Association of Faecalibactorium 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 of a strain of the species Faecalibacterium prausnitzii deposited with CNCM under deposit number CNCM I-4573 with mesalamine or a derivative thereof, more particularly to an association for use in the treatment and prevention of inflammatory gastrointestinal diseases (IGD), especially inflammatory bowel diseases (IBD), in individuals. [Background technology]

[0002] Inflammation is a natural biological process that constitutes a normal part of the body's response to injury or infection and contributes to protecting the organism from internal or external attacks.

[0003] However, dysfunction of the inflammatory mechanism, particularly 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 still lack established or appropriate treatments.

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

[0005] Inflammatory bowel disease (IBD) 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 etiology involves inappropriate and persistent activation of the mucosal immune system caused by the presence of a gut microbiota in genetically predisposed patients.

[0006] Aminosalicylate (especially, 5-ASA, also called mesalamine or mesalazine) or its derivatives 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 thus cannot be administered in large amounts. In fact, the incidence of renal dysfunction in patients with IBD treated with 5-ASA is estimated to be 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 it is also known to have significantly lower efficacy in more severe disease forms. Therefore, when 5-ASA is identified as being inefficient, the only alternative available is the use of immunosuppressive therapy. However, such therapies are very expensive and are potentially associated with serious side effects, such as infections and tumor formation.

[0009] Therefore, when 5-ASA is not sufficient in the treatment and / or prevention of inflammatory gastrointestinal diseases, an alternative solution to immunosuppressive therapy is needed. In particular, in the treatment and / or prevention of inflammatory gastrointestinal diseases, there is a need for a novel solution that enables the improvement of the properties of mesalamine and its derivatives. More generally, there is always a need for novel substances or combinations of such substances for the treatment and / or prevention of inflammatory gastrointestinal diseases, especially inflammatory bowel diseases, in an individual.

[0010] The present invention provides a solution to these problems.

Summary of the Invention

Problems to be Solved by the Invention

[0011] The object of the present invention is to describe novel associations of substances and compositions containing them for the treatment and / or prevention of inflammatory gastrointestinal diseases, particularly inflammatory bowel disease, in individuals.

[0012] In the context of this invention, the term "prevent" means reducing to a lower degree the likelihood of a given phenomenon occurring, namely, gastroenteritis, in particular inflammatory bowel disease, in this invention. The term "prevent" should also be understood to include reducing to a lower degree the risk or likelihood of recurrence of a disease according to this invention, in particular inflammatory bowel disease.

[0013] In the context of this invention, when the word “treatment” is used particularly in relation to a disease, it means slowing or stopping the onset or progression of a disease, causing regression of associated clinical symptoms, or partially or completely alleviating the disease. The word “treatment” should also be understood to include a reduction in the number of relapses and / or a reduction in the intensity of relapses and / or an increase in the time separating two relapses of a disease according to this invention, particularly inflammatory bowel disease.

[0014] This invention is based on the inventors' discovery that when mesalamine or its derivatives are used in combination with Faecalibacterium prausnitzii strain CNCM I-4573, this results in an improvement in its anti-inflammatory properties.

[0015] In particular, the present inventors have discovered that when mesalamine or its derivatives are used alone in low amounts, administering mesalamine or its derivatives to an individual in association with Faecalibacterium prausnitzii strain CNCM I-4573 (when used alone and in low amounts) can unexpectedly provide anti-inflammatory properties.

[0016] According to the inventors' experimental results, the association of mesalamine or its derivatives with a specific strain of Faecalibacterium prausnitzii, deposited with the CNCM on January 31, 2012, under deposit number CNCM I-4573, possesses an unexpected ability to synergistically alleviate gastroenteritis, particularly enteritis, in individuals.

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

[0018] Derivatives of mesalamine can be selected from the group consisting of, for example, mesalazine, orsalazine, 4-ASA (4-aminosalicylic acid), and sulfasalazine.

