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    • 专利摘要:
    The present invention relates to a bacterial strain of the species Faecalibacterium prausnitzii deposited with the CNCM under the accession number CNCM I-4573, for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in a patient. individual.
    公开号:FR3046934A1
    申请号:FR1650567
    申请日:2016-01-25
    公开日:2017-07-28
    发明作者:Philippe Langella；Rosique Rebeca Martin；Humaran Luis Bermudez；Florian Chain；Harry Sokol
    申请人:Pierre Et Marie Curie Dgrtt-Aipi Umpc, University of；Assistance Publique Hopitaux de Paris APHP；Institut National de la Recherche Agronomique INRA；
    IPC主号:
    专利说明:

    Field of the invention
    The present invention relates to a strain of Faecalibacterium prausnitzii for use in the treatment and prevention of inflammatory gastrointestinal diseases (IBD) in an individual, particularly inflammatory bowel disease (IBD).
    Background Art Inflammation is a natural biological process, which is a normal part of the response to injury or infection and contributes to the body's protection against internal or external aggression.
    However, dysfunctional mechanisms of inflammation, particularly persistent or over-abundant inflammation, can cause painful and life-threatening conditions. Such diseases include, for example, skin disorders, intestinal disorders, neurological disorders, arthritis and autoimmune diseases. Many of these inflammatory diseases remain without treatment or adequate treatment.
    Therefore, studying and researching new anti-inflammatory treatment strategies is a major topic in medicine and biomedical research.
    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 implements an inappropriate and continuous activation of the mucosal immune system caused by the presence of the intestinal microbiota in a genetically predisposed patient.
    There is a continuing need for new substances, particularly probiotics, or compositions for the treatment and / or prevention of inflammatory gastrointestinal diseases, particularly inflammatory bowel diseases, in an individual. SUMMARY OF THE INVENTION The object of the present invention is to describe novel substances, in particular probiotics, and compositions for the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular intestinal disorders. inflammatory conditions in an individual.
    In the context of the present invention, the term "prevent" means the reduction to a lesser degree of the risk or probability of occurrence of a given phenomenon, i.e., in the present invention, an inflammation. gastrointestinal, especially intestinal inflammation.
    The present invention is based on the discovery by the present inventors of the anti-inflammatory properties of the strain of Faecalibacterium prausnitzii deposited with the CNCM under accession number CNCM1-4573.
    According to the experimental results of the inventors, a specific strain of Faecalibacterium prausnitzii (F. prausnitzii) deposited with the CNCM on January 21, 2012 under accession number CNCM 1-4573 has the unexpected ability to reduce in vitro and in vivo inflammation. gastrointestinal tract, particularly intestinal inflammation, in an individual. As illustrated in the examples and described below, the inventors have demonstrated that, on the other hand, the F. prausnitzii 1-4575 strain does not have such advantageous properties.
    The strain according to the invention is more particularly capable of reducing the production of pro-inflammatory molecules, such as interleukin-8 (IL-8), interleukin-2 (IL-2), interleukin-4 (IL-4). ), interleukin 6 (IL-6) and gamma interferon (INFy), and increase the production of anti-inflammatory molecules, such as interleukin 10 (IL-10).
    According to a first subject, the present invention relates to a bacterial strain of the species Faecalibacterium prausnitzii deposited with the CNCM under the accession number CNCM 1-4573, for its use in the treatment and / or prevention of gastrointestinal disease. Inflammatory bowel disease in an individual, particularly inflammatory bowel disease in an individual, more particularly an inflammatory bowel disease in an individual.
    This strain identified by the inventors is therefore a probiotic strain that can be used for the applications indicated above.
    An individual according to the invention is preferably a mammal, including a non-human mammal, and is, in particular, a human.
    Inflammatory gastrointestinal disease is, in particular, an inflammatory bowel disease (IBD), more particularly an intestinal inflammatory bowel disease.
    Said intestinal inflammatory bowel disease may, in particular, be selected from the group consisting of Crohn's disease, ulcerative colitis and pouchitis, in particular Crohn's disease and ulcerative colitis.
    According to another embodiment, the bacterial strain for its use according to the invention is comprised in a composition comprising a physiologically acceptable medium, preferably in an oral composition, and more particularly preferably in a dietary supplement.
