Fatty acid metabolite that suppresses inflammatory bowel disease

Abstract

The purpose of the present invention is to provide a treatment for treating and / or preventing inflammatory bowel disease, such as ulcerative colitis or Crohn's disease.　The present invention relates to a pharmaceutical or food composition for treating and / or preventing inflammatory bowel disease, the pharmaceutical or food composition containing a compound represented by formula (I) [in the formula, R1 is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocyclyl] or a pharmacologically acceptable salt thereof.

Description

Fatty acid metabolites that suppress inflammatory bowel disease

[0001] This patent application claims priority under the Paris Convention and the benefit of Japanese Patent Application No. 2023-119284 (filed July 21, 2023), as well as priority under Article 41 of the Japanese Patent Act, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a pharmaceutical composition for treating and / or preventing inflammatory bowel diseases, particularly to a pharmaceutical composition for treating and / or preventing inflammatory bowel diseases such as ulcerative colitis or Crohn's disease, which comprises a compound group including 11-hydroxy-eicosapentaenoic acid.

[0003] Inflammatory bowel disease (IBD) is an immune disorder designated as an intractable disease, characterized by diarrhea, bloody stools, and abdominal pain as its main symptoms. It is broadly divided into two types: ulcerative colitis and Crohn's disease. Currently, the number of ulcerative colitis patients in Japan is estimated at approximately 200,000, while the number of Crohn's disease patients is estimated at approximately 45,000, with the number of patients increasing year by year. Ulcerative colitis causes chronic inflammation that continues from the large intestine to the rectum, while Crohn's disease causes chronic inflammation throughout the entire digestive tract, from the mouth to the anus. In both cases, IBD occurs when intestinal immune cells react to intestinal bacteria that normally do not elicit an immune response, resulting in the production of inflammatory cytokines. The development of drugs that neutralize inflammatory cytokines has made it possible to control the disease to some extent.

[0004] Medical treatments for ulcerative colitis include 5-aminosalicylates (e.g., 5-ASA: salazosulfapyridine, mesalazine), corticosteroids (e.g., prednisolone, budesonide), cytapheresis, immunomodulatory or suppressive drugs (e.g., azathioprine, 6-mercaptopurine, cyclosporine, tacrolimus), anti-TNFα antagonists (e.g., infliximab, adalimumab, golimumab), anti-adhesion molecule antibodies (e.g., vedolizumab), anti-interleukin-12 / 23 antagonists (e.g., ustekinumab), and Janus kinase inhibitors (e.g., tofacitinib) ( https: / / www.nanbyou.or.jp / entry / 62 ).

[0005] A 2001 cohort study reported that patients who underwent appendectomy before the age of 20 years had a reduced lifetime risk of developing ulcerative colitis (Non-Patent Document 1). It has been reported that the appendix serves as a safehouse for intestinal bacteria and is a site for the accumulation of lymphoid tissue and production of immunoglobulin A (Non-Patent Document 2). However, the mechanism by which appendectomy suppresses colitis remains unknown. Therefore, the present inventors generated appendectomized mice and analyzed in vivo changes. They also induced colonic inflammation in these mice and analyzed the effect of appendectomy on the development of colitis, thereby investigating the mechanism by which appendectomy suppresses colitis. The results revealed that appendectomy induces hyperplasia of tuft cells (brush cells), epithelial cells known to produce large amounts of IL-25 during parasitic infection and induce the activation of type 2 cytokine-producing cells. This hyperplasia leads to increased production of IL-25, the main cytokine produced by tuft cells, which plays an important role in alleviating colitis (Non-Patent Document 3). On the other hand, appendectomy has been reported to alter the colonic microbiota in both mice and humans (Non-Patent Document 4). Therefore, to verify whether the colitis-alleviating effect of appendectomy is dependent on changes in the microbiota, the inventors housed sham-operated and appendectomized groups in the same cages and shared their microbiota. Sharing the microbiota eliminated the tuft cell hyperplasia effect in the appendectomized group. These findings suggest that changes in the microbiota caused by appendectomy induce tuft cell formation (Non-Patent Document 3). These results have been presented at the Interferon and Cytokine Society (May 21 and 22, 2021) and the Japanese Society for Immunology (December 8-10, 2021).

[0006] Roland E. Andresson, et al. New England Journal of Medicine 2001; Kazunori Masahata, et al. Nature communications 2014; 2021 Annual Report: Elucidation of the mechanism by which appendectomy suppresses colitis (https: / / kaken.nii.ac.jp / ja / report / KAKENHI-PROJECT-21J12194 / 21J121942021jisseki / ); Kazunori Masahata, et al. Nature communications 2014, Shuntian Cai, et al. Frontier in Microbiology 2021.

[0007] As mentioned above, medical treatments for ulcerative colitis include 5-aminosalicylic acid, corticosteroids, cytapheresis, and immunomodulators or suppressants. However, these treatments only improve the condition in approximately 50% of patients, and many patients still suffer from symptoms. Furthermore, ulcerative colitis carries the risk of developing colorectal cancer if the disease persists for a long time, and in severe cases, colectomy is necessary. Given this current situation, there is a need for the development of new treatments based on an understanding of the mechanisms underlying ulcerative colitis.

[0008] The present inventors focused on the changes in the colonic bacterial flora caused by appendectomy and conducted extensive research to elucidate the factors that induce tuft cell hyperplasia due to changes in the bacterial flora. As a result, they found that a long-chain fatty acid (LCFA) called 11-hydroxyeicosapentaenoic acid (11-HEPE) was significantly increased in the feces of appendectomized mice, and that intrarectal administration of 11-HEPE suppressed dextran sulfate-induced colitis and induced tuft cell hyperplasia, leading to the completion of the present invention.

[0009] Therefore, the present invention includes the following aspects: <Composition> [1] Formula (I): [wherein R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl] or a pharmaceutically acceptable salt thereof for treating and / or preventing inflammatory bowel disease. [2] The composition of [1], wherein R1 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [3] The composition of [2], wherein R1 is hydrogen or unsubstituted alkyl having 1 to 4 carbon atoms. [4] The composition of [1], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [5] The pharmaceutical composition of [4], wherein the inflammatory bowel disease is ulcerative colitis. [6] The composition of any of [1] to [5], wherein the composition is a pharmaceutical composition. [6-2] A pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising linoleic acid-11-lipoxygenase. [6-3] A pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus.

[0010] <Food Compositions> [7] The composition according to [1], which is a food composition. [8] The food composition according to [7], for treating and / or preventing diarrhea, bloody stool and / or abdominal pain. [9] A food composition comprising linoleic acid-11-lipoxygenase, for treating and / or preventing inflammatory bowel disease.

[10] The food composition according to [9], for treating and / or preventing diarrhea, bloody stool and / or abdominal pain.

[11] A food composition comprising Acaryochloris marina and / or Myxococcus xanthus, for treating and / or preventing inflammatory bowel disease.

[12] The food composition according to

[11] , for treating and / or preventing diarrhea, bloody stool and / or abdominal pain.

[13] The food composition according to any of [9] to

[12] , further comprising eicosapentaenoic acid.

[14] The food composition according to any of [9] to

[12] , which is administered together with a normal meal.

[15] The food composition according to any one of [7] to

[14] , which is prepared as a supplement, a functional food, a health food, a food for special dietary uses, a food with health claims, a food for specified health uses, or a food with nutrient functions.