[0019] Another object of the present invention is a pharmaceutical composition comprising the aggregate of the present invention in a pharmaceutically acceptable medium.

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

[0021] The individual according to the present invention is preferably a mammal, for example a mammal that includes non-human mammals, and in particular a human.

[0022] The inflammatory gastrointestinal disease in question is more specifically inflammatory bowel disease (IBD), and more specifically, inflammatory bowel disease of the colon.

[0023] The above-mentioned inflammatory bowel diseases can be selected from the group consisting of Crohn's disease, ulcerative colitis, and cystitis, or more specifically from the group consisting of Crohn's disease and ulcerative colitis.

[0024] According to other embodiments, the association for use according to the present invention is in a pharmaceutically acceptable medium of the pharmaceutical composition, preferably in an oral composition, and more preferably in a pharmaceutical.

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

[0026] The composition of the present invention is preferably for oral administration.

[0027] The compositions of the present invention for oral administration may be selected from the group consisting of foods, beverages, pharmaceuticals, nutritional supplements, food additives, nutritional supplements, and dairy products. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows the Disease Activity Index (DAI) scores obtained from the following mice, from left to right on the horizontal axis: (i) control mice administered with water alone and PBS containing glycerol (no colitis); (ii) control mice with DSS-induced colitis treated with PBS containing glycerol; (iii) mice with DSS-induced colitis treated with F. Prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis treated with an association of F. Prausnitzii strain CNCM I-4573 and Pentasa®; and (v) mice with DSS-induced colitis treated with PBS containing Pentasa® and glycerol. The DAI score is evaluated on a scale from 0 (no inflammation) to 4 (vertical coordinate) (n=10 / group, excluding water + PBS / glycerol n=5). [Figure 2]Figure 2 shows, from left to right on the horizontal axis, the presence of blood in the feces of (i) control mice administered with water alone and PBS containing glycerol (no colitis); (ii) control mice with DSS-induced colitis treated with PBS containing glycerol; (iii) mice with DSS-induced colitis treated with F. Prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis treated with an association of F. Prausnitzii strain CNCM I-4573 and Pentasa®; and (v) mice with DSS-induced colitis treated with PBS containing Pentasa® and glycerol. The greater the amount of blood present in the feces, the greater the inflammation and damage in the individual considered. Blood formation is assessed according to a baseline of 0 (absent) or 1 (present) (n=10 / group, except for water + PBS / glycerol n=5). [Figure 3] Figure 3 shows, from left to right on the horizontal axis, the colon weight / colon length ratio for (i) control mice administered with water alone and PBS containing glycerol (no colitis); (ii) control mice with DSS-induced colitis treated with PBS containing glycerol; (iii) mice with DSS-induced colitis treated with F. Prausnitzii strain CNCM I-4573; (iv) mice with DSS-induced colitis treated with an association of F. Prausnitzii strain CNCM I-4573 and Pentasa®; and (v) mice with DSS-induced colitis treated with PBS containing Pentasa® and glycerol. The 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. [Modes for carrying out the invention]

[0029] The inventors conducted thorough research to identify the ability of associations of specific strains of Faecalibacterium prausnitzii with mesalamine or its derivatives to synergistically treat and / or prevent inflammatory gastrointestinal diseases, particularly inflammatory bowel disease, in individuals.

[0030] In fact, the inventors unexpectedly discovered that the F. prausnitzii strain deposited with the CNCM under deposit number CNCM I-4573 in association with mesalamine or its derivatives provides a superior ability to alleviate gastroenteritis, particularly enteritis, in individuals compared to the same drug used alone.

[0031] Faecalibacterium prausnitzii strain F. prausnitzii is a major member of the phylum Firmicutes and is one of the most abundant symbiotic bacteria in the gut microbiota of healthy humans.