    The term "physiologically acceptable medium" is intended to mean a medium that is compatible with the organism of the individual to whom said composition is to be administered. It may be, for example, a non-toxic solvent such as water. In particular, said medium is compatible with oral administration.
    A composition of the invention is preferably for the oral route.
    A composition of the invention for the oral route may be selected from the group consisting of a food product, a beverage, a pharmaceutical, a nutraceutical, a food additive, a dietary supplement and a dairy product and is, in particular, in the form of a dietary supplement. Legends of the figures
    Figure 1 illustrates the concentration of interleukin-8 (IL-8) (in μg IL-8 / mg protein) in TNFα-stimulated Ht-29 cells: (a) only in YBHI medium (control); (b) treated with F. prausnitzii strain A2-165; (c) treated with the 1-4573 strain of F. prausnitzii according to the invention; or (d) treated with F. prausnitzii strain 1-4575. Trials are conducted in triplicate. The results are normalized using, as a reference value, IL-8 produced after co-induction with PBS as a negative control. * P <0.05.
    Figure 2 illustrates the concentration of interleukin 10 (IL-10) (in μg of IL-10 / ml of protein) in peripheral blood mononuclear cells (PBMC): (a) only in YBHI medium (control); (b) treated with F. prausnitzii strain A2-165; (c) treated with the 1-4573 strain of F. prausnitzii according to the invention; or (d) treated with F. prausnitzu strain 1-4575. Trials are performed in triplicate. *** P <0.001.
    Figure 3 illustrates the experimental protocol for the model of chronic colitis in mice (DNBS).
    Figure 4 illustrates the macroscopic scores of the colon and small intestine (a) of control mice (without colitis) receiving only EtOH; (b) control mice with DNBS colitis and treated with PBS; (c) mice with DNBS colitis treated with F. prausnitzu strain A2-165; (d) mice with DNBS colitis treated with F. prausnitzu strain 1-4573; and (e) mice with DNBS colitis treated with F. prausnitzu strain 1-4575. Macroscopic criteria (evaluated on a scale of 0 (without damage) to 9) include macroscopic mucosal damage (such as ulcers, thickening of the colon wall, presence of adhesions between the colon and other organs). intra-abdominal), the consistency of feces (as an indicator of diarrhea) and the presence of hyperemia. n = 8. ** p <0.01.
    Figure 5 illustrates the myeloperoxidase (MPO) activity (U / mg) in the distal colon (a) of control (colitis-free) mice receiving only EtOH; (b) control mice with DNBS colitis and treated with PBS; (c) mice with DNBS colitis treated with F. prausnitzu strain A2-165; (d) mice with DNBS colitis treated with F. prausnitzu strain 1-4573; and (e) mice with DNBS colitis treated with F. prausnitzu strain 1-4575. n = 8. * P <0.05.
    Figure 6 illustrates the concentrations of colonic cytokines ((Figure 6A) IL-2, (Figure 6B) IL-4 (Figure 6C) IL-6 and (Figure 6D) IFNg) (in μg / ml) (a) Mouse controls (without colitis) receiving only EtOH; (b) control mice with DNBS colitis and treated with PBS; (c) mice with DNBS colitis treated with F. prausnitzü strain A2-165; (d) mice with DNBS colitis treated with F. prausnitzu strain 1-4573; and (e) mice with DNBS colitis treated with F. prausnitzu strain 1-4575.
    Detailed description of the invention
    The present inventors have conducted extensive work to identify the ability of a specific strain of Faecalibacterium prausnitzu to treat and / or prevent inflammatory gastrointestinal diseases in an individual, particularly inflammatory bowel diseases, in an individual.
    Indeed, the inventors have unexpectedly determined that the strain of F. prausnitzii 1-4573 has the ability to reduce gastrointestinal inflammation, particularly intestinal inflammation, in an individual.
    It is presently described that the bacterial strain of the invention can, in particular, reduce the concentration of pro-inflammatory molecules, such as interleukin-8 (IL-8), interleukin-2 (IL-2), interleukin 4 (IL-4) and interleukin 6 (IL-6).
    It is also presently demonstrated that the bacterial strain of the invention is, in particular, capable of increasing the concentration of anti-inflammatory molecules, such as interleukin 10 (IL-10).