[16] The food composition according to

[15] , which is prepared in the form of a tablet, pill, capsule, powder, granule, fine granule, troche, liquid, nasogastric tube feeding agent, or enteral nutrition agent.

[0011] This allows for treatment to prevent colitis.

[0012] Figure 1 shows that appendectomy generally enhances the mucin layer. Figure 1A shows the results of q-PCR for muc2 from colons isolated from sham-operated (sham) and appendectomized (APX) mice. * indicates p<0.05. Figure 1B shows the results of periodic acid-Schiff (PAS) staining of colons isolated from sham-operated (sham) and appendectomized (APX) mice. Figure 1C shows the results of fluorescent in situ hybridization (FISH) staining of colons isolated from sham-operated (sham) and appendectomized (APX) mice. The mucus layer is enclosed within the white dotted line. Figure 1D shows the area of ​​the mucus layer in Figure 1C. Figure 2 shows the bacterial counts in feces from sham-operated (sham) and appendectomized (APX) mice. Figure 2A shows previously reported results, and Figure 2B shows the results of this experiment. In Figure 2B, 1-6 indicate the individual mouse numbers. Figure 3 shows a schematic diagram of sham-operated and appendectomized mice housed in single cages and shared cages, respectively. "Single-housed" and "Co-housed" on the left indicate the housing method, while "sham-operated" and "appendectomized" on the top indicate the type of surgery. Figure 4A shows the weight change during colitis induction in sham-operated (sham) and appendectomized (APX) mice housed in single cages or shared cages. Figure 4B shows the length of the colon. Figure 4C shows the levels of inflammatory cytokines IL-1β and IL-6 in colon tissue suspensions. Figure 4D shows the results of H&E staining of the colon. Note that in the figures, "co-housed sham-operated" and "co-housed appendectomized" refer to the sham-operated mice in the same cage, and "co-housed appendectomized" refers to the appendectomized mice in the same cage when sham-operated and appendectomized mice were housed in the same cage.

[0013] Figure 5 shows the changes in body weight (A) and colon length (B) in mice treated with four antibiotics (ampicillin, vancomycin, metronidazole, and neomycin) and co-housed with sham-operated or appendectomized mice, followed by dextran sulfate sodium (DSS) administration. Figure 6 shows the tuft cell (A) and IL-25 levels (B) in sham-operated and appendectomized mice housed in single cages, and in co-housed sham-operated and appendectomized mice. Figure 7A shows the peaks of metabolites measured by LCMS in sham-operated (sham) and appendectomized (APX) mice. Figure 7B shows the significant suppression of body weight loss during DSS-induced colitis. Figure 7C shows the significant suppression of colon shortening during DSS-induced colitis. Figure 8 shows the difference in abundance of bacterial (A) or fungal (B) species identified by shotgun metagenomics analysis of feces from sham-operated (sham) or appendectomized (APX) mice. Figure 9 shows the OTU counts of Acaryochloris marina and Myxococcus xanthus in fecal samples from single-cage sham-operated and single-cage appendectomized mice, and from co-cage sham-operated and single-cage appendectomized mice.

[0014] In one aspect, the present invention provides a compound of formula (I):

[0013] In the present invention, there is provided a composition for treating and / or preventing inflammatory bowel disease, comprising a compound represented by the formula:

[0014] wherein R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl, preferably hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and more preferably hydrogen or unsubstituted alkyl having 1 to 4 carbon atoms], or a pharmaceutically acceptable salt thereof.

[0015] As described above, mouse experiments suggest that changes in the bacterial flora caused by appendectomy induce the formation of tuft cells. This invention is based on the discovery that 11-HEPE acts directly on epithelial cells in colonic organoids to enhance IL-25 expression. The enhanced IL-25 production associated with tuft cell activation by 11-HEPE activates group 2 innate lymphoid cells (ILC2s) and promotes IL-13 production. IL-13 acts on epithelial stem cells to promote the formation of mucin-producing goblet cells and tuft cells. Without being bound by any particular theory, it is thought that the thickened mucin layer segregates intestinal bacteria from epithelial cells, suppressing their inadvertent adhesion and thereby reducing the risk of colitis.

[0016] The following summarizes the background technology regarding 11-HEPE. 1. Metabolites 2021, 11, 106. https: / / doi.org / 10.3390 / metabo11020106 discloses 66 eicosanoids, including 11-HEPE, as biomarkers for inflammatory bowel disease (IBD), but 11-HEPE is merely an example. 2. WO2018 / 150257 (Patent Publication No. 2020-508286) discloses the use of eicosapentaenoic acid as a highly purified free fatty acid to reduce inflammation or modify microbial sacs in patients with ulcerative colitis, but does not mention 11-HEPE. 3. WO 2007 / 076531 (JP 2009-525949) discloses a method for preventing or treating inflammatory bowel disease (IBD) in cats, comprising administering a composition containing docosahexaenoic acid (DHA) and, optionally, one or more fatty acids selected from the group consisting of eicosapentaenoic acid (EPA), arachidonic acid (ARA), linoleic acid (LA), and α-linoleic acid (ALA). However, there is no mention of 11-HEPE. 4. WO 2021 / 019037 (JP 2022-542513) discloses a method for resolving inflammatory symptoms by significantly and unexpectedly enhancing the biosynthesis of specific inflammation-resolving lipid mediators (SPMs) using a preparation containing a specific extract and ω-3 fatty acids. Here, 11-HEPE is mentioned merely as an example of an SPM.

[0017] 5. JP 2015-163607 A discloses a method for obtaining hydroxyeicosapentaenoic acid (8-HEPE, 9-HEPE, 12-HEPE) by extraction from krill and / or shrimp. It also describes that 11-HEPE has excellent activation properties for PPARα, PPARγ, and PPARδ, and that HEPE with excellent PPAR activation properties has a hydroxy group bonded to it near the center of the carbon chain (positions 8-12). Activation of PPAR is expected to have effects such as activating fatty acid metabolism, promoting body fat burning, suppressing obesity, suppressing fatty liver, preventing and improving diabetes, preventing and improving insulin resistance, and improving endurance, but there is no mention of ulcerative colitis. 6. JP 2010-248213 A discloses a method for treating or preventing inflammation, characterized by administering 15-hydroxyeicosapentaenoic acid, 18-hydroxyeicosapentaenoic acid, 5,12,18-hydroxyeicosapentaenoic acid, or 5,6,15-hydroxyeicosapentaenoic acid. However, there is no mention of 11-HEPE. 7. WO 2007 / 076531 (JP 2008-526867 A) discloses a method for treating or preventing gastrointestinal conditions (ulcerative colitis, Crohn's disease, etc.) characterized by administering 5,6,15-hydroxyeicosapentaenoic acid or the like. However, there is no mention of 11-HEPE. 8. WO2003 / 076531 (JP 2003-525880 A) discloses a method for treating or preventing inflammation, which comprises administering 15-hydroxyeicosapentaenoic acid, 18-hydroxyeicosapentaenoic acid, 5,12,18-hydroxyeicosapentaenoic acid, or 5,6,15-hydroxyeicosapentaenoic acid, but does not disclose 11-HEPE.