[0032] F. prausnitzii is an extremely oxygen-sensitive (EOS) bacterium, and therefore, it 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 digestive tract, and butyrate short-chain fatty acids are very important for the physiological function of the intestines, 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] Furthermore, International Public Publication No. WO2017129515 describes the ability of the Faecalibacterium prausnitzii strain, deposited with CNCM under deposit number CNCM I-4573, to reduce gastrointestinal inflammation, particularly intestinal inflammation, both in vitro and in vivo when used alone.

[0035] The anti-inflammatory properties of strains A2-165 and I-4573 cannot generally be attributed to the F. Prausnitzii species, given that the presence of anti-inflammatory properties cannot be predicted for any given strain of F. Prausnitzii. In fact, such specific anti-inflammatory activity is demonstrated in International Publication No. WO2017129515, which presents comparative studies using the CNCM I-4575 F. Prausnitzii strain, which lacks anti-inflammatory activity.

[0036] A suitable daily dose of the bacterial strain according to the present invention is 10 of the composition of the present invention. 3 ~l0 11 It can be a number of bacteria, for example, 10 9 It can be in the form of a daily dose corresponding to one bacterium. The number of bacteria in the composition can be easily measured by those skilled in the art, for example, using flow cytometry.

[0037] The bacterial strains according to the present invention may be in live, semi-active, inactivated, or dead form, or a combination thereof.

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

[0039] In other embodiments, the strains according to the present invention are used in an inactivated or dead form.

[0040] A “deactivated” strain according to the present invention is a strain that can no longer temporarily form colonies in culture. According to the present invention, a “dead” strain is a strain that can no longer definitively form colonies in culture. Dead or inactivated strains may have intact or ruptured cell membranes. Thus, the term “deactivated” also means the strain extracts and lysates detailed below in this specification. Dead or inactivated strains may be produced by any method known to those skilled in the art.

[0041] The inactivated bacterial strains described above can be prepared by irradiation, thermal inactivation, pH inactivation, inactivation by exposure to air or oxygen, or freeze-drying of the strain preparation. These methods are known to those skilled in the art.

[0042] More specifically, inactivation of bacterial strains by irradiation may include exposure to gamma rays, X-rays, UV rays, or heat, or the use of reduced pressure.

[0043] Inactivation by freeze-drying can be carried out by any method known in this field. Conveniently, strains inactivated by freeze-drying can be re-cultured.

[0044] Thermal inactivation may be carried out by incubating the bacterial strain of the present invention at 170°C for an extended period, for example, at least 2 hours. Thermal inactivation may also be carried out by autoclaving the bacterial strain of the present invention at a temperature of 121°C and atmospheric pressure of 2 bar for at least 20 minutes. Thermal inactivation processes may include, for example, pasteurization, tyndallization, etc.

[0045] Alternatively, thermal inactivation can be performed by exposing the bacterial strain to freezing temperatures for an extended period.

[0046] pH inactivation can be performed by incubating the bacterial strain of the present invention at a low or high pH for an extended period, for example, at pH 2 for 30 minutes.

[0047] Since Faecalibacterium prausnitzii is an extremely oxygen-sensitive organism (EOS), it can be inactivated by exposure to air. This process can be carried out by incubating the target bacteria in an airy atmosphere for a certain period of time.

[0048] The bacterial strains according to the present invention may be used in their complete form, i.e., essentially in their natural form, or in the form of extracts or lysates of decomposed suspensions containing fractions and / or metabolites of this bacterium.

[0049] The term "metabolite" means any substance derived from bacterial metabolism, in particular a substance secreted by the bacteria under consideration in accordance with the present invention and having efficacy in treating and / or preventing disorders of the microreliefs of the skin.

[0050] For the purposes of this invention, the term "fraction" means, more particularly, fragments of the bacteria described above.

[0051] An extract or lysate suitable for use in the present invention can be prepared from the strain at the end of the growth phase.

[0052] The bacterial strains suitable for use in this invention can be used in the form of a lysate.

