ASSOCIATION OF FAECALIBACTERIUM PRAUSNITZII STRAIN CNCM I-4573 WITH PENTASA® FOR THE TREATMENT AND PREVENTION OF GASTROENTERITIS

Abstract

The present invention relates to an association between a strain of the species Faecalibacterium prausnitzii deposited at the CNCM under accession number CNCM I-4573 and mesalamine or a derivative thereof, and in particular to the use of this association in the treatment and / or prevention of inflammatory gastrointestinal diseases in individuals.

Description

[Technical field]

[0001] The present invention relates to an association between a strain of the species Faecalibacterium prausnitzii deposited at the CNCM under deposit number CNCM I-4573 and mesalamine or a derivative thereof, in particular for use in the treatment and prevention of inflammatory gastrointestinal diseases (IGD), in particular inflammatory bowel diseases (IBD), in an individual. [Background technology]

[0002] Inflammation is a natural biological process that forms a normal part of the response to injury or infection and contributes to protecting the organism from internal or external aggression.

[0003] However, malfunction of the inflammatory mechanism, especially persistent or excessive inflammation, can cause painful diseases and endanger the patient's life. Such diseases include, for example, skin diseases, intestinal diseases, neurological diseases, arthritis and autoimmune diseases. Some of these inflammatory diseases have no established or suitable treatments yet.

[0004] As a result, the search and search for new anti-inflammatory therapeutic strategies constitutes a major topic in medicine and in biomedical research.

[0005] 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 inappropriate and continuous activation of the mucosal immune system caused by the presence of intestinal microflora in genetically predisposed patients.

[0006] Aminosalicylates (particularly 5-ASA, also called mesalamine or mesalazine) or derivatives thereof have been used successfully for a long time, especially in the treatment of ulcerative colitis and Crohn's disease.

[0007] The problem with treatment with mesalamine is that it raises concerns about nephrotoxicity and therefore cannot be administered in large doses. In fact, the incidence of renal dysfunction in patients with IBD treated with 5-ASA is estimated at 1 in 100 patients, and interstitial nephritis occurs in 1 in 500 patients.

[0008] Moreover, 5-ASA is known to be effective in mild to moderate disease forms, but is also known to be significantly less effective in more severe disease forms.Therefore, when 5-ASA is identified as ineffective, the only available alternative is the use of immunosuppressive therapy.However, such therapy is very expensive and potentially associated with serious side effects, such as infection and tumor formation.

[0009] Therefore, there is a need for alternative solutions to immunosuppressive therapy when 5-ASA is not sufficient in the treatment and / or prevention of inflammatory gastrointestinal diseases.In particular, there is a need for new solutions that allow improving the properties of mesalamine and its derivatives in the treatment and / or prevention of inflammatory gastrointestinal diseases.More generally, there is a constant need for new substances or combinations of substances for the treatment and / or prevention of inflammatory gastrointestinal diseases, particularly inflammatory bowel diseases, in individuals.

[0010] The present invention provides a solution to these problems. Summary of the Invention [Problem to be solved by the invention]

[0011] The object of the present invention is to describe a novel association of substances, and compositions comprising same, for the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual, in particular inflammatory bowel diseases in an individual.

[0012] In the context of the present invention, the term "prevent" means to reduce to a lower extent the likelihood of the occurrence of a given phenomenon, i.e. in the present invention gastroenteritis, in particular inflammatory bowel disease. The term "prevent" must also be understood to include reducing to a lower extent the risk or likelihood of recurrence of a disease according to the present invention, in particular inflammatory bowel disease.

[0013] In the context of the present invention, the term "treat", especially when used in relation to a disease, means slowing or stopping the onset or progression of the disease, causing the regression of associated clinical symptoms, or partially or completely alleviating the disease. The term "treat" should also be understood to encompass a reduction in the number of relapses and / or a reduction in the intensity of the relapses and / or an increase in the time separating two relapses of a disease according to the present invention, especially inflammatory bowel disease.

[0014] The present invention is based on the discovery by the inventors that when mesalamine or a derivative thereof is used in combination with Faecalibacterium prausnitzii strain CNCM I-4573, this results in improved anti-inflammatory properties.

