Fecal microbiota and metabolites in the pathogenesis and precision medicine for inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, and its pathogenesis is believed to be associated with an imbalance between commensal organisms and the intestinal immune system. This imbalance is significantly influenced by the intestinal microbiota and metabolites and plays a critical role in maintaining intestinal mucosal homeostasis. However, disturbances in the intestinal microbiota cause dysregulated immune responses and consequently induce intestinal inflammation. Recent studies have illustrated the roles of the intestinal microbiota in the pathogenesis of IBD and underscored the potential of precision diagnosis and therapy. This work summarises recent progress in this field and particularly focuses on the application of the intestinal microbiota and metabolites in the precision diagnosis, prognosis assessment, treatment effectiveness evaluation, and therapeutic management of IBD.

Keywords

inflammatory bowel disease / fecal microbiota / metabolite / diagnosis / treatment / pathogenesis

Abbreviations

IBD: inflammatory bowel disease; CD: Crohn's disease; UC: ulcerative colitis; SCFA: short-chain fatty acids; Tregs: regulatory T cells; SFB: segmented filamentous bacteria; Th: helper T cells; FMT: fecal microbiota transplantation; GPR: G protein-coupled receptor; IFX, infliximab; MAM: microbial anti-inflammatory molecule; MAT: mesenteric adipose tissue; ADA: adalimumab.

Acknowledgements

The study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82370532, 82341219) and Shanghai Hospital Development Center Foundation (Grant No. SHDC12022118). We thank all the physicians, nurses, and students of the Shanghai Tenth People's Hospital Affiliated to Tongji University for their assistance.

Author contributions

L.J., Z.S., and J.L. contributed to conceptualization and writing of the manuscript. Z.L. contributed to conceptualization and review and editing of the manuscript.

Conflict of interest

None declared. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author Z.L. was blinded from reviewing and making decisions on this manuscript.

References

[1] Ahlawat S, Kumar P, Mohan H et al. Inflammatory bowel disease: tri-directional relationship between microbiota, immune system and intestinal epithelium. Crit Rev Microbiol 2021;47:254-73. https://doi.org/10.1080/1040841x.2021.1876631

[2] Khalili H, Chan SSM, Lochhead P et al. The role of diet in the aetiopathogenesis of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2018;15:525-35. https://doi.org/10.1038/s41575-018-0022-9

[3] Wu W, Gao X, Liu Z. Psychological stress as a detrimental factor in colitis. Med (New York, NY) 2023;4:401-3. https://doi.org/10.1016/j.medj.2023.06.008

[4] Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307-17. https://doi.org/10.1038/nature10209

[5] Quaglio AEV, Grillo TG, De Oliveira ECS et al. Gut microbiota, inflammatory bowel disease and colorectal cancer. World J Gastroenterol 2022;28:4053-60. https://doi.org/10.3748/wjg.v28.i30.4053

[6] Chen H, Li H, Liu Z. Interplay of intestinal microbiota and mucosal immunity in inflammatory bowel disease: a relationship of frenemies. Therapeutic Advances in Gastroenterology 2020;13:1756284820935188. https://doi.org/10.1177/1756284820935188

[7] Ooijevaar RE, Terveer EM, Verspaget HW et al. Clinical application and potential of fecal microbiota transplantation. Annu Rev Med 2019;70:335-51. https://doi.org/10.1146/annurev-med-111717-122956

[8] Sender R, Fuchs S, Milo R. Revised estimates for the number of Human and bacteria cells in the body. PLoS Biol 2016;14:e1002533. https://doi.org/10.1371/journal.pbio.100 2533

[9] Eckburg PB, Bik EM, Bernstein CN et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635-8. https://doi.org/10.1126/science.1110591

[10] Yao S, Zhao Z, Wang W et al. Bifidobacterium longum: protection against inflammatory bowel disease. J Immunol Res 2021;2021:1. https://doi.org/10.1155/2021/8030297

[11] Vich Vila A, Hu S, Andreu-Sánchez S et al. Faecal metabolome and its determinants in inflammatory bowel disease. Gut 2023;72:1472-85. https://doi.org/10.1136/gutjnl-2022-328048

