps d'exposition sont ajustés par l’homme du métier selon la quantité et la nature des souches bactériennes à inactiver. More particularly, the inactivation of bacterial strains by irradiation can include the use of gamma rays, X-rays or UV exposure. The type of radiation, the intensity, the dose and the exposure time are adjusted by those skilled in the art depending on the quantity and nature of the bacterial strains to be inactivated.
L’inactivation par lyophilisation peut être effectuée par toute méthode connue dans le domaine. Avantageusement, des souches bactériennes inactivées par lyophilisation peuvent être remises en culture. Inactivation by lyophilization can be carried out by any method known in the field. Advantageously, bacterial strains inactivated by lyophilization can be returned to culture.
Une souche bactérienne selon l'invention peut être mise en œuvre sous forme entière, c'est- à-dire pour l'essentiel dans sa forme native, ou sous forme d'extraits ou de lysats comprenant des fractions et/ou des métabolites de ce microorganisme. Un tel lysat peut notamment être préparé comme indiqué ci-après. Un lysat conforme à l'invention peut comprendre tout ou partie des éléments fractionnés et/ou des métabolites résultant de la lyse de la souche bactérienne. A bacterial strain according to the invention can be used in whole form, that is to say essentially in its native form, or in the form of extracts or lysates comprising fractions and / or metabolites of this microorganism. Such a lysate can in particular be prepared as indicated below. A lysate in accordance with the invention can comprise all or part of the fractionated elements and / or of the metabolites resulting from the lysis of the bacterial strain.
Un lysat au sens de l'invention désigne le produit obtenu à l'issue de la destruction ou dissolution de cellules biologiques par un phénomène de lyse cellulaire provoquant la libération des constituants biologiques intracellulaires naturellement contenus dans les cellules de la souche bactérienne considérée. A lysate within the meaning of the invention denotes the product obtained at the end of the destruction or dissolution of biological cells by a phenomenon of cell lysis causing the release of the intracellular biological constituents naturally contained in the cells of the bacterial strain considered.
Au sens de la présente invention, le terme « lysat » est utilisé indifféremment pour désigner l'intégralité du lysat obtenu par lyse de la souche bactérienne concernée ou seulement une fraction de celle-ci. For the purposes of the present invention, the term “lysate” is used interchangeably to denote the whole of the lysate obtained by lysis of the bacterial strain concerned or only a fraction thereof.
Au sens de la présente invention, les termes « lysat entier » sont utilisés pour désigner plus précisément l'intégralité du lysat obtenu par lyse de la souche bactérienne concernée. For the purposes of the present invention, the terms “entire lysate” are used to designate more precisely the entire lysate obtained by lysis of the bacterial strain concerned.
Le lysat mis en œuvre est donc formé en tout ou partie des constituants biologiques intracellulaires et des constituants des parois et membranes cellulaires. The lysate used is therefore formed in all or part of the intracellular biological constituents and of the constituents of the cell walls and membranes.
Selon un mode de réalisation, un lysat utilisé pour l'invention est l'intégralité du lysat obtenu par lyse de la souche bactérienne concernée. According to one embodiment, a lysate used for the invention is the entire lysate obtained by lysis of the bacterial strain concerned.
Cette lyse cellulaire peut être réalisée à l’aide de différentes technologies, telles que par exemple un choc thermique, par ultrasons, un choc osmotique, ou sous contrainte mécanique, telle que par centrifugation. This cell lysis can be carried out using different technologies, such as, for example, thermal shock, ultrasound, osmotic shock, or under mechanical stress, such as by centrifugation.
Selon un mode de réalisation, un surnageant de culture de la première souche bactérienne telle que définie ci-dessus et/ou un surnageant de culture de la seconde souche bactérienne telle que définie ci-dessus peut être mis en œuvre dans une composition selon l’invention. Par « surnageant de culture » on désigne au sens de la présente invention le milieu de culture dans lequel les souches bactériennes ont séjourné lors de leur culture, ou milieu extracellulaire. According to one embodiment, a culture supernatant of the first bacterial strain as defined above and / or a culture supernatant of the second bacterial strain as defined above can be used in a composition according to the invention. For the purposes of the present invention, the term “culture supernatant” denotes the culture medium in which the bacterial strains have resided during their culture, or extracellular medium.