[0018] Compounds Represented by Formula (I) As described above, in one aspect, the present invention provides a composition for treating and / or preventing inflammatory bowel disease, comprising a compound represented by formula (I) containing 11-HEPE, or a pharmaceutically acceptable salt thereof. The substituents in formula (I) are defined as follows: In the present invention, "alkyl" refers to a linear or branched hydrocarbon group having 1 to 10 carbon atoms. It includes alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, and alkyl having 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl. Particularly preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0019] In the present invention, "alkenyl" means a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and having one or more double bonds at any position. It includes alkenyl having 2 to 8 carbon atoms, alkenyl having 2 to 6 carbon atoms, etc. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, etc. Particularly preferred are vinyl, propenyl, isopropenyl, butenyl, isobutenyl, etc.

[0020] In the present invention, "alkynyl" means a linear or branched hydrocarbon group having 2 to 10 carbon atoms and having one or more triple bonds at any position. It includes alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, etc. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. The alkynyl may further have a double bond in addition to one or more triple bonds at any position. Ethynyl, propynyl, butynyl, etc. are particularly preferred.

[0021] In the present invention, "aryl" means a monocyclic or polycyclic aromatic carbocyclic group, and a group in which one or two 3- to 8-membered rings are further condensed to such a monocyclic or polycyclic aromatic carbocyclic group. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Phenyl is particularly preferred.

[0022] In the present invention, the term "heteroaryl" includes 5- to 6-membered aromatic ring groups having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring. For example, monocyclic aromatic heterocyclic groups such as pyrazolyl, tetrazolyl, furanyl, thienyl, pyridyl, imidazolyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, and oxadiazolyl; indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolinecinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinazolinyl, quinazolinyl, naphthyridinyl, quinazolinyl, quinazolinyl, quinazolinyl, quinazin ... Examples of the fused aromatic heterocyclic groups include fused aromatic heterocyclic groups such as benzoxalinyl, purine, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzotriazolyl, imidazopyridinyl, triazolopyridinyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazolinyl, etc. Particularly preferred are pyrazolyl, tetrazolyl, furanyl, thienyl, pyridyl, imidazolyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc.

[0023] In the present invention, "cycloalkyl" includes monocyclic or polycyclic saturated carbocyclic groups having 3 to 10 carbon atoms. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononanyl, cyclodecanyl, etc. Examples of polycyclic cycloalkyl include norbornanyl, tetrahydronaphthalenyl, adamantanyl, etc. In particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. are preferred.

[0024] In the present invention, "cycloalkenyl" includes non-aromatic monocyclic or polycyclic groups having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. Examples of monocyclic cycloalkenyl include cyclopentenyl and cyclohexenyl. Examples of polycyclic cycloalkenyl include norbornenyl and indenyl. Cyclopentenyl, cyclohexenyl, and the like are particularly preferred.

[0025] In the present invention, the term "heterocyclyl" includes a 5- to 7-membered non-aromatic cyclic group having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring, a non-aromatic cyclic group in which two or more of these are independently fused, a cyclic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring is fused with one or more ring moieties of the above-mentioned "cycloalkyl" or "cycloalkenyl", and a cyclic group in which a 5- to 7-membered non-aromatic heterocyclic group having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring is fused with one or more ring moieties of the above-mentioned "aryl" or "heteroaryl". Examples include monocyclic non-aromatic heterocyclic groups such as pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropyridinyl, dihydropyridazinyl, dihydropyrazinyl, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuranyl, tetrahydrothiazolinyl, and tetrahydroisothiazolinyl, and fused non-aromatic heteroaromatic ring groups such as indolinyl, isoindolinyl, benzopyranyl, benzodioxanyl, tetrahydroquinolinyl, and tetrahydrobenzothiophenyl. In particular, piperidinyl, piperazinyl, morpholinyl, and the like are preferred.

[0026] In the present invention, substituents for "substituted alkyl", "substituted alkenyl" and "substituted alkynyl" include halogen, hydroxy, mercapto, nitro, nitroso, cyano, etc. Halogen is particularly preferred.

[0027] In the present invention, preferred substituents for "substituted aryl," "substituted heteroaryl," "substituted cycloalkyl," "substituted cycloalkenyl," and "substituted heterocyclyl" are halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, etc. In particular, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, etc. are preferred.

[0028] The compound represented by formula (I) exists in the S-form and the R-form, and in the present invention, the compound represented by formula (I) encompasses each of the optically active S-form and the R-form, and the racemic form, as well as a mixture in which the S-form and the R-form are present in any amounts.

[0029] Pharmaceutically Acceptable Salts In one embodiment, the present invention provides a composition for treating and / or preventing inflammatory bowel disease, which comprises a pharmaceutically acceptable salt of a compound represented by formula (I). Pharmaceutically acceptable salts of the compound of formula (I) include salts of the compound of formula (I) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids, or salts of inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, etc. These salts can be formed by conventional methods.

[0030] Prodrugs The compound of Formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug. In one embodiment, the present invention provides a composition for treating and / or preventing inflammatory bowel disease, comprising a prodrug of the compound of Formula (I). A prodrug is a derivative of the compound of Formula (I) having a chemically or metabolically decomposable group, and is converted to a pharmaceutically active compound in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted to the compound of Formula (I) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in vivo, and compounds that are converted to the compound of Formula (I) by hydrolysis with gastric acid, etc. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985." A prodrug may itself be active.

[0031] Since the compound represented by formula (I) has a hydroxyl group, examples of prodrugs include acyloxy derivatives and sulfonyloxy derivatives, which are produced by reacting the compound represented by formula (I) with an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, or a mixed anhydride, or by reacting the compound represented by formula (I) with a condensing agent. Examples include prodrugs in which a hydroxyl group has been converted to a group represented by the formula: CH3COO-, C2H5COO-, t-BuCOO-, C15H31COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOOCCH2CH2COO-, CH3CH(NH2)COO-, CH2N(CH3)2COO-, CH3SO3-, CH3CH2SO3-, CF3SO3-, CH2FSO3-, CF3CH2SO3-, p-CH3-O-PhSO3-, PhSO3-, p-CH3PhSO3-, etc.

[0032] In the present invention, the prodrug of the compound represented by formula (I) may be the prodrug described above, or may form a triglyceride, diglyceride, or monoglyceride in which one, two, or three of the three hydroxyl groups of glycerin are esterified with the compound represented by formula (I) and / or other fatty acids. When forming a triglyceride, triglycerides in which all three hydroxyl groups of glycerin are esterified with the compound represented by formula (I), triglycerides in which two compounds represented by formula (I) and other fatty acids, or triglycerides in which one compound represented by formula (I) and two other fatty acids can be formed. When forming a diglyceride, diglycerides in which all two hydroxyl groups of glycerin are esterified with the compound represented by formula (I), or diglycerides in which one compound represented by formula (I) and other fatty acids can be formed.

[0033] Compositions The compositions of the present invention can be pharmaceutical compositions and food compositions. The pharmaceutical compositions of the present invention are compositions for treating and / or preventing inflammatory bowel disease. On the other hand, the food compositions of the present invention may be compositions for treating and / or preventing inflammatory bowel disease, or may be compositions for treating and / or preventing diarrhea, bloody stools and / or abdominal pain, particularly diarrhea, bloody stools and / or abdominal pain that are thought to be caused by inflammatory bowel disease.