[12] Wang Y, Dong Q, Hu S et al. Decoding microbial genomes to understand their functional roles in human complex diseases. iMeta 2022;1:e14. https://doi.org/10.1002/imt2.14

[13] Lavelle A, Sokol H. Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020;17:223-37. https://doi.org/10.1038/s41575-019-0258z

[14] Prame Kumar K, Ooi JD, Goldberg R. The interplay between the microbiota, diet and T regulatory cells in the preservation of the gut barrier in inflammatory bowel disease. Front Microbiol 2023;14:1291724. https://doi.org/10.3389/fmicb.2023.1291724

[15] Yang Y, Torchinsky MB, Gobert M et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 2014;510:152-6. https://doi.org/10.1038/nature13279

[16] Ivanov II, Atarashi K, Manel N et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485-98. https://doi.org/10.1016/j.cell.2009.09.033

[17] Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 2008;453:620-5. https://doi.org/10.1038/nature07008

[18] Lu H, Suo Z, Lin J et al. Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease. Biomark Res 2024;12:76. https://doi.org/10.1186/s40364-024-00612-x

[19] He X, Zhou H. Decoding the IBD paradox: A triadic interplay between REG3, enterococci, and NOD2. Cell Host Microbe 2023;31:1425-7. https://doi.org/10.1016/j.chom.2023.08.008

[20] Atarashi K, Tanoue T, Shima T et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011;331:337-41. https://doi.org/10.1126/science.1198469

[21] Sefik E, Geva-Zatorsky N, Oh S et al. MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of ror γ⁺ regulatory T cells. Science 2015;349:993-7. https://doi.org/10.1126/science.aaa9420

[22] Sugihara K, Kamada N. Metabolic network of the gut microbiota in inflammatory bowel disease. Inflamm Regener 2024;44:11. https://doi.org/10.1186/s41232-024-00321-w

[23] Wu X, Chen H, Gao X et al. Natural herbal remedy wumei decoction ameliorates intestinal mucosal inflammation by inhibiting Th1/Th17 cell differentiation and maintaining microbial homeostasis. Inflamm Bowel Dis 2022;28:1061-71. https://doi.org/10.1093/ibd/izab348

[24] Wu W, Sun M, Chen F et al. Microbiota metabolite shortchain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43. Mucosal Immunology 2017;10:946-56. https://doi.org/10.1038/mi.2016.114

[25] Yang W, Yu T, Huang X et al. Intestinal microbiota-derived short-chain fatty acids regulation of immune cell IL-22 production and gut immunity. Nat Commun 2020;11:4457. https://doi.org/10.1038/s41467-020-18262-6

[26] Sun M, Wu W, Chen L et al. Microbiota-derived short-chain fatty acids promote Th 1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun 2018;9:3555. https://doi.org/10.1038/s41467-018-05901-2

[27] Li G, Lin J, Zhang C et al. Microbiota metabolite butyrate constrains neutrophil functions and ameliorates mucosal inflammation in inflammatory bowel disease. Gut Microbes 2021;13:1968257. https://doi.org/10.1080/19490976.2021.1968257

[28] Guo X, Okpara ES, Hu W et al. Interactive relationships between intestinal flora and bile acids. Int J Mol Sci 2022;23:8343. https://doi.org/10.3390/ijms23158343

[29] Xiao F, Dong F, Li X et al. Bifidobacterium longum CECT 7894 improves the efficacy of Infliximab for DSS-induced colitis via regulating the gut microbiota and bile acid metabolism. Front Pharmacol 2022;13:902337. https://doi.org/10.3389/fphar.2022.902337

[30] Yang M, Gu Y, Li L et al. Bile acid-gut microbiota axis in inflammatory bowel disease: from bench to bedside. Nutrients 2021;13:3143. https://doi.org/10.3390/nu13093143

[31] Paik D, Yao L, Zhang Y et al. Human gut bacteria produce T(H)17-modulating bile acid metabolites. Nature 2022;603:90712. https://doi.org/10.1038/s41586-022-04480-z