Selon un mode de réalisation, la composition selon l’invention comprend au moins un surnageant de culture d’une souche bactérienne de l’espèce Faecalibacterium prausnitzii. Selon un mode de réalisation, la composition selon l’invention comprend au moins une souche bactérienne de l’espèce Faecalibacterium prausnitzii. According to one embodiment, the composition according to the invention comprises at least one culture supernatant of a bacterial strain of the species Faecalibacterium prausnitzii. According to one embodiment, the composition according to the invention comprises at least one bacterial strain of the species Faecalibacterium prausnitzii.
Selon un mode de réalisation, la composition selon l’invention comprend au moins une souche bactérienne de l’espèce Faecalibacterium prausnitzii et au moins un surnageant de culture d’une souche bactérienne de l’espèce Faecalibacterium prausnitzii. Selon l’un quelconque de ces modes de réalisation, la souche bactérienne de l’espèce Faecalibacterium prausnitzii est une souche de l’espèce F. prausnitzii ayant des propriétés anti-inflammatoires . According to one embodiment, the composition according to the invention comprises at least one bacterial strain of the species Faecalibacterium prausnitzii and at least one culture supernatant of a bacterial strain of the species Faecalibacterium prausnitzii. According to any one of these embodiments, the bacterial strain of the species Faecalibacterium prausnitzii is a strain of the species F. prausnitzii having anti-inflammatory properties.
Selon l’un quelconque de ces modes de réalisation, la souche bactérienne de l’espèce Faecalibacterium prausnitzii est la souche de référence A2-165. According to any of these embodiments, the bacterial strain of the species Faecalibacterium prausnitzii is the reference strain A2-165.
Selon un mode de réalisation, la composition selon l’invention comprend un surnageant de culture d’au moins une souche bactérienne choisie dans le groupe constitué de Christensenella timonensis, Christensenella minuta et/ou leurs mélanges. According to one embodiment, the composition according to the invention comprises a culture supernatant of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or mixtures thereof.
Selon un mode de réalisation, la composition selon l’invention comprend au moins une souche bactérienne choisie dans le groupe constitué de Christensenella timonensis , Christensenella minuta et/ou leurs mélanges et un surnageant de culture d’au moins une souche bactérienne choisie dans le groupe constitué de Christensenella timonensis , Christensenella minuta et/ou leurs mélanges. According to one embodiment, the composition according to the invention comprises at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or their mixtures and a culture supernatant of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or mixtures thereof.
Selon un mode de réalisation particulier de l’invention, la composition comprend au moins : According to a particular embodiment of the invention, the composition comprises at least:
(a) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; et (a) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii; and
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
Selon un mode de réalisation particulier de l’invention, une composition de l’invention est adaptée pour l’administration d’une dose journalière représentant de 107 à 1011 unités formant des colonies (ufc) d’au moins une souche bactérienne de l’espèce Faecalibacterium prausnitzii, de préférence une dose journalière équivalente à 109 ufc. According to a particular embodiment of the invention, a composition of the invention is suitable for the administration of a daily dose representing from 10 7 to 10 11 colony-forming units (cfu) of at least one bacterial strain of the species Faecalibacterium prausnitzii, preferably a daily dose equivalent to 10 9 cfu.
En particulier, une composition de l’invention est adaptée pour l’administration d’une dose journalière représentant de 107 à 1011 unités formant des colonies (ufc) d’au moins une souche bactérienne choisie dans le groupe constitué de Christensenella timonensis, Christensenella minuta et/ou leurs mélanges, de préférence une dose journalière équivalente à 109 ufc. In particular, a composition of the invention is suitable for the administration of a daily dose representing from 10 7 to 10 11 colony-forming units (cfu) of at least one bacterial strain chosen from the group consisting of Christensenella timonensis, Christensenella minuta and / or their mixtures, preferably a daily dose equivalent to 10 9 cfu.
Dans le cas de la mise en œuvre d’un surnageant de culture de l’une quelconque des souches bactériennes susmentionnées, une composition selon l’invention peut notamment en comprendre, indépendamment, une teneur comprise entre 0,1 % et 99,0 % en poids, notamment entre 5,0 % et 90,0 % en poids, en particulier de 25 à 70 % en poids et plus particulièrement de 30 à 50 % en poids, par rapport au poids total de la composition. In the case of the use of a culture supernatant of any one of the aforementioned bacterial strains, a composition according to the invention can in particular comprise, independently, a content of between 0.1% and 99.0%. in weight, in particular between 5.0% and 90.0% by weight, in particular from 25 to 70% by weight and more particularly from 30 to 50% by weight, relative to the total weight of the composition.