[0015] In particular, the inventors have discovered that when mesalamine or a derivative thereof is used in an amount that is less effective when used alone, administering mesalamine or a derivative thereof to an individual in association with Faecalibacterium prausnitzii strain CNCM I-4573 (when used alone and in an amount that is less effective) can unexpectedly provide anti-inflammatory properties.

[0016] According to the inventors' experimental results, an association between mesalamine or a derivative thereof and a specific strain of F. prausnitzii, deposited at the CNCM on January 31, 2012 under the accession number CNCM I-4573, has the unexpected ability to synergistically alleviate gastroenteritis, in particular enteritis, in an individual.

[0017] Thus, according to a first subject, the invention relates to an association between a strain of the species Faecalibacterium prausnitzii deposited at the CNCM under deposit number CNCM I-4573 and mesalamine or a derivative thereof.

[0018] The derivative of mesalamine may, for example, be selected from the group consisting of mesalazine, olsalazine, 4-ASA (4-aminosalicylic acid), and sulfasalazine.

[0019] Another object of the present invention is a pharmaceutical composition comprising the association of the invention in a pharma- ceutically acceptable medium.

[0020] The present invention further relates to an association according to the invention for use in the treatment and / or prevention of an inflammatory gastrointestinal disease in an individual.

[0021] An individual according to the invention is preferably a mammal, such as a mammal including a non-human mammal, and in particular a human.

[0022] The inflammatory gastrointestinal disease is in particular an inflammatory bowel disease (IBD), more in particular a colonic inflammatory bowel disease.

[0023] Said colonic inflammatory bowel disease may 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.

[0024] According to another embodiment, the association for the use according to the invention is in a pharma- ceutically acceptable medium of a pharmaceutical composition, preferably an oral composition, more particularly preferably in a medicinal product.

[0025] The term "pharmaceutical acceptable medium" is intended to mean a medium that is compatible with the body of an individual to which the composition must be administered. It is, for example, a non-toxic solvent, such as water. In particular, the medium is suitable for oral administration.

[0026] The compositions of the present invention are preferably for oral administration.

[0027] The composition of the present invention for oral administration can be used in the form of food, beverage, pharmaceutical, Nutraceutical , food additives, A food supplement and dairy products. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows, from left to right on the horizontal axis, the Disease Activity Index (DAI) scores obtained for: (i) control mice administered water only and PBS with glycerol (no colitis); (ii) control mice with DSS-induced colitis and treated with PBS with glycerol; (iii) mice with DSS-induced colitis and treated with F. prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis and treated with an association of F. prausnitzii strain CNCM I-4573 with Pentasa®; and (v) mice with DSS-induced colitis and treated with PBS with Pentasa® and glycerol. The DAI score is assessed on a scale of 0 (no inflammation) to 4 (ordinate) (n=10 / group, except for water+PBS / glycerol n=5). [Diagram 2]2 shows, from left to right on the horizontal axis, the presence of blood in the feces of (i) control mice administered only water and PBS with glycerol (no colitis); (ii) control mice with DSS-induced colitis and treated with PBS with glycerol; (iii) mice with DSS-induced colitis and treated with F. prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis and treated with the association of F. prausnitzii strain CNCM I-4573 with Pentasa®; and (v) mice with DSS-induced colitis and treated with PBS with Pentasa® and glycerol. The higher the amount of blood present in the feces, the higher the inflammation and damage in the individual under consideration. The occurrence of blood is scored according to the criteria 0 (absent) or 1 (present) (n=10 / group, except for water+PBS / glycerol n=5). [Diagram 3] Figure 3 shows, from left to right on the horizontal axis, the colon weight / colon length ratios of (i) control mice administered only water and PBS with glycerol (no colitis); (ii) control mice with DSS-induced colitis and treated with PBS with glycerol; (iii) mice with DSS-induced colitis and treated with F. prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis and treated with the association of F. prausnitzii strain CNCM I-4573 with Pentasa®; and (v) mice with DSS-induced colitis and treated with PBS with Pentasa® and glycerol. A decrease in colon size is caused by severe inflammation, and an increase in colon weight due to edema / inflammatory infiltration caused by severe inflammation is also observed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The present inventors have conducted extensive research to identify the ability of an association between a specific strain of Faecalibacterium prausnitzii and mesalamine or a derivative thereof to synergistically treat and / or prevent inflammatory gastrointestinal disease in an individual, particularly inflammatory bowel disease in an individual.