[0034] Pharmaceutical Composition In one embodiment, the present invention relates to a pharmaceutical composition for treating and / or preventing inflammatory bowel disease, which comprises a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0035] In another embodiment, the present invention relates to a pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising linoleate 11-lipoxygenase (11-LOX). It has been reported that eicosapentaenoic acid is enzymatically converted by linoleate 11-lipoxygenase (11-LOX) to produce 11-hydroxyeicosapentaenoic acid (11-HEPE). In the present invention, it has been found that compounds represented by formula (I), such as 11-HEPE, can treat and / or prevent inflammatory bowel disease. Therefore, it is believed that 11-LOX, which can induce 11-HEPE, can also treat, manage, and / or prevent inflammatory bowel disease.

[0036] In yet another embodiment, the present invention relates to a pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus. As described above, it is believed that 11-LOX can also treat and / or prevent inflammatory bowel disease. Therefore, the present inventors searched for the origin of 11-LOX and found that it is derived from Acaryochloris marina or Myxococcus xanthus. Since 11-LOX can treat and / or prevent inflammatory bowel disease in the present invention, it is believed that its origin, Acaryochloris marina or Myxococcus xanthus, can also treat and / or prevent inflammatory bowel disease.

[0037] In this embodiment, the present invention relates in another embodiment to Acaryochloris marina and / or Myxococcus xanthus as probiotics for treating and / or preventing inflammatory bowel disease. Probiotics are live microorganisms that, when ingested in sufficient amounts, confer a beneficial effect on the host.

[0038] In this aspect, in yet another embodiment, the present invention relates to a microbial pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus.

[0039] In yet another embodiment, the present invention relates to fecal microbiota transplantation (FMT) using a microbiota containing Acaryochloris marina and / or Myxococcus xanthus. Fecal transplantation is a treatment method generally known as intestinal microbiota transplantation, in which intestinal bacteria contained in the feces of healthy individuals are administered to an ill patient. For example, a donor can be selected by confirming that the feces contain Acaryochloris marina and / or Myxococcus xanthus, and the microbiota obtained from the donor can be administered to a patient to treat and / or prevent inflammatory bowel disease.

[0040] Furthermore, in another aspect, the present invention relates to a bacterial flora comprising Acaryochloris marina and / or Myxococcus xanthus for treating or preventing inflammatory bowel disease. In yet another aspect, the present invention relates to use of a bacterial flora comprising Acaryochloris marina and / or Myxococcus xanthus for manufacturing a medicament for treating or preventing inflammatory bowel disease.

[0041] As used herein, "treatment" refers to a method or process that aims to (1) delay the onset of inflammatory bowel disease; (2) slow or stop the progression, worsening, or deterioration of the symptoms of inflammatory bowel disease; (3) bring about the amelioration of the symptoms of inflammatory bowel disease; or (4) cure inflammatory bowel disease. Treatment may be administered prior to the onset of the disease or condition as a preventative measure, or treatment may be administered after the onset of the disease.

[0042] In the present invention, inflammatory bowel disease refers to an immune disease designated as an intractable disease whose main symptoms are diarrhea, bloody stool, and abdominal pain, and includes ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease in which chronic inflammation occurs continuously from the large intestine to the rectum, while Crohn's disease is a disease in which chronic inflammation occurs throughout the entire digestive tract from the mouth to the anus.

[0043] In the present invention, "prevention" means preventing the onset of inflammatory bowel disease in advance.

[0044] The pharmaceutical compositions of the present invention can be administered by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously or subcutaneously. Additionally, the compositions of the present invention can be administered intranasally or as a rectal suppository.

[0045] The pharmaceutical compositions of the present invention can be administered in single or multiple doses, with the active ingredient alone or in combination with a pharmaceutically acceptable carrier, vehicle, or diluent.Suitable pharmaceutical carriers, vehicles, and diluents include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents.The pharmaceutical compositions formed by combining the composition with a pharmaceutically acceptable carrier, vehicle, or diluent can be easily administered in various dosage forms, such as tablets, powders, lozenges, syrups, and injections.These pharmaceutical compositions can contain additional ingredients, such as flavorings, binders, and excipients, if desired.

[0046] For parenteral administration, the composition solution can be prepared in, for example, sesame oil or peanut oil, aqueous propylene glycol, or can be used in sterile aqueous solution.If necessary, such aqueous solution is suitably buffered, and sufficient saline or glucose is first used to make the diluent isotonic.These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

[0047] The dosage is determined taking into consideration the severity of inflammatory bowel disease, the age, health condition, and weight of the patient. The composition of the present invention can be provided in unit dosage forms containing an appropriate amount of the active ingredient for administration to humans and animals, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile parenteral solutions of suspensions, and oral solutions or suspensions.

[0048] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as powdered agar, calcium carbonate, etc. (5) poor solvents, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds; (7) wetting agents, such as acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol solids, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0049] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0050] In addition to the subject compositions, suspensions can contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, powdered agar, and tragacanth, and mixtures thereof.

[0051] The pharmaceutical composition of the present invention can be administered as a rectal composition, for example, as a suppository. Suppositories can be prepared by mixing with one or more suitable non-irritating carriers, including, for example, cocoa butter, polyethylene glycol, a suppository wax, or salicylic acid, and the suppository is solid at room temperature but liquid at body temperature, so that it melts in a suitable body cavity and releases the encapsulated compound(s) and composition(s).

[0052] In one embodiment of the present invention, a composition for rectal administration is preferred. Compositions for rectal administration include pharmaceutically acceptable liquid dosage forms such as emulsions, microemulsions, solutions, and suspensions. These liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, corn oil, peanut oil, sunflower oil, soybean oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. Alternatively, prodrug technology can be used to prepare prodrug derivatives of the orally administered compound of Formula (I) that are converted into active compounds in the rectum.

[0053] In another aspect, the present invention relates to a method for treating or preventing inflammatory bowel disease, which method comprises administering a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, etc. Furthermore, in another aspect, the present invention relates to a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof for treating or preventing inflammatory bowel disease. In yet another aspect, the present invention relates to use of a compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof for producing a medicament for treating or preventing inflammatory bowel disease.

[0054] In a further embodiment, the present invention relates to a method for treating or preventing inflammatory bowel disease, the method comprising administering 11-HEPE to a subject in need of such treatment, etc. In another embodiment, the present invention relates to 11-HEPE for treating or preventing inflammatory bowel disease. In yet another embodiment, the present invention relates to use of 11-HEPE for manufacturing a medicament for treating or preventing inflammatory bowel disease.

[0055] In another aspect, the present invention relates to a method for treating or preventing inflammatory bowel disease, the method comprising administering an Acaryochloris marina and / or Myxococcus xanthus salt to a subject in need of such treatment, etc. In yet another aspect, the present invention relates to Acaryochloris marina and / or Myxococcus xanthus for treating or preventing inflammatory bowel disease. In yet another aspect, the present invention relates to the use of Acaryochloris marina and / or Myxococcus xanthus for the manufacture of a medicament for treating or preventing inflammatory bowel disease.