    Faecalibacterium prausnitzii strain of the invention F. prausnitzii is a major member of the phylum Firmicutes and is one of the most abundant commensal bacteria in the microbiota of the human healthy large intestine. F. prausnitzii is an extremely sensitive oxygen (EOS) bacterium and is therefore difficult to cultivate, even under anaerobic conditions (Duncan et al 2002, Int J. System Evol Microbiol 52 (Pt 6): 2141- 6 and Lopez-Siles et al., Appl Environ Microbiol, January 2012, 78 (2): 420-8). F. prausnitzii is, in particular, known to be one of the most abundant butyrate-producing bacteria in the human gastrointestinal tract, the short chain butyrate fatty acid being very important in gut physiology, systemic functions and beneficial effects on human health (Macfarlane and Macfarlane (2011), J. Clin Gastroenterol 45 Suppl: S120-7).
    F. prausnitzii strain A2-165 is also known to have anti-inflammatory and protective effects in murine models of acute and chronic colitis, i.e., in inflammatory disorders (Martin et al., Inflamm Bowel Mar. 2014, 20 (3): 417-30 and Sokol et al., Proc Natl Acad Sci USA, 28 Oct. 2008; 105 (43): 16731-6).
    The anti-inflammatory properties of strain A2-165 can not generally be attributed to F. prausnitz, since the existence of anti-inflammatory properties is unpredictable for a given F. prausnitzii strain.
    Indeed, such specific anti-inflammatory activity is illustrated in the examples, in which a comparative test was conducted with a strain of F. prausnitzii not forming part of the invention, namely the CNCM 1-4575 strain, which does not possess the anti-inflammatory activity of the strain of the invention.
    A suitable daily dose of a bacterial strain according to the invention is from 107 to 1011 colony-forming units (cfu) as a drug, for example in the form of a daily dose equivalent to 109 cfu.
    A strain of Faecalibacterium prausnitzii of the invention is for use in the treatment and / or prevention of gastrointestinal inflammation in an individual, particularly inflammation of the intestine in an individual.
    The strain of the invention is a probiotic whose activity is located in the intestine. A probiotic bacterium according to the invention denotes a bacterium which, when it is ingested in sufficient quantities, can have beneficial effects on human health.
    Therefore, this strain must be administered live to the intestine.
    The bacterial strain of the invention can be administered to the intestine of an individual to be treated in different ways, namely orally or rectally. A bacterium according to the invention is preferably administered orally.
    According to a preferred embodiment, the bacterial strain of the invention is comprised in a composition comprising a physiologically acceptable medium. Such a composition is preferably for the oral route, and in particular in the form of a dietary supplement.
    compositions
    The present invention further relates to a composition comprising, in a physiologically acceptable medium, at least the bacterial strain of Faecalibacterium prausnitzii 1-4573 of the invention.
    A composition according to the invention is provided for the digestive tract, in particular the intestine.
    Therefore, a composition according to the invention is selected from an oral or rectal composition. A composition of the invention is preferably an oral or rectal composition, more preferably an oral composition.
    According to one embodiment, a composition of the invention is an oral composition, that is to say that it is intended for oral administration to a subject.
    Such a composition may be in the form of a suspension, a tablet, a pill, a capsule, a granule or a powder.
    The composition according to the invention for the oral route may be chosen from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a food supplement or a dairy product, and is, in particular , a food supplement.
    According to a preferred embodiment, a composition according to the invention is a dietary supplement.
    A dietary supplement for oral administration may be present in capsules, capsules, soft capsules, tablets, coated tablets, pills, pastes, lozenges, gums, oral solutions or emulsions, syrup or gel.
    Advantageously, a composition according to the invention, provided for oral administration, may be provided with a coating resistant to gastric juice, to ensure that the bacterial strain of the invention included in said composition can pass through the damaged stomach. The release of the bacterial strain can thus occur for the first time in the upper intestinal tract.
    A dietary supplement according to the invention may further comprise a sweetener, a stabilizer, an antioxidant, an additive, a flavoring agent and / or a dye.
    The formulation thereof is carried out by the usual methods for producing coated tablets, capsules, gels, controlled release hydrogels, emulsions, tablets or capsules.
    A composition according to the invention may also be in the form of a nutritional composition.
    A nutritional composition according to the invention is in the form of a yogurt, a cereal bar, cereals for breakfast, a dessert, a frozen food, a soup, a pet food, a liquid suspension, a powder, a tablet, a gum or a candy.
    In another embodiment of the invention, a composition containing the bacterial strain of the invention is administered intrarectally.