[0053] For the purposes of this invention, "lysate" generally refers to a substance obtained after the destruction or lysis of living cells via a phenomenon known as cell lysis, and thus causes the release of intracellular biological components naturally present in the cells of the bacteria under consideration.

[0054] For the purposes of this invention, the term “lysate” is used to preferentially refer to the total lysate obtained through the lysis of the bacterium under consideration, or to refer to only a fraction thereof. Accordingly, the lysate used is formed whole or partially from intracellular biological components, as well as from the cell wall and membrane components of the bacterium.

[0055] In certain embodiments, the lysate used for the present invention may be a total lysate obtained through the lysis of the bacterial strain under consideration.

[0056] This cell lysis can be achieved by various known techniques, such as osmotic shock, thermal shock, sonication, or alternatively, under centrifugation-type mechanical stress. In particular, the lysates of the present invention can be obtained by sonication of the culture medium of the present invention to release the cytoplasmic fraction, cell wall fragments, and metabolic products from the culture medium containing the strain of the present invention in a suspension state. Then, all of these naturally distributed components are stabilized in a weakly acidic aqueous solution.

[0057] The bacterial strains of the present invention can be administered to the intestines of the individual to be treated by various methods, particularly orally or rectally. The bacteria from the association of the present invention are preferably administered orally.

[0058] According to one preferred embodiment, the bacterial strain of the association of the present invention is contained in a composition comprising a physiologically acceptable culture medium. Such a composition is preferably for oral administration.

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

[0060] Mesalamine derivatives specifically refer to their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable polymorphs thereof.

[0061] Mesalamine and mesalamine derivatives are sold, for example, in various types of dosage forms, 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 HD (登録商標) and Delzicol (登録商標) and the like. 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) and the like also exist.

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

[0063] The amount of mesalamine or its derivative used in the compounds or compositions 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 its derivative.

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

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

[0066] When present in two individual compositions, F. Prausnitzii strain and mesalamine or its derivatives can be administered simultaneously (or substantially simultaneously) or to each other, through the same or different routes. For example, one may be administered rectally and the other orally. Administering them successively means that the two active substances constituting the association of the present invention are administered to each other within minutes or within hours.

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

[0068] In other embodiments, F. prausnitzii strain and mesalamine or its derivatives are administered simultaneously in separate compositions, independently orally or rectally, preferably both orally.

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

[0070] composition The present invention also relates to compositions, particularly pharmaceutical compositions, comprising at least an aggregate according to the present invention in a pharmaceutically acceptable medium.

[0071] The compositions according to the present invention are intended for the digestive tract, particularly the intestines.

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

[0073] According to one embodiment, the composition of the present invention is an oral composition, that is, 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 present invention for oral administration may be selected from the group consisting of foods, beverages, pharmaceuticals, nutritional supplements, food additives, nutritional supplements, or dairy products, and are particularly nutritional supplements or pharmaceuticals.

[0076] Nutritional supplements or pharmaceuticals for oral administration may exist, for example, as capsules, gel capsules, soft capsules, tablets, sugar-coated tablets, pills, pastes, sweetened tablets (lozenges), gums, oral solutions or emulsions, syrups, or gels.

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

[0078] Advantageously, compositions according to the present invention intended for oral administration may be provided with a gastric acid-resistant coating to ensure that the bacterial strains and mesalamine or derivatives of the present invention contained in the composition can pass through the stomach without damage. Thus, the release of the activator may occur only in the upper intestinal tract.

[0079] Compositions according to the present invention may also contain sweeteners, stabilizers, antioxidants, additives, flavorings, and / or colorants.

[0080] The formulation is carried out by conventional methods for manufacturing sugar-coated tablets, gel capsules, gels, controlled-release hydrogels, emulsions, tablets, or capsules.

[0081] In another embodiment of the present invention, a composition containing the bacterial strain of the present invention is administered rectally.