Ainsi, une composition selon l’un quelconque des modes de réalisation susmentionnés peut indépendamment comprendre une teneur comprise entre 0,1 % et 99,0 % en poids, notamment entre 5,0 % et 90,0 % en poids, par exemple entre 10,0 % et 90,0 % en poids ; en particulier de 25 à 70 % en poids et plus particulièrement de 30 à 50 % en poids, de surnageant d’une première souche bactérienne ou d’une seconde souche bactérienne telles que définies précédemment, par rapport au poids total de la composition. Thus, a composition according to any one of the aforementioned embodiments can independently comprise a content of between 0.1% and 99.0% by weight, in particular between 5.0% and 90.0% by weight, for example between 10.0% and 90.0% by weight; in particular from 25 to 70% by weight and more particularly from 30 to 50% by weight, of supernatant of a first bacterial strain or of a second bacterial strain as defined above, relative to the total weight of the composition.
En particulier, une composition selon l’invention est une composition pharmaceutique. In particular, a composition according to the invention is a pharmaceutical composition.
Maladies gastro-intestinales inflammatoires Inflammatory gastrointestinal diseases
Comme indiqué précédemment, une composition selon l’invention, telle que décrite ci- dessus, est mise en œuvre dans le traitement et/ou la prévention d’une maladie gastro intestinale inflammatoire chez un individu, plus particulièrement un être humain. As indicated above, a composition according to the invention, as described above, is used in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual, more particularly a human being.
Au sens de la présente invention, une maladie gastro-intestinale inflammatoire est, en particulier, une affection intestinale inflammatoire, plus particulièrement une affection intestinale inflammatoire colique. Within the meaning of the present invention, an inflammatory gastrointestinal disease is, in particular, an inflammatory bowel disease, more particularly an inflammatory bowel disease of the colon.
Ladite affection intestinale inflammatoire colique peut, en particulier, être choisie dans le groupe constitué de la maladie de Crohn (MC), la recto-colite hémorragique (RCH) et la pochite, en particulier la maladie de Crohn et la recto-colite hémorragique. Said colonic inflammatory bowel disease can, in particular, be chosen from the group consisting of Crohn's disease (CD), ulcerative colitis (UC) and pouchitis, in particular Crohn's disease and ulcerative colitis.
La maladie de Crohn et la recto-colite hémorragique sont deux maladies qui se caractérisent par l'inflammation de la paroi d'une partie du tube digestif, liée à une hyperactivité du système immunitaire digestif. Crohn's disease and ulcerative colitis are two diseases characterized by inflammation of the lining of part of the digestive tract, linked to an overactive digestive immune system.
En particulier, les affections intestinales inflammatoires notamment coliques, plus particulièrement la maladie de Crohn (MC), la recto-colite hémorragique (RCH) et la pochite, sont des maladies frappant avec prédilection l'adulte jeune, i.e. entre 20 et 30 ans, et qui évoluent par poussées entrecoupées de périodes de rémission. Ces maladies peuvent toucher tout le tube digestif, de la bouche à l'anus. In particular, inflammatory bowel disorders, in particular colic, more particularly Crohn's disease (CD), ulcerative colitis (UC) and pouchitis, are diseases predominantly affecting young adults, ie between 20 and 30 years old, and which evolve in spurts interspersed with periods of remission. These diseases can affect the entire digestive tract, from the mouth to the anus.
Par « maladie de Crohn » on désigne une maladie gastro-intestinale inflammatoire qui peut atteindre tout le tube digestif. La maladie de Crohn, de cause inconnue, est caractérisée par une inflammation le plus souvent retrouvée au niveau de l'iléon, du côlon et de l’anus, qui est d'origine multifactorielle, faisant intervenir entre autres une composante génétique et le microbiome. La maladie de Crohn évolue typiquement par poussées espacées par des phases dites de rémission, asymptomatiques. Les signes digestifs sont le plus souvent à type de diarrhée, de douleur abdominale ou de lésion proctologique. Le diagnostic de la maladie de Crohn nécessite une fibroscopie œsogastrique et une coloscopie avec réalisation de biopsies. La maladie de Crohn peut aussi être détectée grâce à une vidéo-capsule, celle-ci permettant de visualiser les intestins et plus particulièrement le grêle. By "Crohn's disease" is meant an inflammatory gastrointestinal disease which can affect the entire digestive tract. Crohn's disease, of unknown cause, is characterized by inflammation most often found in the ileum, colon and anus, which is of multifactorial origin, involving among other things a genetic component and the microbiome. Crohn's disease typically progresses in flare-ups spaced by so-called remission phases, asymptomatic. Digestive signs are most often diarrhea, abdominal pain or proctological lesion. Diagnosis of Crohn's disease requires esogastric fibroscopy and colonoscopy with biopsies. Crohn's disease can also be detected thanks to a video-capsule, this one allowing to visualize the intestines and more particularly the small intestine.