[0056] Food Composition In another embodiment, the present invention relates to a food composition for treating and / or preventing inflammatory bowel disease, or a food composition for treating and / or preventing diarrhea, bloody stool, and / or abdominal pain, particularly diarrhea, bloody stool, and / or abdominal pain thought to be caused by inflammatory bowel disease, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In the present invention, "treatment" refers to a method or process aimed at (1) delaying the onset of diarrhea, bloody stool, and / or abdominal pain; (2) slowing or halting the progression, worsening, or aggravation of the symptoms of diarrhea, bloody stool, and / or abdominal pain; or (3) bringing about the alleviation of the symptoms of diarrhea, bloody stool, and / or abdominal pain. Treatment may be administered before the onset of a disease or condition as a preventative measure, or may be administered after the onset of the disease. In the present invention, "prevention" refers to preventing the onset of diarrhea, bloody stool, and / or abdominal pain.

[0057] The food composition of the present invention may consist solely of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, solely of a prodrug of the compound represented by formula (I), solely of a monoglyceride, diglyceride, or triglyceride of the compound represented by formula (I), or may be a composition obtained by incorporating any of these into a food (food additive, food, beverage, etc.) The food composition of the present invention may be any composition that contains the compound represented by formula (I), etc., and that can be orally ingested by a subject, and there are no particular limitations on the type, form, etc. of the food composition.

[0058] In yet another embodiment, the present invention relates to a food composition containing linoleate 11-lipoxygenase (11-LOX) for treating and / or preventing inflammatory bowel disease, or a food composition for treating and / or preventing diarrhea, bloody stool, and / or abdominal pain, particularly diarrhea, bloody stool, and / or abdominal pain thought to be caused by inflammatory bowel disease. The food composition of this embodiment may further contain eicosapentaenoic acid or may be administered with a meal.

[0059] It has been reported that eicosapentaenoic acid contained in food is enzymatically converted by linoleic acid-11-lipoxygenase (11-LOX) to produce 11-hydroxy-eicosapentaenoic acid (11-HEPE). In the present invention, it was found that compounds represented by formula (I), such as 11-HEPE, can treat and / or prevent inflammatory bowel disease. Therefore, it is believed that 11-LOX, which can induce 11-HEPE, can also treat and / or prevent inflammatory bowel disease.

[0060] The food composition of the present invention may consist solely of 11-HEPE, or may be a composition containing 11-HEPE in a food (food additive, food, beverage, etc.) There are no particular limitations on the type or form of the food composition as long as it contains 11-HEPE and can be orally ingested by a subject.

[0061] In yet another embodiment, the present invention relates to a food composition for treating and / or preventing inflammatory bowel disease, or a food composition for treating and / or preventing diarrhea, bloody stool and / or abdominal pain, particularly diarrhea, bloody stool and / or abdominal pain thought to be caused by inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus. The food composition in this embodiment may further comprise eicosapentaenoic acid or may be administered with a meal.

[0062] As described above, since 11-LOX is also believed to be capable of treating and / or preventing inflammatory bowel disease, the present inventors searched for the origin of 11-LOX and found that it is derived from Acaryochloris marina or Myxococcus xanthus. Since 11-LOX can treat and / or prevent inflammatory bowel disease in the present invention, it is believed that its origin, Acaryochloris marina or Myxococcus xanthus, can also treat and / or prevent inflammatory bowel disease.

[0063] The food composition of the present invention may consist solely of Acaryochloris marina and / or Myxococcus xanthus, or may be a composition obtained by blending them into a food (food additive, food, beverage, etc.) etc. The food composition of the present invention is not particularly limited as long as it contains Acaryochloris marina or Myxococcus xanthus and can be orally ingested by a subject, and there are no particular limitations on the type, form, etc. of the food composition.

[0064] In this embodiment, the invention relates in another embodiment to Acaryochloris marina and / or Myxococcus xanthus as probiotics for treating and / or preventing diarrhea, bloody stool and / or abdominal pain, particularly diarrhea, bloody stool and / or abdominal pain thought to be due to inflammatory bowel disease. Probiotics are live microorganisms that, when ingested in sufficient amounts, confer a beneficial effect on the host.

[0065] As described above, one aspect of the present invention relates to a food composition. Examples of the food composition of the present invention include confectioneries such as lozenges, drops, candies, soda pop, gummies, and chewing gum; Western confectioneries such as cookies, crackers, biscuits, potato chips, bread, cakes, chocolates, donuts, puddings, and jellies; Japanese confectioneries such as rice crackers, yokan, daifuku, ohagi, manju, and castella; frozen desserts such as ice cream, popsicles, sorbets, and gelato; breads such as bread, French baguettes, and croissants; noodles such as udon, soba, Chinese noodles, and kishimen; fish paste products such as kamaboko, chikuwa, and fish sausage; meat products such as ham, sausage, hamburger steak, and corned beef; salt, pepper, miso, soy sauce, sauces, dressings, mayonnaise, ketchup, and sweeteners ( For example, condiments such as sugar, honey, powdered syrup, starch syrup, jam, marmalade, etc., and spices (e.g., mustard, pepper, etc.); teppanyaki foods such as akashiyaki, takoyaki, monjayaki, okonomiyaki, yakisoba, and yakiudon; dairy products such as cheese, butter, margarine, and yogurt; various prepared foods such as natto, deep-fried tofu, tofu, konjac, dumplings, pickles, tsukudani (simmered foods in soy sauce), gyoza, shumai, croquettes, sandwiches, pizza, hamburgers, and salads; livestock products such as beef, pork, and chicken; seafood products such as shrimp, scallops, clams, and kelp; various powders made from vegetables, fruits, plants, yeast, algae, etc.; powdered oils and flavorings (vanilla, citrus fruits, bonito, etc.); vegetable oils (olive oil, soybean oil, etc.); and beverages.

[0066] Examples of beverages include food and drink such as soup and miso soup; powdered food and drink such as instant coffee, instant tea, instant milk, instant soup, and instant miso soup; alcoholic beverages such as whiskey, bourbon, spirits, liqueur, wine, fruit wine, Japanese sake, Chinese sake, shochu, beer, non-alcoholic beer with an alcohol content of 1% or less, happoshu, and chuhai; beverages containing fruit juice (e.g., apple, mandarin orange, grape, banana, pear, plum juice, etc.), and vegetable juice (e.g., Examples of non-alcoholic beverages include beverages containing vegetable juices (such as tomato, carrot, celery, cucumber, and watermelon), beverages containing fruit and vegetable juices, soft drinks, milk, soy milk, dairy drinks, drink-type yogurt, coffee, cocoa, tea drinks (black tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, roasted green tea, oolong tea, turmeric tea, pu-erh tea, rooibos tea, rose tea, chrysanthemum tea, and herbal teas (such as mint tea and jasmine tea)), energy drinks, sports drinks, and mineral water.

[0067] Suitable examples of such food compositions include those obtained by adding a compound represented by formula (I) to foods or beverages such as natto, yogurt, vegetable oil, jelly, tea drinks, alcoholic drinks, drops, candy, lemonade, cookies, crackers, biscuits, chocolate, cheese, butter, margarine, and chewing gum.

[0068] The food composition of the present invention may also be prepared as a functional food, health food, food for specified health uses, food for special dietary uses (e.g., food for sick people such as hospital food, food for sick people, and nursing care food), supplement, etc., and is preferably prepared as a food for specified health uses, food for special dietary uses, or supplement.