    Preferably, rectal administration is conducted in the form of a suppository, enema or foam.
    In particular, a composition of the invention is suitable for administering a daily dose of from 107 to 1011 colony-forming units (cfu) as a drug, preferably a daily dose equivalent to 109 cfu.
    For example, a composition according to the invention can be administered to an individual in need of a single daily dose of 1 g containing the bacterial strain 1-4573 of the invention in an amount equivalent to a dose of between 107 and 1011 cfu preferably 109 cfu.
    In another example, a composition according to the invention can be administered to an individual in need at a single daily dose of 0.2 g containing the bacterial strain 1-4573 of the invention in an amount equivalent to an amount between 107 and 1011 cfu, preferably 109 cfu.
    In another example, a composition according to the invention may be administered to an individual in need thereof twice daily on the basis of two doses of 1 g, each dose containing, independently, the bacterial strain 1-4573 of the invention. in an amount equivalent to between 5 × 10 6 and 5 × 10 10 cfu (based on dry weight), preferably 5 × 10 8 cfu, so that the total daily dose of bacterial strain 1-4573 of the invention administered to the individual is as indicated above.
    A composition according to the invention may furthermore comprise at least one of: antioxidants, fish oils, DHA, EPA, vitamins, minerals, phytonutrients, a protein, a lipid, probiotics and combinations of them. The invention is described below in more detail by way of the following examples which are presented by way of illustration only.
    All references to percentages are percentages by weight unless otherwise indicated.
    EXAMPLES
    The strain of F. prausnitzii according to the invention deposited with the CNCM under accession number CNCM 1-4573 was tested and compared with two other strains of F. prausnitzii, A2-165 and CNCM 1-4575, for its ability to modulate in vitro and in vivo immune response and to have a direct impact on intestinal inflammation.
    In vitro assays, two different cell models are used: HT-29 and PBMC.
    In in vivo tests, a murine colitis model is used.
    In vitro tests I. Bacterial strains and culture conditions
    Isolates of the F. prausnitzii strains tested were grown in YBHI medium (brain-heart perfusion medium supplemented with 0.5% yeast extract) (Difco, Detroit, USA) supplemented with 1 mg / ml of cellobiose (Sigma-Aldrich Chemie GmbH, Buchs, Switzerland), 1 mg / ml maltose (Sigma-Aldrich) and 0.5 mg / ml cysteine (Sigma-Aldrich) at 37 ° C in an anaerobic chamber filled with N2 = 85%, CO2 = 10% and H2 = 5%.
    The strains are isolated from healthy patients: - strains CNCM-I4573 and CNCM-I4575 from a man aged 40; and - strain A2-165 (DSMZ 17677) from a 34-year-old female Duncan SH et al. IJSEM, 2002, 52 (Pt 6): 2141-2146. II. Immunomodulatory properties using HT-29 cells A. Cell culture
    The HT-29 (ATCC HTB-38) cell line (LGC-Standars) is cultured in Dulbecco's Minimalized Minimal Eagle Essential Medium (DMEM) (Sigma-Aldrich) supplemented with 10% (w / v) fetal bovine serum ( FBS) inactivated by heat (GibcoBRL, Eragny, France) and penicillin G / streptomycin (5000 IU / ml, 5000 μg / ml) (Sigma-Aldrich). The cultures are incubated in 25 cm 2 tissue culture flasks (Nunc, Roskilde, Denmark) at 37 ° C in a 5% (v / v) CO2 atmosphere until confluent. B. Anti-inflammatory tests
    Anti-inflammatory tests using HT-29 are conducted according to the procedure described by Kechaou et al. (Applied and environmental microbiology 2012, 79 (5): 1491-1499).
    Briefly, 50,000 HT-29 cells per well are seeded in 24-well culture plates (Nunc). Twenty-four hours before bacterial stimulation, the culture medium is replaced by a medium with 5% FBS.
    The tests begin at day 7 after seeding, when the cells are at confluence (1.83 × 10 6 cells / well). Twenty-four hours before bacterial co-culture (day 6), the culture medium is replaced by a medium with 5% FBS inactivated by heat and 1% glutamine.
    On the day of co-culture, 10% of the bacterial supernatant is added in DMEM in a total volume of 500 μΐ. The cells are stimulated simultaneously with human TNF-α (5 ng / ml, Peprotech, NJ) for 6 h at 37 ° C in 10% CO 2.