Par « recto-colite hémorragique » on désigne une maladie inflammatoire chronique de l'intestin qui affecte l'extrémité distale du tube digestif, i.e. le côlon et le rectum. Elle se caractérise par des lésions continues le plus souvent superficielles qui débutent dans le rectum et peuvent s'étendre sur l'ensemble du colon sans jamais atteindre d'autres segments du tube digestif. Elle évolue par poussées entrecoupées de périodes de rémissions (périodes calmes sans symptômes). By "ulcerative colitis" is meant a chronic inflammatory disease of the intestine which affects the distal end of the digestive tract, i.e. the colon and the rectum. It is characterized by continuous lesions, most often superficial, which begin in the rectum and can extend over the entire colon without ever reaching other segments of the digestive tract. It evolves in spurts interspersed with periods of remissions (calm periods without symptoms).
Par « pochite » on désigne l'inflammation du réservoir iléal obtenu après qu’un chirurgien ait effectué une anastomose entre deux parties des intestins, i.e. l'iléon et l'anus. Elle concerne avant tout les patients souffrant de recto-colite hémorragique, et ayant subi une coloprotectomie totale. By "pouchitis" is meant the inflammation of the ileal reservoir obtained after a surgeon has performed an anastomosis between two parts of the intestines, i.e. the ileum and the anus. It primarily concerns patients suffering from ulcerative colitis, and having undergone total coloprotectomy.
Une composition selon la présente invention est notamment prévue pour le tube digestif, en particulier l’intestin. A composition according to the present invention is in particular intended for the digestive tract, in particular the intestine.
Par conséquent, une composition selon l’invention peut être adaptée à une administration par la voie orale ou rectale. Therefore, a composition according to the invention may be suitable for oral or rectal administration.
Selon un mode de réalisation, une composition de l’invention est une composition orale, c’est-à-dire qu’elle est adaptée à une administration par la voie orale à un individu. According to one embodiment, a composition of the invention is an oral composition, that is, it is suitable for oral administration to an individual.
Une telle composition peut être sous la forme d’une suspension, un comprimé, une pilule, une capsule, un granulé ou une poudre. Such a composition can be in the form of a suspension, a tablet, a pill, a capsule, a granule or a powder.
La composition selon l’invention pour la voie orale peut être choisie dans le groupe constitué d’un produit alimentaire, une boisson, un produit pharmaceutique, un nutraceutique, un additif alimentaire, un supplément alimentaire ou un produit laitier, et est, en particulier, un complément alimentaire. The composition according to the invention for the oral route can be chosen from the group consisting of a food product, a drink, a pharmaceutical product, a nutraceutical, a food additive, a food supplement or a dairy product, and is, in particular , a food supplement.
Selon un mode de réalisation particulier, une composition selon la présente invention est un complément alimentaire. According to a particular embodiment, a composition according to the present invention is a food supplement.
Un complément alimentaire pour une administration orale peut être présent dans des capsules, des gélules, des capsules molles, des comprimés, des comprimés dragéifiés, des pilules, des pâtes, des pastilles, des gommes, des solutions ou émulsions buvables, un sirop ou un gel. A dietary supplement for oral administration may be present in capsules, hard capsules, soft capsules, tablets, sugar-coated tablets, pills, pastes, lozenges, gums, drinkable solutions or emulsions, syrup or gel.
Avantageusement, une composition selon la présente invention, prévue pour une administration orale, peut être pourvu d’un enrobage résistant au suc gastrique, afin d’assurer que la souche bactérienne de la présente invention comprise dans ladite composition puisse traverser l’estomac endommagé. La libération de la souche bactérienne peut ainsi se produire pour la première fois dans le tractus intestinal supérieur. Advantageously, a composition according to the present invention, intended for oral administration, can be provided with a coating resistant to gastric juice, in order to ensure that the bacterial strain of the present invention included in said composition can pass through the damaged stomach. The release of the bacterial strain may thus occur for the first time in the upper intestinal tract.