[0030] Indeed, the inventors have unexpectedly determined that the F. prausnitzii strain deposited at the CNCM under deposit number CNCM I-4573 in association with mesalamine or a derivative thereof provides a superior ability to alleviate gastroenteritis, and in particular enteritis, in an individual than the same agent used alone.

[0031] Faecalis bacterium prausnitzii strain F. prausnitzii is a major member of the phylum Firmicutes and is some of the most abundant commensal bacteria in the healthy human large intestine microbiota.

[0032] F. prausnitzii is an extremely oxygen-sensitive (EOS) bacterium, and therefore, F. prausnitzii is difficult to culture even under anaerobic conditions (Duncan et al. 2002, Int. J. Syst. Evol. Microbiol. 52(Pt 6):2141-6 and Lopez-Siles et al. Appl. Environ Microbiol. January 2012;78 (2):420-8). F. prausnitzii is known to be one of the most abundant butyrate-producing bacteria in the human gastrointestinal tract, and butyrate short-chain fatty acids are of great importance in gut physiology, systemic function, and beneficial effects on human health (Macfarlane and Macfarlane (2011), J. Clin. Gastroenterol. 45 Suppl:S120-7).

[0033] F. prausnitzii A2-165 is also known to have anti-inflammatory and protective effects in mouse models of acute and chronic colitis, i.e., inflammatory diseases (Martin et al., Inflamm Bowel Dis. March 2014;20(3):417-30 and Sokol et al., Proc Natl Acad Sci USA. October 28, 2008;105(43):16731-6).

[0034] Moreover, International Publication No. WO2017129515 describes the ability of the Faecalibacterium prausnitzii strain, deposited at the CNCM under accession number CNCM I-4573, when used alone to reduce gastrointestinal inflammation, in particular intestinal inflammation, in vitro and in vivo.

[0035] The anti-inflammatory properties of the A2-165 and I-4573 strains cannot be generally attributed to the F. prausnitzii species, given that the presence of anti-inflammatory properties is unpredictable for a given strain of F. prausnitzii. Indeed, such specific anti-inflammatory activity is shown in International Publication No. WO2017129515, where comparative studies were carried out with the CNCM I-4575 F. prausnitzii strain, which does not have anti-inflammatory activity.

[0036] A suitable daily dose of the strain according to the invention is 10 3 ~l0 11 The number of bacteria can be, for example, 10 9 The composition may be in the form of a daily dose equivalent to 1000 bacteria. The number of bacteria in the composition can be easily determined by one skilled in the art, for example, using flow cytometry.

[0037] The strains according to the invention may be in live, semi-active, inactivated or killed form, or combinations thereof.

[0038] According to a particular embodiment, the strains according to the invention are used in live or semi-active form, in particular in live form.

[0039] In another embodiment, the strains according to the invention are used in inactivated or killed form.

[0040] An "inactivated" strain according to the invention is a strain that is no longer temporarily capable of forming colonies in culture. A "dead" strain according to the invention is a strain that is definitively no longer capable of forming colonies in culture. Dead or inactivated strains may have intact or ruptured cell membranes. Thus, the term "inactivated" also refers to strain extracts and lysates, which are detailed herein below. Dead or inactivated strains may be produced by any method known to the skilled artisan.

[0041] The inactivated strains described above can be prepared by irradiation, heat inactivation, pH inactivation, inactivation by exposure to air or oxygen, or by lyophilization of the strain preparation, methods known to those skilled in the art.

[0042] More particularly, inactivation of the strain by irradiation may involve exposure to gamma rays, X-rays, UV or heat, or the use of reduced pressure.

[0043] Inactivation by lyophilization may be accomplished via any method known in the art. Advantageously, strains inactivated by lyophilization may be recultured.

[0044] Heat inactivation may be performed by incubating the bacterial strain of the invention for an extended period of time, e.g., at least 2 hours, at 170° C. Heat inactivation may also be performed by autoclaving the bacterial strain of the invention for at least 20 minutes at a temperature of 121° C. and atmospheric pressure of 2 bar. Heat inactivation processes may be included, e.g., pasteurization, tyndallisation, etc.