    All samples are analyzed in triplicate.
    After co-incubation, the cell supernatants are collected and stored at -80 ° C until further analysis of interleukin-8 (IL-8) concentrations by ELISA (Biolegend, San Diego, CA).
    Total proteins are determined using the Bradford reagent test (Sigma-Aldrich). The tests are conducted at least in triplicate.
    The results are expressed as IL-8 / protein (μg / mg) and are normalized using IL-8 produced as a reference value after co-incubation with PBS as a negative control. C. Statistical Analysis Statistical analysis is performed using GraphPad software (GraphPad Software, La Jolla, CA, USA). All data are expressed as mean +/- SEM.
    Comparisons are made with the non-parametric Kruskal-Wallis test followed by a Dunn multiple comparison test.
    Correlation tests are performed using the Spearman test.
    A p-value less than 0.05 is considered significant. D. Results
    The results obtained are shown in FIG.
    It can be seen from these tests that the CNCM 1-4573 strain is capable of significantly reducing IL-8 pro-inflammatory cytokine production induced by TNF-α stimulation in HT-29 epithelial cells.
    As expected, F prausnitzii strain A2-165 also produces such a reduction in IL-8 production.
    In contrast, the 1-4575 F. prausnitzii strain does not induce a statistically significant decrease in IL-8.
    III. Immunomodulatory properties using PBMC A. Cell culture
    Commercial PBMCs (StemCell Technologies, France) of five healthy donors are used.
    Donors have the following characteristics: men, less than 65 years of age, body mass index <30, non-smoker, no drugs with known anti-inflammatory effects taken in the 15 days prior to selection, and negative test for HIV, hepatitis A and hepatitis B.
    After reception, the cells are stored in liquid nitrogen until use. B. Anti-inflammatory tests
    In order to prepare PBMCs for co-culture assays with F. prausnitzii bacteria, the flasks are thawed at 37 ° C in a water bath and then transferred to media containing RPMI-1640 medium supplemented with 10% FCS inactivated. by heat, 1% L-glutamine and 0.1% penicillin / streptavidin (the middle components are purchased in Lonza, Switzerland). DNase (100 μg / ml, Roche Applied Science, France) is added to the mixture to prevent agglomeration of the cells.
    The cells are then centrifuged at 200 g for 15 min, counted using trypan blue and plated on 24 well plates at 1x106 cells / well. Supernatants are added in triplicate (three wells per donor) at 10% in a total volume of 1 ml. The plates are incubated for 24 h at 37 ° C with 10% CO2.
    The culture supernatants are collected, mixed with an anti-protease cocktail according to the manufacturer's instructions (EDTA-complete protease inhibitor, Roche Applied Bioscience) and stored at -80 ° C until further analysis of interleukin-10 concentrations ( IL-10) by ELISA (Mabtech, Sweden). C. Statistical Analysis Statistical analysis is performed using GraphPad software (GraphPad Software, La Jolla, CA, USA). All data are expressed as mean +/- SEM.
    Comparisons are made with the non-parametric Kruskal-Wallis test followed by a Dunn multiple comparison test.
    Correlation tests are performed using the Spearman test.
    A p value less than 0.05 is considered significant. D. Results
    The results obtained are shown in FIG.
    These tests demonstrate that the CNCM 1-4573 strain is capable of significantly increasing the production of IL-10 anti-inflammatory cytokine in PBMCs.
    As expected, F. prausnitzu strain A2-165 also produces such an increase in IL-10 production.
    In contrast, the 1-4575 F. prausnitzii strain does not induce a statistically significant increase in IL-10.
    In vivo tests A. Induction of DNBS colitis and administration of bacteria
    The DNBS-induced colitis protocol as previously described (Martin R, et al., Inflamm Bowel Dis., Mar. 2014; 20 (3): 417-30).
    Briefly, mice are anesthetized with enflurane (Abbott, Abbott Park, IL) and a 10 cm long segment of PE-90 tubing (ClayAdam, Parsippany, NJ) is attached to a tuberculin syringe and inserted at 3 , 5 cm in the colon.
    Colitis is induced by intrarectal (/>) injection via this tube of 200 mg / kg DiNitroBenzene-Sulfonic Acid (DNBS) solution (ICN, Biomedical Inc.) in 30% ethanol ( EtOH).