[0069] The food composition of the present invention may be in the form of, for example, tablets, pills, capsules (including hard capsules, soft capsules, and microcapsules), powders, granules, fine granules, troches, liquids (including syrups, emulsions, and suspensions), nasogastric tube feeding preparations, enteral nutritional preparations, etc., with tablets or capsules being preferred. Another preferred embodiment of the food composition of the present invention is a food or beverage containing a compound represented by formula (I) or the like added thereto.

[0070] The food composition of the present invention is preferably a food for specified health uses, a food for special dietary uses, or a supplement in the form of a tablet or capsule.

[0071] In this specification, supplements do not only mean nutritional supplements, nutritional functional foods, etc. for supplementing nutrients, etc., but also health supplements, health functional foods, etc. that have functions that are useful for maintaining, restoring, improving, etc. health.

[0072] The food composition of the present invention can be produced, for example, by adding a compound represented by formula (I) or the like by known methods. Specifically, for example, a tablet food composition can be produced by adding and mixing a compound represented by formula (I) or the like with excipients (e.g., lactose, sucrose, mannitol, corn starch, etc.), sweeteners, flavoring agents, and other ingredients, and then molding the mixture into a tablet shape using a tablet press or the like under pressure. If necessary, other ingredients (e.g., vitamins such as vitamin C, minerals such as iron, dietary fiber, crystalline cellulose, rapeseed (hardened rapeseed oil), and other additives) can also be added. For example, a capsule food composition can be produced by filling a liquid, suspension, paste, powder, or granular food composition containing a compound represented by formula (I) or the like into a capsule or by encapsulating it with a capsule base.

[0073] The food composition of the present invention can contain physiologically acceptable carriers in addition to commonly used food ingredients, food additives, various nutrients, vitamins, flavoring substances (e.g., cheese, chocolate, etc.), as long as the effects of the present invention are not impaired. Physiologically acceptable carriers include various conventional organic or inorganic carrier substances, such as excipients, binders, disintegrants, lubricants, colorants, sweeteners, preservatives, antioxidants, thickeners, and emulsifiers. Food additives include colorants, sweeteners, preservatives, antioxidants, and flavoring agents. The food composition may also contain other ingredients, such as minerals (e.g., iron, calcium, etc.), and dietary fibers (e.g., pectin, carrageenan, mannan, etc.).

[0074] Examples of the excipient, binder, disintegrant, lubricant, solvent, solubilizer, suspending agent, buffer, thickener, colorant, sweetener, preservative, and antioxidant include those similar to those used in the pharmaceutical composition of the present invention described above.

[0075] Vitamins may be water-soluble or fat-soluble, and examples thereof include retinol palmitate, α-tocopherol (vitamin E), bisbentiamine, riboflavin, pyridoxine hydrochloride, cyanocobalamin, sodium ascorbate (vitamin C), cholecalciferol, nicotinamide, calcium pantothenate, folic acid, biotin, choline bitartrate, niacin, and nicotinamide mononucleotide (NMN).

[0076] Food compositions in the form of tablets, granules, or fine granules may be coated with a coating substrate by a method known per se for the purposes of taste masking, improving light stability, improving appearance, enteric coating, etc. Examples of the coating substrate include the same ones as those used for the pharmaceutical composition of the present invention described above, and coating can be carried out in the same manner.

[0077] The content of the compound represented by formula (I) in the food composition of the present invention is not particularly limited, and is, for example, 0.1% by weight or more and 50% by weight or less based on the total weight of the food composition. The lower limit is preferably 0.5% by weight or more, more preferably 1.0% by weight or more based on the total weight of the food composition. Meanwhile, the upper limit is preferably 20% by weight or less, more preferably 10% by weight or less based on the total weight of the food composition.

[0078] The food composition thus obtained is safe and can be continuously given to subjects, particularly preferably humans.

[0079] The present invention will be described in detail below with reference to examples. However, it should be noted that these examples do not limit the scope of the present invention and are merely illustrative.

[0080] Example 1: Appendectomy Strengthens the Mucin Layer Example 1-1: Quantitative PCR Colons were removed from sham-operated (sham) or appendectomized (APX) mice. Each colon was opened longitudinally, and the contents were washed with PBS. The colons were cut into 2 mm cubes, and 15 ml of prewarmed EDTA buffer (5 mM EDTA / PBS) was placed in an Erlenmeyer flask and stirred at 37°C for 30 minutes. The supernatant was collected through a 100 μm filter, and the pellet was recovered by centrifugation at 1500 rpm for 5 minutes. RNAIso was added to the resulting pellet and thoroughly dissolved. Chloroform (0.2 times the volume of RNAIso), mixed vigorously, and allowed to stand at room temperature for 5 minutes. The mixture was centrifuged at 12,000 x G and 4°C for 15 minutes. The supernatant was transferred to a new tube, an equal volume of isopropanol was added, mixed, and allowed to stand at room temperature for 10 minutes. The mixture was centrifuged at 12,000 x G and 4°C for 10 minutes. The samples were washed with 75% ethanol and centrifuged at 7500xG for 5 minutes at 4°C. The supernatant was discarded, leaving the precipitate, and the sample was dried. The RNA was then dissolved in water and recovered. The RNA was reverse transcribed to prepare cDNA. q-PCR was performed using the cDNA. β-actin was simultaneously measured as a housekeeping gene (normalizer), and the ΔΔCT value of mucin-2 (mcu2) gene expression, a component of secretory mucus in the small intestine, was calculated. The results are shown in Figure 1A. A significant increase in muc2 gene expression in the large intestine was confirmed after appendectomy (APX), supporting the strengthening of the mucin layer.

[0081] Example 1-2: Periodic Acid-Schiff (PAS) Staining. Colons were removed from sham-operated (sham) or appendectomized (APX) mice and fixed overnight in 10% formalin solution. Paraffin blocks were prepared by dehydrating in three phases of methanol, infiltrating and embedding in two phases of xylene, and then paraffin. Sections were prepared at a thickness of 4 mm. Slides were immersed in 0.5% periodic acid for 5 minutes, immersed in Schiff's reagent for 15 minutes, rinsed thoroughly with running water, immersed in hematoxylin for 1 minute, and rinsed thoroughly with running water. The sections were dehydrated in three phases of ethanol, dialyzed against three phases of xylene, mounted, and observed under a microscope. The results are shown in Figure 1B. Appendectomy (APX) confirmed an expansion of the area of ​​darkly stained mucus.

[0082] Example 1-3: FISH (Fluorescence In Situ Hybridization) Staining. Colons were removed from sham-operated (sham) or appendectomized (APX) mice. They were immersed in Carnoy's solution and fixed at room temperature for 2 hours. Paraffin blocks were prepared using the same method as for PAS staining, and 4-mm-thick sections were prepared. Fluorescent staining was performed using DAPI antibody for nuclear staining, MUC2 antibody, and EUB338 antibody for intestinal bacteria staining, and the sections were observed under a fluorescent microscope. The results are shown in Figure 1C. The mucus layer is enclosed within the white dotted line. It can be seen that the mucus layer expands after appendectomy. Figure 1D shows the area of ​​the mucus layer in Figure 1C. These results confirm that appendectomy (APX) increases the area of ​​the mucus layer and increases the distance between epithelial cells and bacteria.