Un complément alimentaire selon la présente invention peut comprendre en outre un édulcorant, un stabilisant, un antioxydant, un additif, un agent aromatisant et/ou un colorant. La formulation de celui-ci est effectuée au moyen des procédés usuels pour produire des comprimés dragéifiés, des gélules, des gels, des hydrogels pour libération contrôlée, des émulsions, des comprimés ou des capsules. 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 colorant. The formulation thereof is carried out by means of the usual processes for producing sugar-coated tablets, hard capsules, gels, controlled release hydrogels, emulsions, tablets or capsules.
Une composition selon la présente invention peut également être sous la forme d’une composition nutritionnelle. A composition according to the present invention can also be in the form of a nutritional composition.
Une composition nutritionnelle selon la présente invention est sous la forme d’un yogourt, une barre de céréale, des céréales pour le petit-déjeuner, un dessert, un aliment congelé, une soupe, un aliment pour animaux de compagnie, une suspension liquide, une poudre, un comprimé, une gomme ou un bonbon. A nutritional composition according to the present invention is in the form of yogurt, cereal bar, breakfast cereal, dessert, frozen food, soup, pet food, liquid suspension, a powder, tablet, gum or candy.
Dans un autre mode de réalisation de la présente invention, une composition contenant la souche bactérienne de l’invention est administrée par voie intrarectale. In another embodiment of the present invention, a composition containing the bacterial strain of the invention is administered intrarectally.
En particulier, une composition selon l’invention administrée par la voie rectale peut se présenter sous la forme d’un suppositoire, d’un lavement ou d’une mousse. In particular, a composition according to the invention administered rectally can be in the form of a suppository, an enema or a foam.
Une composition selon l’invention peut comprendre en outre au moins un ingrédient choisi parmi : des antioxydants, des huiles de poisson, DHA, EPA, des vitamines, des minéraux, des phytonutriments, une protéine, un lipide, des probiotiques et des combinaisons de ceux- ci. A composition according to the invention can also comprise at least one ingredient chosen from: antioxidants, fish oils, DHA, EPA, vitamins, minerals, phytonutrients, a protein, a lipid, probiotics and combinations of these.
L’invention est décrite ci-dessous de façon plus détaillée au moyen des exemples suivants qui sont présentés à titre d’illustration uniquement. The invention is described in more detail below by way of the following examples which are presented by way of illustration only.
Exemple Example
Souches bactériennes, culture cellulaire et conditions de croissance Toutes les souches décrites ci-après sont issues de la collection allemande DSMZ (Institut Leibnitz DSMZ). Les souches Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 et Faecalibacterium prausnitzii A2-165 (déposée à la German Collection of Microorganisms and Cell Cultures under number DSM-17677 en 1996) sont cultivées à 37 °C dans un milieu YBHI [milieu de perfusion cerveau-coeur complété avec 0.5 % d'extrait de levure (Difco)] additionné de cellobiose (1 mg/ml ; Sigma), de maltose (1 mg/ml ; Sigma), de cystéine (0,5 mg/ml ; Sigma) et de mucine (1 mg/ml ; Sigma) dans une chambre anaérobie remplie avec N2 = 85 %, CO2 = 10 % et ¾ = 5 %. Bacterial strains, cell culture and growth conditions All the strains described below come from the German DSMZ collection (Leibnitz DSMZ Institute). The strains Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 and Faecalibacterium prausnitzii A2-165 (deposited in the German Collection of Microorganisms and Cell Cultures under number DSM-17677 in 1996) are cultured at 37 ° C in YBHI medium [perfusion medium brain-heart supplemented with 0.5% yeast extract (Difco)] supplemented with cellobiose (1 mg / ml; Sigma), maltose (1 mg / ml; Sigma), cysteine (0.5 mg / ml; Sigma ) and mucin (1 mg / ml; Sigma) in an anaerobic chamber filled with N2 = 85%, CO2 = 10% and ¾ = 5%.
La lignée cellulaire HT-29 (ATCC HTB-38) (LGC-Standars) est cultivée dans le milieu minimal essentiel de l'aigle modifié de Dulbecco (DMEM) (Sigma- Aldrich) complété avec 10% (p/v) de sérum foetal bovin (FBS) thermo-inactivé (GibcoBRL, Eragny, France) et de pénicillin G/ streptomycine (5000 IU/mL, 5000 pg/ml) (Sigma- Aldrich). Les cultures sont incubées dans des flacons de culture tissulaire de 25 cm2 (Nunc, Roskilde, Danemark) à 37 °C dans une atmosphère de CO2 à 5% (v/v) jusqu'à confluence. The HT-29 (ATCC HTB-38) cell line (LGC-Standars) is cultured in Dulbecco's Modified Eagle's Minimal Essential Medium (DMEM) (Sigma-Aldrich) supplemented with 10% (w / v) serum heat-inactivated fetal bovine (FBS) (GibcoBRL, Eragny, France) and penicillin G / streptomycin (5000 IU / mL, 5000 pg / ml) (Sigma-Aldrich). The cultures are incubated in 25 cm 2 tissue culture flasks (Nunc, Roskilde, Denmark) at 37 ° C. in an atmosphere of 5% CO 2 (v / v) until confluence.