    Control mice (without colitis) receive only EtOH.
    The mice are fed with 6% sucrose in drinking water for the first 3 days after the injection of DNBS to prevent dehydration (DNBS period). 10 days after the DNBS period, 200 μΐ containing 1 × 10 9 CFU of one of the bacterial strains are administered intragastrically, each day for 10 days (feeding period) (see FIG. 3).
    The study groups were as follows: non-colite control group (EtOH + PB S), control group colitis (DNBS + PB S), strain group F. prausnitzii A2-165 (DNBS + A2-165), F CNCM-I4573 (DNBS + CNCM-I4573) and F. prausnitzii CNCM-I4575 (DNBS + CNCM-I4575).
    The colitis is reactivated 21 days after the first injection of DNBS (recovery period) with a second injection of 100 mg / kg of DNBS solution.
    The severity of the colitis is then determined by monitoring the weight loss (results not shown) during the 3 days following the second injection. B. Macroscopic scores
    The mice are sacrificed by cervical dislocation and the abdominal cavity is opened. The colon and small intestine are removed and opened longitudinally; macroscopic damage is evaluated immediately.
    Macroscopic scores are recorded using a previously described system for DNBS colitis.
    Briefly, the macroscopic criteria (evaluated on a scale of 0 to 9) include macroscopic mucosal damage (such as ulcers, thickening of the colon wall, presence of adhesions between the colon and other intra-organ organs). abdominal), the consistency of feces (as an indicator of diarrhea) and the presence of hyperemia.
    The results obtained are shown in Figure 4. C. Myeloperoxidase Activity (iMPO) The myeloperoxidase (MPO) activity, used as a neutrophilic infiltration marker, is assayed by a modified version of the method described by Bradley et al. (J. Invest Dermatol 1982, 78 (3): 206-209).
    A 1 cm length of distal colon is recovered and homogenized (50 mg / ml) in ice-cold 50 mM potassium phosphate buffer (pH 6) containing 5% hexadecyltrimethylammonium bromide (Sigma-Aldrich) and peroxide. hydrogen (H2O2).
    The colorimetric reaction is monitored by measuring the absorbance with a spectrophotometer.
    The results obtained are shown in Figure 5. D. Cytokine assays
    A length of one centimeter of distal colon is recovered and homogenized in 400 μl of Tris-HCl buffer containing protease inhibitors (Sigma-Aldrich) in a tissue lyser.
    The samples are centrifuged for 20 min and the supernatant is frozen at -80 ° C until further analysis.
    Prior to sacrifice, the blood samples are obtained from the retro-orbital venous plexus and centrifuged, and the sera are stored at -80 ° C until analysis.
    Proinflammatory cytokines (IL-6, IL-4, IFN-gamma, and IL-2) are assayed by at least one cytometric ball array system (BD, NJ, USA).
    The results obtained are shown in FIGS. 6a (IL-2), 6b (IL-4), 6c (IFN-gamma) and 6d (IL-6). E. Statistical analysis
    GraphPad software (GraphPad Sofware, La Jolla, CA, USA) is used for statistical analysis.
    The results are presented as bar graphs +/- SEM.
    Comparisons are made with the non-parametric Kruskal-Wallis test followed by a Dunn multiple comparison test. Correlation tests are performed using the Spearman test.
    A p value less than 0.05 is considered significant. F. Results 1. The macroscopic scores of FIG. 4 show that a very good score is obtained in DNBS mice treated with the 1-4573 strain, equivalent to that obtained in the control mice having no colitis.
    On the contrary, the scores obtained with DNBS mice treated with the strain A2-165 or the strain 1-4575 are higher on the scale of the macroscopic criteria than those obtained with the control mice having no colitis and the treated DNBS mice. with strain 1-4573. 2. For the measured myeloperoxidase activities, the activities obtained with DNBS mice treated with 1-4573 strain or A2-165 strain are almost similar to the activity obtained with non-colitis control mice.
    In contrast, the activity obtained with DNBS mice treated with the 1-4575 strain is similar to the activity obtained with untreated control DBNS mice. 3. Finally, the profile of pro-inflammatory cytokines obtained with DNBS mice treated with the 1-4573 strain and DNBS mice treated with the A2-165 strain clearly demonstrates the anti-inflammatory effect of these two strains.