[0083] Example 2: Changes in the Gut Microbiota Following Appendectomy Bacterial DNA was extracted from mouse fecal samples (n = 6) using the DNeasy PowerSoil Kit (Qiagen, Hilden, Germany) according to the manufacturer's protocol. 251-bp paired-end sequencing of the V1-V2 variable region of the 16S rRNA gene was performed on the Illumina MiSeq platform (Illumina, San Diego, CA, USA). The resulting paired-end sequences were merged, filtered, and denoised using DADA2. Taxonomic assignment was performed using the QIIME2 feature-classifier plugin with the Greengenes 13_8 database. The results are shown in Figure 2. Consistent with previous reports, appendectomy (APX) resulted in a decrease in fecal Bacteroidia and an increase in Clostridia.

[0084] Example 3: Suppression of Colitis Dependent on Microbiota Altered by Appendectomy (APX) Example 3-1: Co-cage Rearing Experiment As shown in Figure 3, a group of sham-operated mice and a group of appendectomized mice were housed in the same cage for two weeks from the day of surgery, allowing for the sharing of microbiota. Single-housed groups were housed solely for each surgical group. Example 3-2: Weight Change Rate As shown in the schematic diagram in Figure 3, cages containing only the sham-operated group, cages containing only appendectomized mice, and cages containing both sham-operated and appendectomized mice were prepared. After two weeks of rearing under the above conditions after surgery, the weight change rate when colitis was induced with DSS is shown. The results are shown in Figure 4A. Co-housing eliminated the suppression of weight loss due to appendectomy.

[0085] Example 3-3: Shortening of the large intestine The length of the large intestine was examined under the above conditions. The results are shown in Figure 4B. By co-rearing, shortening of the large intestine due to appendectomy was no longer observed.

[0086] Example 3-4: Inflammatory Cytokines. Colons were removed from sham-operated (sham) or appendectomized (APX) mice. The colons were cut longitudinally and the contents were washed with PBS. The colons were cut into 2 mm cubes, and 15 ml of prewarmed EDTA buffer (5 mM EDTA / PBS) was placed in an Erlenmeyer flask and stirred at 37°C for 30 minutes. The supernatant was collected through a 100 μm filter and centrifuged at 1500 rpm for 5 minutes to obtain a pellet. The collected pellet was dissolved in cell lysis buffer and centrifuged at 1500 rpm for 5 minutes to obtain the supernatant (epithelial fraction). The epithelium-free colons were homogenized in cell lysis buffer and centrifuged at 1500 rpm for 5 minutes to obtain the supernatant (lamina propria fraction). The levels of IL-1β, IL-6, and TNF-α in the lamina propria fraction were measured by ELISA. Total protein content was measured using the Bradford assay and normalized. The results are shown in Figure 4C. The pro-inflammatory cytokines IL-1β and IL-6, which were reduced by appendectomy, were no longer observed in the co-rearing group, and inflammation occurred at the same level as in the sham operation.

[0087] Example 3-5: H&E Staining Slides were prepared according to the method of Example 1-2. The obtained slides were immersed in hematoxylin solution for 30 seconds. They were then thoroughly washed with running water and then immersed in eosin solution for 1 minute. The slides were dehydrated, dialyzed, mounted, and observed under a microscope. The results are shown in Figure 4D. Appendectomy suppressed the loss of crypts, muscularis hypertrophy, and inflammatory cell infiltration, which are indicators of the severity of colitis, but these suppressions were no longer observed when the animals were kept together.

[0088] Example 4: Antibiotic Experiments. Mice were given free access to water containing four antibiotics: ampicillin, vancomycin, metronidazole, and neomycin, for two weeks. These mice were housed in cages with sham-operated or appendectomized mice for two weeks (regular water intake). After the two-week period, the previously antibiotic-treated mice were administered dextran sulfate sodium (DSS) to induce colitis. Body weight was measured for eight days after the start of DSS drinking, and colon length was measured eight days later. The results are shown in Figures 5A and 5B. Compared to the group housed with sham-operated mice, the group housed with appendectomized mice showed significantly reduced weight loss and colon shortening.

[0089] Example 5 Tuft Cell Hyperplasia Depends on Alterations in Microbiota Example 5-1: Tuft Cell Count Colons were removed from sham-operated (sham) or appendectomized (APX) mice. The colons were cut longitudinally and the contents were washed with PBS. The colons were cut into 2 mm cubes, and 15 ml of prewarmed EDTA buffer (5 mM EDTA / PBS) was placed in an Erlenmeyer flask and stirred at 37°C for 30 minutes. The supernatant was collected through a 100 μm filter and pelleted by centrifugation at 1500 rpm for 5 minutes. The pellet was stained with anti-CD45.2, anti-CD326, anti-CD24, and anti-Siglec-F. CD45.2-negative, CD326-positive, CD24-positive, and Siglec-F-positive cells were identified as tuft cells using a flow cytometer, and the cell numbers were counted. The results are shown in Figure 6A. The increase in colonic tuft cells that occurs after appendectomy is abolished when mice are co-housed with sham-operated mice.

[0090] Example 5-2: IL-25 Protein Levels Colons were excised from sham-operated (sham) or appendectomized (APX) mice. The colons were cut longitudinally and the contents were washed with PBS. The colons were cut into 2 mm cubes, and 15 ml of prewarmed EDTA buffer (5 mM EDTA / PBS) was placed in an Erlenmeyer flask and stirred at 37°C for 30 minutes. The supernatant was collected through a 100 μm filter and centrifuged at 1500 rpm for 5 minutes to obtain a pellet. The collected pellet was dissolved in cell lysis buffer and centrifuged at 1500 rpm for 5 minutes to obtain the supernatant (epithelial fraction). The colons, from which the epithelium had been removed, were homogenized in cell lysis buffer and centrifuged at 1500 rpm for 5 minutes to obtain the supernatant (lamina propria fraction). IL-25 levels in the epithelial fraction were measured by ELISA. Total protein levels were measured using the Bradford assay and normalized. The results are shown in Figure 6B. Colonic IL-25 increases after appendectomy, but this increase is not observed when mice are reared in sham-operated mice.

[0091] Example 6: Increased 11-HEPE in the colon by APX suppresses colitis. Example 6-1: Identification of metabolites. The peaks of each metabolite were identified by LCMS, and metabolites with significant increases were selected. Specifically, methanol was added to the feces, and disruption and extraction were performed using zirconia beads (6500 rpm, 15 seconds x 2). Extraction was performed overnight at -30°C. The resulting sample was centrifuged (1600g x 10 minutes, 4°C), and 200 μl of the supernatant was transferred to a new tube. 200 μl of ultrapure water was added, vortexed, and centrifuged (10000g x 1 minute, 4°C).

[0092] A 200 μl sample was loaded onto a spin column and centrifuged (3500 rpm x 2 min, 25°C). 300 μl of ultrapure water was loaded onto the spin column and centrifuged (3500 rpm x 2 min, 25°C). 300 μl of 50% methanol was loaded onto the spin column and centrifuged (3500 rpm x 2 min, 25°C). The tube was replaced with a new one for collection, and 200 μl of 90% methanol + 2% acetic acid solution was loaded onto the spin column and centrifuged (3500 rpm x 2 min, 25°C). The resulting sample was transferred to a 15 μl vial and analyzed using a Shimadzu method package. The results are shown in Figure 7A. A long-chain fatty acid called 11-hydroxyeicosapentaenoic acid (11-HEPE) was found to be significantly increased in the feces of appendectomized mice.