Expériences d'alimentation croisée Cross-feeding experiments
Les cultures simples et les co-cultures composées des combinaisons entre les souches énumérées sont préparées au temps 0. A 24h, les échantillons bactériens sont centrifugés pendant 10 minutes à 6000 rpm. Les surnageants ainsi obtenus sont conservés à -80°C afin de poursuivre l'analyse de leurs propriétés immunomodulatrices in vitro. The single cultures and the co-cultures composed of the combinations between the listed strains are prepared at time 0. At 24 hours, the bacterial samples are centrifuged for 10 minutes at 6000 rpm. The supernatants thus obtained are stored at -80 ° C. in order to continue the analysis of their immunomodulatory properties in vitro.
Propriétés immunomodulatrices utilisant des cellules HT-29 Immunomodulatory properties using HT-29 cells
Des tests anti-inflammatoires sont effectués selon la procédure décrite par Kechaou et al. , 2012 (Kechaou N et a/. :Appl Environ Microbiol 2012, 79: 1491-1499). Spécifiquement, 50000 cellules HeLa ou HT-29 par puits sont semées dans des plaques de culture de 24 puits (Nunc). Vingt-quatre heures avant la mise en contact bactérienne, le milieu de culture est remplacé par un milieu contenant 5 % de FBS. Les expériences sont entreprises le 7e jour après l'ensemencement, alors que les cellules sont à confluence (1,83x106 cellules/puits). Vingt-quatre heures avant la co-culture bactérienne (jour 6), le milieu de culture est remplacé par un milieu contenant 5% de FBS inactivé à la chaleur et 1% de glutamine. Le jour de la co-culture, 10 % de surnageant bactérien sont ajoutés au DMEM dans un volume total de 500 pL. Les cellules sont stimulées simultanément avec du TNF-a humain (5 ng/mL ; Peprotech, NJ) pendant 6 h à 37°C dans 10% de CO2. Après la co-incubation, les surnageants cellulaires sont prélevés et stockés à -80 °C jusqu'à ce qu’une mesure plus poussée des concentrations d'interleukine-8 (IL-8) par ELISA (Biolegend, San Diego, CA) soit effectuée. Ces expériences ont été réalisées au moins en trois exemplaires. Anti-inflammatory tests are carried out according to the procedure described by Kechaou et al. , 2012 (Kechaou N et a /.: Appl Environ Microbiol 2012, 79: 1491-1499). Specifically, 50,000 HeLa or HT-29 cells per well are seeded in 24-well culture plates (Nunc). Twenty-four hours before the bacterial contact, the culture medium is replaced by a medium containing 5% FBS. The experiments are undertaken on the 7th day after seeding, while the cells are at confluence (1.83 × 10 6 cells / well). Twenty-four hours before the bacterial co-culture (day 6), the culture medium is replaced with a medium containing 5% heat inactivated FBS and 1% glutamine. On the day of the co-culture, 10% of bacterial supernatant is added to DMEM in a total volume of 500 μL. The cells are simultaneously stimulated with human TNF-α (5 ng / mL; Peprotech, NJ) for 6 h at 37 ° C in 10% CO2. After co-incubation, cell supernatants are removed and stored at -80 ° C until further measurement of interleukin-8 (IL-8) concentrations by ELISA (Biolegend, San Diego, CA) be performed. These experiments were carried out at least in triplicate.
Les résultats obtenus sont représentés en Figure 1. The results obtained are shown in Figure 1.
Ces résultats sont exprimés en IL-8 (pg/mL) et sont normalisés en utilisant comme valeur de référence l'IL-8 produit après la co-incubation avec le PB S comme témoin négatif. These results are expressed in IL-8 (pg / mL) and are normalized using as reference value IL-8 produced after co-incubation with PB S as negative control.