[0045] Alternatively, heat inactivation can be performed by subjecting the strain to freezing temperatures for extended periods of time.

[0046] pH inactivation can be performed by incubating the strains of the invention at low or high pH for extended periods of time, for example at pH 2 for 30 minutes.

[0047] Since Faecalibacterium prausnitzii is an extremely oxygen sensitive (EOS) organism, inactivation by air exposure can be achieved by incubating the bacteria in an air atmosphere for a period of time.

[0048] The bacterial strain according to the invention can be used in its intact form, i.e. essentially in its native form, or in the form of an extract or lysate of a degraded suspension containing fractions and / or metabolic products of this bacterium.

[0049] The term "metabolite" means any substance resulting from the metabolism of the bacteria, in particular a substance secreted by the bacteria under consideration according to the invention and having efficacy in the treatment and / or prevention of lesions of the microrelief of the skin.

[0050] For the purposes of the present invention, the term "fraction" more particularly refers to fragments of the abovementioned bacteria.

[0051] Extracts or lysates suitable for use in the present invention may be prepared from the strains at the end of the growth phase.

[0052] The strains suitable for use in the present invention may be used in the form of a lysate.

[0053] For the purposes of the present invention, "lysate" generally refers to the material obtained following the disruption or lysis of biological cells via a phenomenon known as cell lysis, thus resulting in the release of intracellular biological components naturally contained within the bacterial cells under consideration.

[0054] For the purposes of the present invention, the term "lysate" is used to preferentially denote the total lysate obtained via lysis of the bacterium under consideration or to denote only a fraction thereof. The lysate used is therefore formed in whole or in part from intracellular biological components as well as from cell wall and membrane components of said bacterium.

[0055] In a particular embodiment, the lysate used for the present invention may be a total lysate obtained via lysis of the strain under study.

[0056] This cell lysis can be achieved through various known techniques, such as osmotic shock, heat shock, through sonication, or alternatively under mechanical stress of centrifugation type. In particular, the lysate of the invention can be obtained through ultrasonic disruption of a medium containing the strain of the invention in suspension, in order to release from said medium the cytoplasmic fraction, cell wall fragments and products of metabolic origin. All their naturally distributed components are then stabilized in a weakly acidic aqueous solution.

[0057] The strains of the invention can be administered to the intestine of the individual to be treated in various ways, in particular orally or rectally. Bacteria from the association of the invention are preferably administered orally.

[0058] According to one preferred embodiment, the strain of the association of the invention is included in a composition comprising a physiologically acceptable medium, such a composition being preferably for oral administration.

[0059] Mesalamine or its derivatives Mesalamine refers to the active compound aminosalicylic acid, and is also called 5-ASA or mesalazine.

[0060] Mesalamine derivatives specifically refer to pharma- ceutically acceptable salts, pharma- ceutically acceptable solvates, pharma- ceutically acceptable hydrates, pharma- ceutically acceptable enantiomers, pharma- ceutically acceptable derivatives, and pharma- ceutically acceptable polymorphs thereof.

[0061] Mesalamine and mesalamine derivatives are, for example, commercially available in a variety of dosage forms, including, for example, Pentasa by Ferring. (登録商標) , and Lialda by Shire (登録商標) or Asacol by Warner-Chilcott (登録商標) , Asacol H.D. (登録商標) and Delzicol (登録商標) Apriso by Salix (登録商標) , Canasa by Aptalis Pharma (登録商標) , Rowasa by Meda Pharms (登録商標) enema, Fivasa by Tillots Pharma France (登録商標) , Dipentum by Pharmacia (登録商標) Or Quadrasa by Norgine (登録商標) etc. also exist.

[0062] In certain embodiments, Pentasa (登録商標) is used in the association or composition according to the invention.

[0063] The amount of mesalamine or a derivative thereof used in the association or composition of the present invention can range from about 100 to about 8000 mg, particularly from about 100 to about 5000 mg. In certain embodiments, the composition of the present invention contains 400 mg, 600 mg, or 800 mg of mesalamine or a derivative thereof.

[0064] In certain embodiments, the amount of mesalamine or a derivative thereof that can be administered daily to a patient can be between 1000 mg and 5000 mg.