[0082] Preferably, rectal administration is carried out in the form of suppositories, enemas, or foam.

[0083] In particular, the composition of the present invention, as a pharmaceutical, contains 10 strains of Faecalibacterium prausnitzii species CNCM I-4573.3 individual bacteria ~ 10 12 The daily dose representing a single bacterium, in particular, as a pharmaceutical product, is 10 4 individual bacteria ~ 10 12 The daily dose representing a number of bacteria, more specifically, as a pharmaceutical product, 10 6 ~10 12 A daily dose representing a number of bacteria, preferably 10 10 It is suitable for administering a daily dose equivalent to one bacterium (i.e., the total number of cells determined by cytometry).

[0084] In particular, the composition of the present invention is derived from the strain of Faecalibacterium prausnitzii species CNCM I-4573, 10 3 individual bacteria ~ 10 12 The daily dose representing a number of bacteria, in particular, 10 4 individual bacteria ~ 10 12 The daily dose representing a number of bacteria, more specifically, 10 6 ~10 12 A daily dose representing a number of bacteria, preferably 10 10 It is suitable for administering a daily dose equivalent to one bacterium (i.e., the total number of cells determined by cytometry).

[0085] For example, a composition according to the present invention contains 10 CNCM I-4573 strains of the present invention. 3 ~10 12 Dosage of individual bacteria, 10 4 ~10 12 Dosage of individual bacteria, more particularly 10 6 ~10 12 Dosage of bacteria per individual, preferably 10 10 It can be administered to an individual in a once-daily dose of 1g, containing an amount equivalent to one bacterium.

[0086] In another example, a composition according to the present invention is given to an individual that requires it. 3 ~10 12 A single bacterium, especially 10 4 ~10 12 Dosage of individual bacteria, more particularly 10 6 ~10 12 Dosage of bacteria per individual, preferably 10 10It can be administered in a once-daily dose of 0.2 g, which is equivalent to the amount of one bacterium.

[0087] In another example, a composition according to the present invention may be administered to an individual requiring it twice daily based on two doses of 1 g each, with each dose independently containing 5 x 10⁻⁶ of the CNCM I-4573 strain of the present invention. 3 individual bacteria ~5x10 11 Individual bacteria, especially 5 x 10 6 Individual bacteria ~5 x 10 11 A number of bacteria, preferably 5 × 10 9 The amount of CNCM I-4573 strain of the present invention is equivalent to that of a certain number of bacteria, and therefore the total daily dose administered to an individual is as stated above.

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

[0089] The present invention is described in more detail below by the following embodiments, which are provided merely for illustrative purposes.

[0090] Unless otherwise specified, all percentages refer to weight percentages. Examples F. Prausnitzii strain and PENTASA deposited with CNCM under deposit number CNCM I-4573 (登録商標) However, their ability to modulate the immune response and directly affect intestinal inflammation in vivo was tested both individually and in combination.

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

[0092] More specifically, C57BL / 6 mice (8-9 weeks old at the start of the assay) were kept at room temperature in a 12-hour light / dark cycle and given free access to food and water, except for the day before the induction of colitis, and the mice were fasted for 12 hours. Colon inflammation was induced by treatment with dextran sodium sulfate (DSS). In detail, DSS was dissolved in drinking water (2.5 wt% / volume) from day 7 to day 12, and the animals were given free access to this solution for 5 days. Water consumption in the DSS-treated group was measured and compared to a group of naive mice that drank water. No difference in the volume of liquid consumed was observed between mice that drank water and mice that drank DSS. The mice were treated orally daily by gastric tube feeding with 200 μL: Group 1: F. Prausnitzii strain CNCM I-4573 1.10 9 Colony forming units (CFUs) I-4573; and Group 2: F. Plausnitzii strain CNCM I-4573 + Pentasa (登録商標) 1.10 9 Each colony-forming unit (CFU) can be freely mixed into food (2.88g 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 administered to the mouse was 150 mg / day / kg body weight).