Analyse statistique Statistical analysis
Le logiciel GraphPad (GraphPad Sofware, La Jolla, CA, USA) a été utilisé pour l'analyse statistique. Des comparaisons sont réalisées avec le test non paramétrique de Kruskal-Wallis suivi d'une comparaison multiple de Dunn. Une valeur p inférieure à 0,05 a été jugée significative (*p< 0,05 ; **p<0,01). GraphPad software (GraphPad Sofware, La Jolla, CA, USA) was used for the statistical analysis. Comparisons are made with the nonparametric Kruskal-Wallis test followed by a multiple Dunn comparison. A p value of less than 0.05 was considered significant (* p <0.05; ** p <0.01).
Résultats Results
Christensenella minuta DSMZ 22607 et Christensenella timonensis DSMZ 102800 présentent des propriétés anti -inflammatoire s in vitro. Christensenella minuta DSMZ 22607 and Christensenella timonensis DSMZ 102800 exhibit anti-inflammatory properties in vitro.
La souche de référence F. prausnitzii A2-165 est bien connue pour ses propriétés immunomodulatrices et plus particulièrement pour ses effets anti-inflammatoires. Pour déterminer si les souches de C. minuta DSMZ 22607 et C. timonensis DSMZ 102800 sont capables de moduler la réponse immunitaire, les inventeurs ont testé in vitro les propriétés immunomodulatrices des surnageants de ces souches dans un modèle basé sur la capacité à bloquer la production de IL-8 (une cytokine pro-inflammatoire) induite par stimulation TNF- a dans des cellules épithéliales HT-29. The reference strain F. prausnitzii A2-165 is well known for its immunomodulatory properties and more particularly for its anti-inflammatory effects. To determine whether the C. minuta DSMZ 22607 and C. timonensis DSMZ 102800 strains are capable of modulating the immune response, the inventors tested in vitro the immunomodulatory properties of the supernatants of these strains in a model based on the ability to block production. IL-8 (a pro-inflammatory cytokine) induced by TNF-α stimulation in HT-29 epithelial cells.
Ainsi, les inventeurs ont observé que les deux souches sont capables de bloquer la production d'IL-8 de la même manière que le témoin positif (F. prausnitzii A2-165) (Figure 1). Thus, the inventors observed that the two strains are capable of blocking the production of IL-8 in the same way as the positive control (F. prausnitzii A2-165) (FIG. 1).
C. minuta DSMZ 22607 et C. timonensis DSMZ 102800 augmentent les propriétés anti inflammatoires de la souche F. prausnitzii A2-165 in vitro. Afin de tester si les membres de Christensenella étaient capables d'augmenter les propriétés anti-inflammatoires d'autres membres du microbiote intestinale, des co-cultures avec F. prausnitzii A2-165 ont été réalisées. C. minuta DSMZ 22607 and C. timonensis DSMZ 102800 increase the anti-inflammatory properties of the F. prausnitzii A2-165 strain in vitro. In order to test whether the members of Christensenella were able to increase the anti-inflammatory properties of other members of the gut microbiota, co-cultures with F. prausnitzii A2-165 were performed.
Comme le montre également la Figure 1, C. minuta DSMZ 22607 et C. timonensis DSMZ 102800 permettent avantageusement, et de manière tout à fait inattendue, d’augmenter synergiquement les propriétés anti-inflammatoires de la souche F. prausnitzii A2-165 de manière statistiquement significative. As also shown in Figure 1, C. minuta DSMZ 22607 and C. timonensis DSMZ 102800 advantageously, and quite unexpectedly, synergistically increase the anti-inflammatory properties of the strain F. prausnitzii A2-165 in a manner statistically significant.

Claims

Revendications Claims
1. Composition pour son utilisation dans le traitement et/ou la prévention d’une maladie gastro-intestinale inflammatoire chez un individu, la composition comprenant, dans un milieu physiologiquement acceptable, au moins : 1. Composition for use in the treatment and / or prevention of inflammatory gastrointestinal disease in an individual, the composition comprising, in a physiologically acceptable medium, at least:
(I) (a) une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou (I) (a) a first bacterial strain of the species Faecalibacterium prausnitzii, and / or
(b) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; (b) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii;
et and
(II) (a) une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof,
et/ou and or
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
2. Composition pour son utilisation selon la revendication 1, caractérisée en ce que la première souche bactérienne est présente dans la composition sous une forme vivante, inactive et/ou morte, de préférence sous une forme vivante. 2. Composition for its use according to claim 1, characterized in that the first bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form.