[0065] The F. prausnitzii strains according to the present invention can be formulated and / or administered to an individual in the same composition as mesalamine or a derivative thereof or in a separate composition.

[0066] When in two separate compositions, the F. prausnitzii strain and mesalamine or its derivatives can be administered simultaneously (or substantially simultaneously) or with each other, through the same route or through different routes. For example, one can be administered rectally and the other orally. By administered subsequent to each other, it is meant that the two active substances constituting the association of the present invention are administered within minutes of each other or within hours of each other.

[0067] In one embodiment of the invention, the F. prausnitzii strain and mesalamine or a derivative thereof are administered simultaneously in the same composition, either orally or rectally, preferably orally.

[0068] In another embodiment, the F. prausnitzii strain and mesalamine or a derivative thereof are administered simultaneously in separate compositions, independently orally or rectally, preferably both orally.

[0069] In a further embodiment, the F. prausnitzii strain and mesalamine or a derivative thereof are administered one after the other in separate compositions, independently orally or rectally, preferably both orally.

[0070] composition The present invention also relates to compositions, in particular pharmaceutical compositions, comprising at least an association according to the invention in a pharma- ceutically acceptable medium.

[0071] The compositions according to the invention are intended for the digestive tract, in particular the intestine.

[0072] Thus, the composition according to the invention is selected from an oral or rectal composition. The composition of the invention is preferably an oral or rectal composition, more preferably an oral composition.

[0073] According to one embodiment, the composition of the invention is an oral composition, ie intended for oral administration to a subject.

[0074] Such compositions may be in the form of suspensions, tablets, pills, capsules, granules, or powders.

[0075] The compositions according to the invention for oral administration can be used in the form of food, beverages, medicines, Nutraceuticals , food additives, Food supplements or dairy products, in particular Food supplements Or it is a medicine.

[0076] For oral administration Food supplements Or the pharmaceutical preparations may be present, for example, in capsules, gel capsules, soft capsules, tablets, dragees, pills, pastes, lozenges, gums, oral solutions or emulsions, syrups or gels.

[0077] According to one particular embodiment, the composition according to the invention is a pharmaceutical product.

[0078] Advantageously, compositions according to the invention intended for oral administration can be provided with a gastric juice-resistant coating to ensure that the strain of the invention and mesalamine or its derivatives contained in said compositions can pass through the stomach undamaged, so that release of the active agent can only occur in the upper intestinal tract.

[0079] The compositions according to the invention may also contain sweeteners, stabilizers, antioxidants, additives, flavoring agents and / or dyes.

[0080] The formulation is carried out by conventional methods for producing dragees, gel capsules, gels, controlled release hydrogels, emulsions, tablets or capsules.

[0081] In another embodiment of the invention, the composition comprising the bacterial strain of the invention is administered intrarectally.

[0082] Preferably, rectal administration is in the form of a suppository, enema or foam.

[0083] In particular, the composition of the present invention is a pharmaceutical composition comprising a 100% soluble form of the strain Faecalibacterium prausnitzii CNCM I-4573. 3 Bacteria ~10 12 A daily dose representing 10 bacteria, especially as a medicine 4 Bacteria ~10 12 A daily dose representing 10 bacteria, more specifically, a pharmaceutical dose of 10 6 ~10 12 A daily dose representing 10 bacteria, preferably 10 10 It is suitable for administration of a daily dose equivalent to 1000 bacteria (i.e. total cell counts by cytometry).

[0084] In particular, the composition of the present invention comprises a 10 3 Bacteria ~10 12 A daily dose representing 10 bacteria, in particular 4 Bacteria ~10 12 A daily dose representing 10 bacteria, more particularly 10 6 ~10 12 A daily dose representing 10 bacteria, preferably 10 10 It is suitable for administration of a daily dose equivalent to 1000 bacteria (i.e. total cell counts by cytometry).

[0085] For example, the composition according to the invention may contain 10 3 ~10 12 Dose of bacteria: 10 4 ~10 12 A dose of 10 bacteria, more particularly 10 6 ~10 12 A dose of bacteria, preferably 10 10 The bacteria may be administered to an individual in a single daily dose of 1 g containing an amount equivalent to 1000 bacteria.