[0093] Example 6-2: Effect of 11-HEPE Mice were anesthetized and put to sleep 7, 5, 3, and 1 days before the start of DSS drinking, and 11-HEPE was administered enterally. Body weight was measured from the start of DSS drinking until day 8, and the rate of weight change was determined. Colon length on day 8 was also measured. Administration of 11-HEPE significantly suppressed weight loss (Figure 7B) and colon shortening (Figure 7C).

[0094] Example 7: Identification of Long-Chain Fatty Acids That Improve Colitis Through Tuft Cell Hyperplasia. It has been reported that eicosapentaenoic acid (eicosapentaenoic acid) contained in food is enzymatically converted by linoleate 11-lipoxygenase (11-LOX) to produce 11-hydroxy-eicosapentaenoic acid (11-HEPE) (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC6210903 / pdf / jlrM088823.pdf, Stabilization and Improved Activity of Arachidonate 11S-Lipoxygenase from Proteobacterium Myxococcus xanthus). We investigated the origin of 11-LOX, i.e., whether it is present in the host or in enteric bacteria. Specifically, we used the enzyme database BRENDA (https: / / www.brenda-enzymes.org / ). 11-LOX, also known as linoleic acid 11-lipoxygenase, is registered under the EC number 1.13.11.45. The sources of this enzyme are listed as bacteria and fungi, but not animals, particularly mammals. Searching for 11-LOX and 11-linoleate lipoxygenase in the research search engine PubMed reveals reports of bacteria and fungi, but no reports of 11-LOX in mammals. Therefore, we conclude that 11-LOX originates from microorganisms such as bacteria and fungi.

[0095] Next, we performed shotgun metagenomic sequencing to investigate whether appendectomy increases the number of microorganisms expressing 11-LOX. The results are shown in Figure 8. Figure 8 shows that appendectomy significantly altered the bacterial flora, resulting in an increase in various bacterial species (Figure 8A). However, the fungal flora showed little change, and no fungal species were identified that increased after appendectomy (Figure 8B). Therefore, we concluded that bacteria, rather than fungi, are the major source of 11-LOX production.

[0096] As a result, it was found that 11-LOX was derived from intestinal bacteria, not from the host.

[0097] Example 8: Changes in Acaryochloris marina and Myxococcus xanthus in Feces Following Appendectomy A co-cage rearing experiment was conducted according to the method described in Example 3. Cages containing only sham-operated mice, only appendectomized mice, and cages containing both sham-operated and appendectomized mice were prepared. The OTU counts of Acaryochloris marina and Myxococcus xanthus were measured in fecal samples from each cage. Specifically, feces were collected from four groups: singly-housed sham-operated mice, singly-housed appendectomized mice, co-housed sham-operated mice, and co-housed appendectomized mice. Shotgun metagenomic analysis was performed to identify the bacterial species. In identifying these bacteria, we considered that the bacteria that were abundant in the "single-housed appendectomy" group and decreased in the "co-housed appendectomy" group were involved in the alleviation of colitis, because as shown in Example 3, a colitis-inhibitory effect was observed in the "single-housed appendectomy" group, and the colitis-inhibitory effect disappeared in the "co-housed appendectomy" group despite the mice undergoing appendectomy, as shown in Example 3. Therefore, among the bacteria reported as 11-LOX-positive bacteria, we identified bacteria that were increased in the "single-housed appendectomy" group and decreased in the "co-housed appendectomy" group compared to the "single-housed sham-operated" group.

[0098] The results showed that Acaryocloris marina and Myxococcus xanthus were significantly increased in the feces of appendectomized mice (Fig. 9). Furthermore, Fig. 9 shows that the increase of these bacteria was suppressed by co-housing appendectomized mice with sham-operated mice. This indicates that the identified bacteria are strongly involved in colitis and correlate with its alleviating effect.

[0099] Furthermore, the present invention includes the following aspects: <Composition> [1] Formula (I): [wherein R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl] or a pharmaceutically acceptable salt thereof for treating and / or preventing inflammatory bowel disease. [2] The composition of [1], wherein R1 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl. [3] The composition of [1] or [2], wherein R1 is hydrogen or unsubstituted alkyl having 1 to 4 carbon atoms. [4] The composition of any of [1] to [3], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [5] The pharmaceutical composition of [4], wherein the inflammatory bowel disease is ulcerative colitis. [6] The composition of any of [1] to [5], wherein the composition is a pharmaceutical composition. [6-2] A pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising linoleic acid-11-lipoxygenase. [6-3] A pharmaceutical composition for treating and / or preventing inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus.

[0100] <Food Compositions> [7] The composition according to [1], which is a food composition. [8] The food composition according to [7], for treating and / or preventing diarrhea, bloody stool and / or abdominal pain. [9] A food composition comprising linoleic acid-11-lipoxygenase, for treating and / or preventing inflammatory bowel disease.

[10] The food composition according to [9], for treating and / or preventing diarrhea, bloody stool and / or abdominal pain.

[11] A food composition comprising Acaryochloris marina and / or Myxococcus xanthus, for treating and / or preventing inflammatory bowel disease.

[12] The food composition according to

[11] , for treating and / or preventing diarrhea, bloody stool and / or abdominal pain.

[13] The food composition according to any of [9] to

[12] , further comprising eicosapentaenoic acid.

[14] The food composition according to any of [9] to

[12] , which is administered together with a normal meal.

[15] The food composition according to any one of [7] to

[14] , which is prepared as a supplement, a functional food, a health food, a food for special dietary uses, a food with health claims, a food for specified health uses, or a food with nutrient functions.

[16] The food composition according to

[15] , which is prepared in the form of a tablet, pill, capsule, powder, granule, fine granule, troche, liquid, nasogastric tube feeding agent, or enteral nutrition agent.

Claims

1. Formula (I): [wherein R1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclyl] or a pharma- ceutical acceptable salt thereof for treating and / or preventing inflammatory bowel disease.

2. The composition of claim 1, wherein R1 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

3. The composition of claim 2, wherein R1 is hydrogen or unsubstituted alkyl having 1 to 4 carbon atoms.

4. The composition of claim 1, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

5. The composition according to claim 4, wherein the inflammatory bowel disease is ulcerative colitis.

6. The composition according to any one of claims 1 to 5, wherein the composition is a pharmaceutical composition.

7. The composition of claim 1, wherein the composition is a food composition.

8. The food composition according to claim 7 for treating and / or preventing diarrhea, bloody stools and / or abdominal pain.

9. A food composition for treating and / or preventing inflammatory bowel disease, comprising linoleic acid-11-lipoxygenase.

10. The food composition according to claim 9 for treating and / or preventing diarrhea, bloody stools and / or abdominal pain.

11. A food composition for treating and / or preventing inflammatory bowel disease, comprising Acaryochloris marina and / or Myxococcus xanthus.

12. The food composition according to claim 11 for treating and / or preventing diarrhea, bloody stools and / or abdominal pain.

13. A food composition according to any one of claims 9 to 12, further comprising eicosapentaenoic acid.

14. A food composition according to any one of claims 9 to 12, which is administered together with a normal meal.

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