3. Composition pour son utilisation selon la revendication 1 ou 2, caractérisée en ce que la seconde souche bactérienne est présente dans la composition sous une forme vivante, inactive et/ou morte, de préférence sous une forme vivante. 3. Composition for its use according to claim 1 or 2, characterized in that the second bacterial strain is present in the composition in a living, inactive and / or dead form, preferably in a living form.
4. Composition pour son utilisation selon la revendication 1, comprenant au moins :4. Composition for its use according to claim 1, comprising at least:
(a) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; et (a) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii; and
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
5. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que la première souche bactérienne, de l’espèce Faecalibacterium prausnitzii, est la souche A2-165, déposée à la German Collection of Microorganisms and Cell Cultures sous le numéro DSM- 17677 en 1996. 5. Composition for its use according to any one of the preceding claims, characterized in that the first bacterial strain, of the species Faecalibacterium prausnitzii, is strain A2-165, deposited in the German Collection of Microorganisms and Cell Cultures under the number DSM-17677 in 1996.
6. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que la seconde souche est choisie dans le groupe constitué de Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 et leurs mélanges. 6. Composition for its use according to any one of the preceding claims, characterized in that the second strain is selected from the group consisting of Christensenella minuta DSMZ 22607, Christensenella timonensis DSMZ 102800 and mixtures thereof.
7. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que l’individu est un mammifère, plus particulièrement un être humain. 7. Composition for its use according to any one of the preceding claims, characterized in that the individual is a mammal, more particularly a human being.
8. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que la maladie gastro-intestinale inflammatoire est une affection intestinale inflammatoire. 8. Composition for its use according to any one of the preceding claims, characterized in that the inflammatory gastrointestinal disease is an inflammatory bowel disease.
9. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que l’affection intestinale inflammatoire est une affection intestinale inflammatoire colique, en particulier choisie dans le groupe constitué de la maladie de Crohn, la recto-colite hémorragique et la pochite. 9. Composition for its use according to any one of the preceding claims, characterized in that the inflammatory bowel disease is an inflammatory bowel disease of the colon, in particular selected from the group consisting of Crohn's disease, ulcerative colitis and the pouch.
10. Composition pour son utilisation selon la revendication 9, caractérisée en ce que l’affection intestinale inflammatoire colique est choisie dans le groupe constitué de la maladie de Crohn et la recto -colite hémorragique. 10. A composition for its use according to claim 9, characterized in that the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.
11. Composition pour son utilisation selon l’une quelconque des revendications précédentes, caractérisée en ce que la composition est adaptée à une administration par la voie orale. 11. Composition for its use according to any one of the preceding claims, characterized in that the composition is suitable for oral administration.
12. Composition pour son utilisation selon l’une quelconque des revendications précédentes, ladite composition étant sous la forme de poudre ou granulés, d’un produit alimentaire, d’une boisson, d’un produit pharmaceutique, d’un nutraceutique, d’un additif alimentaire, d’un complément alimentaire, d’un produit laitier, d’une capsule ou d’une gélule, en particulier sous la forme d’un complément alimentaire. 12. A composition for its use according to any one of the preceding claims, said composition being in the form of powder or granules, of a food product, of a beverage, of a pharmaceutical product, of a nutraceutical, of an additive food, a food supplement, a dairy product, a capsule or a capsule, in particular in the form of a food supplement.
13. Composition pharmaceutique comprenant, dans un milieu physiologiquement acceptable, au moins : 13. Pharmaceutical composition comprising, in a physiologically acceptable medium, at least:
(I) (a) une première souche bactérienne de l’espèce Faecalibacterium prausnitzii, et/ou (I) (a) a first bacterial strain of the species Faecalibacterium prausnitzii, and / or
(b) un surnageant de culture d’une première souche bactérienne de l’espèce Faecalibacterium prausnitzii ; (b) a culture supernatant of a first bacterial strain of the species Faecalibacterium prausnitzii;
et and
(II) (a) une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges, (II) (a) a second bacterial strain chosen from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof,
et/ou and or
(b) un surnageant de culture d’une seconde souche bactérienne choisie dans le groupe constitué de Christensenella minuta, Christensenella timonensis et leurs mélanges. (b) a culture supernatant of a second bacterial strain selected from the group consisting of Christensenella minuta, Christensenella timonensis and mixtures thereof.
14. Composition pharmaceutique selon la revendication 13, ladite composition étant telle que définie dans l’une quelconque des revendications 2 à 12. 14. A pharmaceutical composition according to claim 13, said composition being as defined in any one of claims 2 to 12.
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