[0086] In another example, the composition according to the present invention is administered to an individual in need thereof in an amount of 10 3 ~10 12 bacteria, especially 10 4 ~10 12A dose of 10 bacteria, more particularly 10 6 ~10 12 A dose of bacteria, preferably 10 10 It may be administered in a single daily dose of 0.2 g containing the equivalent of 10 bacteria.

[0087] In another example, the composition according to the present invention may be administered to an individual in need thereof based on two doses of 1 g twice daily, each dose independently containing 5x10 3 Bacteria ~5x10 11 bacteria, especially 5 × 10 6 bacteria ~5×10 11 bacteria, preferably 5 x 10 9 bacteria, and therefore the total daily dose of the CNCM I-4573 strain of the invention to be administered to an individual is as described above.

[0088] Compositions according to the present invention may also include at least one of antioxidants, fish oil, DHA, EPA, vitamins, minerals, phytonutrients, proteins, lipids, probiotics, and combinations thereof.

[0089] The invention will now be described in more detail by way of the following examples which are given by way of illustration only.

[0090] All references to percentages are by weight unless otherwise specified. Working Example The F. prausnitzii strain and PENTASA, deposited at the CNCM under the accession number CNCM I-4573 (登録商標) have been tested alone and in combination for their ability to modulate immune responses in vivo and to directly affect intestinal inflammation.

[0091] A DSS-induced colitis model in mice is used to study the anti-inflammatory effects of these various factors in vivo.

[0092] More specifically, C57BL / 6 mice (8-9 weeks old at the start of the assay) are maintained on a 12-h light / dark cycle at room temperature and allowed free access to food and water, except for the day before induction of colitis, the mice are fasted for 12 h. Colonic inflammation is induced by treatment with Dextran Sodium Sulfate (DSS). In detail, DSS is dissolved in drinking water (2.5% wt / vol) from day 7 to day 12, and the animals are allowed to drink this solution ad libitum for 5 days. Water consumption in the DSS-treated group is measured and compared to a group of naive mice drinking water. No difference is observed in the volume of liquid consumed between mice drinking water and mice drinking DSS. Mice are treated orally daily by gavage with 200 μL: Group 1: 1.10 of F. prausnitzii strain CNCM I-4573 9 colony forming units (CFU) I-4573; and Group 2: F. prausnitzii strain CNCM I-4573 + Pentasa (登録商標) 1.10 9 colony forming units (CFU), which are ad libitum mixed into food (2.88 g of Pentasa (登録商標) Granules (each granule weighs 0.5 mg and contains 0.26 mg of 5-ASA; the dose of 5-ASA for the mice is 150 mg / day / kg body weight).

[0093] The third group (group 3) was treated with Pentasa (登録商標) The first group consisted of DSS mice mixed with 100 mg / kg / day of ...

[0094] Two control groups will also be studied: One group consisted of non-colitic mice that received only PB glycerol by oral gavage, and One group was DSS mice that received only PBS glycerol by oral gavage.

[0095] Treatment or vehicle is administered orally by oral gavage 7 days (day 0) prior to the first DSS administration in the prophylactic mode. Mice in groups 2 and 3 receive Pentasa (登録商標 Food containing 100 mg / kg / day was also given as the sole food source from day 0. Mice in group 3 were given PBS / glycerol to limit bias introduced by gavage stress. The treatment period for each group lasted until the end of the assay, i.e., day 19.

[0096] On day 7, DSS is added to the drinking water for 5 days (days 7 to 12). Necropsy is performed 7 days after the end of the DSS period on day 19.

[0097] Body weights and survival rates are recorded daily from 2 days before day 2 until euthanasia on day 19.

[0098] To evaluate the effect of the products on colonic inflammation, various parameters are monitored at euthanasia of the experiment. The Disease Activity Index (DAI) is a simple scoring system used to determine the severity of colitis in mice. It is calculated based on the assessment of body weight change, stool consistency, and the presence of blood in the feces. Briefly, the DAI was assessed by a researcher blinded to the protocol according to a standard scoring system. Body weight (BW), stool consistency (scored 0-3, 0=normal, 1=loose stool, 2=diarrhea, 3=watery diarrhea), and the presence of visible blood (rectum of mice) were recorded daily.