    In fact, particularly with regard to DNBS mice treated with 1-4573 strain, the expression levels of IL-2 and IL-4 are similar to those obtained with control mice lacking colitis. The expression levels of IFN-γ and IL-6 are more reduced compared with those obtained with the untreated control DNBS mice.
    In contrast, strain 1-4575 has no anti-inflammatory property. Its expression levels of IL-2, IL-4, IL-6 and IFN-γ are similar, or even higher, than those observed with untreated control DNBS mice.
    Accordingly, it is demonstrated in the present examples that the F. prausnitzii 1-7573 strain advantageously exhibits anti-inflammatory properties and that all F. prausnitzii strains do not possess such properties, as demonstrated with the 1- strain. 4575.
    权利要求:
    Claims (6)
    [1" id="c-fr-0001]
    1. Bacterial strain of the species Faecalibacterium prausnitzii deposited with the CNCM under accession number CNCM 1-4573, for its use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual.
    [2" id="c-fr-0002]
    2. Bacterial strain for use according to claim 1, characterized in that the individual is a mammal, in particular a human.
    [3" id="c-fr-0003]
    3. Bacterial strain for its use according to claim 1 or 2, characterized in that the inflammatory gastrointestinal disease is an inflammatory bowel disease, particularly an intestinal inflammatory bowel disease.
    [4" id="c-fr-0004]
    4. Bacterial strain for use according to claim 3, characterized in that the intestinal inflammatory bowel disease is selected from the group consisting of Crohn's disease, ulcerative colitis and pouchitis, in particular Crohn's disease and Crohn's disease. hemorrhagic rectocolitis.
    [5" id="c-fr-0005]
    Bacterial strain for its use according to any one of the preceding claims, characterized in that the bacterial strain is included in a composition comprising a physiologically acceptable medium, preferably in an oral composition, and more particularly preferably in a supplement food.
    [6" id="c-fr-0006]
    6. Bacterial strain for its use according to claim 5, characterized in that the composition is for the oral route and is selected from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a dietary supplement and a dairy product, and is particularly a dietary supplement.
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    同族专利:
    公开号 | 公开日
    EP3407902B1|2020-07-15|
    ZA201805302B|2019-10-30|
    IL260752A|2021-02-28|
    EP3407902A1|2018-12-05|
    WO2017129515A1|2017-08-03|
    AU2017211244A1|2018-08-09|
    PL3407902T3|2021-04-06|
    CN109310714A|2019-02-05|
    JP2019508486A|2019-03-28|
    BR112018015121A2|2018-12-11|
    US20190030089A1|2019-01-31|
    CA3012214A1|2017-08-03|
    LT3407902T|2020-12-28|
    AU2017211244B2|2019-05-16|
    NZ744528A|2020-02-28|
    HUE050810T2|2021-01-28|
    US10918678B2|2021-02-16|
    FR3046934B1|2018-01-26|
    PT3407902T|2020-09-03|
    JP6935632B2|2021-09-15|
    SG11201806361PA|2018-08-30|
    ES2820338T3|2021-04-20|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2020020540A1|2018-07-26|2020-01-30|Institut National De La Recherche Agronomique |Streptococcus thermophilus cnrz160 strain for the treatment and prevention of intestinal inflammation and associated disorders in an individual|US20160000838A1|2013-03-05|2016-01-07|Rijksuniversiteit Groningen|Use of Faecalibacterium Prausnitzii Htf-f to Suppress Inflammation|
    SI3218524T1|2014-11-13|2020-11-30|Institut National De Recherche Pour L'agriculture, L'alimentation Et L'environnement|Faecalibacterium prausnitzii strains for treating and preventing gastrointestinal pain|CN111107860A|2017-06-16|2020-05-05|表飞鸣制药株式会社|Prophylactic or therapeutic agent for fat-related disease and/or inflammation|
    FR3099053A1|2019-07-24|2021-01-29|Institut National De La Recherche Agronomique |BACTERIAL STRAINS FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL INFLAMMATION|
    EP3838276A1|2019-12-17|2021-06-23|Exeliom Biosciences|Association of faecalibacterium prausnitzii strain cncm i-4573 with pentasa® for the treatment and prevention of gastrointestinal inflammation|
    KR102169794B1|2020-06-24|2020-10-27|주식회사 엔테로바이옴|Novel Faecalibacterium prausnitzii EB-FPDK11 and Use Thereof|