[0093] The third group (Group 3) was feeding Pentasa (登録商標) The group consisted of DSS mice mixed with the drug and freely administered the same doses as shown for the second group.

[0094] The following two control groups will also be investigated: One group consisted of non-colitis mice that were administered only PB glycerol by forced oral administration, and One group consisted of DSS mice that were administered only PBS glycerol via forced oral administration.

[0095] Seven days before the first DSS administration in prophylactic mode (day 0), the treatment or vehicle is administered orally by forced oral administration. Group 2 and Group 3 mice were given Pentasa (登録商標 Foods containing [the specified ingredient] are also given as the sole food source from day 0. Mice in group 3 are given PBS / glycerol to limit the bias introduced by gastric tube feeding stress. The treatment period for each group continues until the end of the assay, i.e., day 19.

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

[0097] Weight and survival rate are recorded daily from two days before day 2 until euthanasia on day 19.

[0098] To evaluate the product's effectiveness against colon inflammation, various parameters are monitored during experimental euthanasia. The Disease Activity Index (DAI) is a simple scoring system used to determine the severity of colitis in mice. It is calculated based on changes in body weight, stool consistency, and the presence of blood in the feces. In short, the DAI was assessed by researchers who were not informed of the protocol, following a standard scoring system. Body weight (BW), stool consistency (scored from 0 to 3, 0=normal, 1=loose stool, 2=diarrhea, 3=watery diarrhea), and the presence of visible blood (in the mouse rectum) were recorded daily.

[0099] In euthanasia, the presence of occult blood (OB) is recorded using the hemocult method. Body weight loss is scored as follows: 0, no weight loss; 1, <10% weight loss from baseline; 2, >10% weight loss. For fecal consistency, a score of 0 is assigned for well-formed pellets, a score of 1 for paste-like or semi-formed feces that do not adhere to the anus, and a score of 2 for liquid feces that adhere to the anus. For OB, a score of 0 is assigned if there is no blood, and a score of 1 is assigned if OB is positive or if there is heavy bleeding. These scores are then totaled.

[0100] The mice are killed by cervical dislocation, and their abdominal cavities are opened. The colon and small intestine are removed. The length of the colon is measured and weighed, and the weight / length ratio of the colon is calculated.

[0101] The results obtained are shown in Figures 1 to 3.

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

[0103] All comparisons are analyzed using permutation tests on two independent samples, with the strongest statistical tests fitted to smaller samples. Statistics are calculated using StatXact software (Cytel Inc., Cambridge, Massachusetts, USA). The comparisons are performed against DSS group controls.

[0104] Considering Figure 1, F. prausnitzii strain alone or Pentasa according to the present invention (登録商標) No statistically significant difference in DAI was observed between the results obtained from untreated DSS mice and treated DSS mice, either individually or in combination. Conversely, when the association of the present invention was administered to DSS mice, the observed DAI results were statistically reduced compared to those of untreated DSS mice.

[0105] The same applies to the colon weight / length results shown in Figure 3.

[0106] Regarding the results shown in Figure 2 and concerning the presence of blood in feces, the results obtained in untreated DSS mice and Pentasa (登録商標) No statistically significant difference was observed between the results obtained in DSS mice treated with only the present compound. The F. Prausnitzii strain according to the present invention, used alone, showed only a slight effect in reducing occult blood in DSS mice (a decrease from approximately 0.9 to approximately 0.6 in the presence of occult blood in untreated DSS mice), while the results obtained with the present compound administered to DSS mice were significantly higher (a decrease from approximately 0.9 to approximately 0.2 in the presence of occult blood in untreated DSS mice).

[0107] Therefore, F. prausnitzii CNCM I-4573 strain and Pentasa in the treatment of inflammatory gastrointestinal disease (登録商標) The synergistic effect of the combined product was unexpectedly demonstrated by the inventors.

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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