[0099] At euthanasia, the presence of occult blood (OB) is recorded using the hemoccult method. BW loss is scored as follows; 0, no weight loss; 1, weight loss <10% from baseline; 2, >10%. For stool consistency, a score of 0 is assigned for a well-formed pellet, a score of 1 for a paste-like or semi-formed stool that does not adhere to the anus, and a score of 2 for liquid stool that adheres to the anus. For OB, a score of 0 is assigned if there is no blood and 1 if OB is positive or there is heavy bleeding. These scores are summed.

[0100] Mice are sacrificed by cervical dislocation and the abdominal cavity is opened. The colon and small intestine are removed. The length of the colon is measured and weighed to calculate the colon weight / length ratio.

[0101] The results obtained are shown in FIGS.

[0102] The results are displayed in the form of a bar graph.

[0103] All comparisons are analyzed using the permutation test for two independent samples, and the most powerful statistical tests are adapted to small sample sizes. Statistics are calculated using StatXact software (Cytel Inc, Cambridge, Massachusetts, USA). The comparisons are performed against the DSS group control.

[0104] Considering FIG. 1, the F. prausnitzii strain according to the invention alone or in combination with Pentasa (登録商標) It can be seen that no statistical difference is observed for DAI between the results obtained in untreated or treated DSS mice, either alone. Conversely, when the association of the present invention is administered to DSS mice, the observed DAI results are statistically reduced compared to those of untreated DSS mice.

[0105] The same applies to the colon weight / length results shown in FIG.

[0106] The results shown in FIG. 2 and regarding the presence of blood in the feces are compared with those obtained in untreated DSS mice. (登録商標) It can be seen that there is no statistical difference between the results obtained with DSS mice treated with F. prausnitzii alone. The F. prausnitzii strain according to the invention used alone shows a slight effect in reducing occult blood in DSS mice (reduction in the presence of occult blood in untreated DSS mice from about 0.9 to about 0.6), while the results obtained with the association of the invention administered to DSS mice are significantly higher (reduction in the presence of occult blood in untreated DSS mice from about 0.9 to about 0.2).

[0107] Therefore, the use of F. prausnitzii CNCM I-4573 and Pentasa in the treatment of inflammatory gastrointestinal diseases is (登録商標) The present inventors have unexpectedly demonstrated a synergistic effect of the association with

Claims

1. A combination of a strain of the species Faecalibacterium prausnitzii deposited at the CNCM under deposit number CNCM I-4573 and mesalamine or a derivative thereof, wherein the mesalamine derivative is selected from the group consisting of mesalazine, olsalazine, 4-ASA (4-aminosalicylic acid), and sulfasalazine.

2. A pharmaceutical composition comprising the combination of claim 1 in a pharma- ceutically acceptable medium.

3. 2. A combination as claimed in claim 1 for use in the treatment and / or prevention of inflammatory gastrointestinal diseases in an individual.

4. The combination of claim 3, wherein the individual is a mammal.

5. The combination according to claim 3 or 4, wherein the individual is a human.

6. The combination according to any one of claims 3 to 5, wherein the inflammatory gastrointestinal disease is inflammatory bowel disease.

7. A combination according to any one of claims 3 to 6, wherein the inflammatory gastrointestinal disease is colonic inflammatory bowel disease.

8. 8. The combination of claim 7, wherein the colonic inflammatory bowel disease is selected from the group consisting of Crohn's disease, ulcerative colitis and pouchitis.

9. 9. The combination according to claim 7 or 8, wherein the colonic inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis.

10. The combination according to any one of claims 3 to 9, wherein said combination is in a pharma- ceutically acceptable vehicle of a pharmaceutical composition.

11. The composition comprises 10 3 Bacteria ~ 10 12 11. The combination according to claim 10, suitable for administration of a daily dose representing 100 microorganisms.

12. The combination according to claim 10 or 11, wherein the composition is for oral administration.

13. The combination according to any one of claims 10 to 12, wherein the composition is selected from the group consisting of a food product, a beverage, a pharmaceutical product, a nutraceutical, a food additive, a food supplement, and a dairy product.

14. 14. The combination according to claim 12 or 13, characterized in that the composition is a medicament.

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