    KR102169795B1|2020-06-24|2020-10-27|주식회사 엔테로바이옴|Novel Faecalibacterium prausnitzii EB-FPDK9 and Use Thereof|
    WO2022035269A1|2020-08-14|2022-02-17|주식회사 고바이오랩|Faecalibacterium prausnitzii strain and uses thereof|
    KR102245415B1|2020-12-14|2021-04-29|주식회사 엔테로바이옴|The Composition of Culture Media for Faecalibacterium prausnitzii|
    法律状态:
    2016-12-30| PLFP| Fee payment|Year of fee payment: 2 |
    2017-07-28| PLSC| Publication of the preliminary search report|Effective date: 20170728 |
    2017-11-29| PLFP| Fee payment|Year of fee payment: 3 |
    2018-01-26| CD| Change of name or company name|Owner name: UNIVERSITE PARIS 6 PIERRE ET MARIE CURIE, FR Effective date: 20171221 Owner name: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, FR Effective date: 20171221 Owner name: INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE , FR Effective date: 20171221 |
    2018-01-26| CA| Change of address|Effective date: 20171221 |
    2019-12-20| PLFP| Fee payment|Year of fee payment: 5 |
    2020-11-26| PLFP| Fee payment|Year of fee payment: 6 |
    2020-12-11| CA| Change of address|Effective date: 20201104 |
    2020-12-11| CD| Change of name or company name|Owner name: INSTITUT NATIONAL DE RECHERCHE POUR L'AGRICULT, FR Effective date: 20201103 Owner name: UNIVERSITE PARIS 6 PIERRE ET MARIE CURIE, FR Effective date: 20201103 Owner name: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, FR Effective date: 20201103 Owner name: ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, FR Effective date: 20201104 Owner name: UNIVERSITE PARIS 6 PIERRE ET MARIE CURIE, FR Effective date: 20201104 Owner name: INSTITUT NATIONAL DE RECHERCHE POUR L'AGRICULT, FR Effective date: 20201104 |
    2021-10-28| PLFP| Fee payment|Year of fee payment: 7 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1650567A|FR3046934B1|2016-01-25|2016-01-25|FAECALIBACTERIUM PRAUSNITZII STRAIN CNCM I-4573 FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL INFLAMMATION|
    FR1650567|2016-01-25|FR1650567A| FR3046934B1|2016-01-25|2016-01-25|FAECALIBACTERIUM PRAUSNITZII STRAIN CNCM I-4573 FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL INFLAMMATION|
    HUE17702322A| HUE050810T2|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    SG11201806361PA| SG11201806361PA|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    PT177023223T| PT3407902T|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    CN201780019735.0A| CN109310714A|2016-01-25|2017-01-23|For treating and preventing gastrointestinal inflammatory Pu Shi bacillus faecalis bacterial strain CNCM I-4573|
    LTEP17702322.3T| LT3407902T|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    PL17702322T| PL3407902T3|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    AU2017211244A| AU2017211244B2|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain CNCM 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    PCT/EP2017/051306| WO2017129515A1|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    JP2018557200A| JP6935632B2|2016-01-25|2017-01-23|Faecalibacterium prausnitzi CNCM I-4573 strain for the treatment and prevention of gastroenteritis|
    NZ744528A| NZ744528A|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm i-4573 for the treatment and prevention of gastrointestinal inflammation|
    EP17702322.3A| EP3407902B1|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    ES17702322T| ES2820338T3|2016-01-25|2017-01-23|Faecaslibacterium Prausnitzii strain CNCM I-4573 for the treatment and prevention of gastrointestinal inflammation|
    US16/072,319| US10918678B2|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain CNCM 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    CA3012214A| CA3012214A1|2016-01-25|2017-01-23|Faecalibacterium prausnitzii strain cncm i-4573 for the treatment and prevention of gastrointestinal inflammation|
    BR112018015121-1A| BR112018015121A2|2016-01-25|2017-01-23|faecalibacterium prausnitzii cncm i-4573 bacterial strain for treatment and prevention of gastrointestinal inflammation|
    IL260752A| IL260752A|2016-01-25|2018-07-24|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
    ZA201805302A| ZA201805302B|2016-01-25|2018-08-10|Faecalibacterium prausnitzii strain cncm 1-4573 for the treatment and prevention of gastrointestinal inflammation|
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