[32] Sun R, Xu C, Feng B et al. Critical roles of bile acids in regulating intestinal mucosal immune responses. Therap Adv Gastroenterol 2021;14:175628482110180. https://doi.org/10.1177/17562848211018098

[33] Hu Y, Chen Z, Xu C et al. Disturbances of the gut microbiota and microbiota-derived metabolites in inflammatory bowel disease. Nutrients 2022;14:5140. https://doi.org/10.3390/nu14235140

[34] Huang R, Wu F, Zhou Q et al. Lactobacillus and intestinal diseases: mechanisms of action and clinical applications. Microbiol Res 2022;260:127019. https://doi.org/10.1016/j.micres.2022.127019

[35] Raithel M, Matek M, Baenkler HW et al. Mucosal histamine content and histamine secretion in Crohn's disease, ulcerative colitis and allergic enteropathy. Int Arch Allergy Immunol 1995;108:127-33. https://doi.org/10.1159/000237129

[36] Smolinska S, Winiarska E, Globinska A et al. Histamine: A mediator of intestinal disorders-A review. Metabolites 2022;12:895. https://doi.org/10.3390/metabo12100895

[37] Sartor RB, Wu GD. Roles for intestinal bacteria, viruses, and fungi in pathogenesis of inflammatory bowel diseases and therapeutic approaches. Gastroenterology 2017;152:327-39. https://doi.org/10.1053/j.gastro.2016.10.012

[38] Zhu M, Song Y, Xu Y et al. Manipulating microbiota in inflammatory bowel disease treatment: clinical and natural product interventions explored. Int J Mol Sci 2023;24:11004. https://doi.org/10.3390/ijms241311004

[39] Gao H, Peng K, Shi Y et al. Development and validation of a novel criterion of histologic healing in ulcerative colitis defined by inflammatory cell enumeration in lamina propria mucosa: A multicenter retrospective cohort in China. Chin Med J (Engl) 2024;137:1316-23. https://doi.org/10.1097/cm9.0000000000003154

[40] Lu H, Zhang C, Wu W et al. MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis. Gut 2023;72:882-95. https://doi.org/10.1136/gutjnl-2022-327183

[41] Li F, Yu C, Zhao Q et al. Exploring the intestinal ecosystem: from gut microbiota to associations with subtypes of inflammatory bowel disease. Front Cell Infect Microbiol 2023;13:1304858. https://doi.org/10.3389/fcimb.2023.1304858

[42] Rhodes JM. The role of Escherichia coli in inflammatory bowel disease. Gut 2007;56:610-2. https://doi.org/10.1136/gut.2006.111872

[43] Conrad MA, Bittinger K, Ren Y et al. The intestinal microbiome of inflammatory bowel disease across the pediatric age range. Gut microbes 2024;16:2317932. https://doi.org/10.1080/19490976.2024.2317932

[44] Chen H, Wu X, Sun R et al. Dysregulation of CD177(+) neutrophils on intraepithelial lymphocytes exacerbates gut inflammation via decreasing microbiota-derived DMF. Gut Microbes 2023;15:2172668. https://doi.org/10.1080/19490976.2023.2172668

[45] Chen L, Collij V, Jaeger M et al. Gut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity. Nat Commun 2020;11:4018. https://doi.org/10.1038/s41467-020-17840-y

[46] Wiredu Ocansey DK, Hang S, Yuan X et al. The diagnostic and prognostic potential of gut bacteria in inflammatory bowel disease. Gut microbes 2023;15:2176118. https://doi.org/10.1080/19490976.2023.2176118

[47] Liu Z, Liu R, Gao H et al. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries. Nat Genet 2023;55:796-806. https://doi.org/10.1038/s41588-023-01384-0

[48] Gao H, Liu Z. The latest breakthrough on genetic characteristics of inflammatory bowel disease in Chinese and other East Asian ancestries. Precision Clinical Medicine 2023;6:pbad017. https://doi.org/10.1093/pcmedi/pbad017

[49] Gao H, Liu R, Huang H et al. Susceptibility gene profiling elucidates the pathogenesis of inflammatory bowel disease and provides precision medicine. Clinical & Translational Med 2023;13:e1404. https://doi.org/10.1002/ctm2.1404

[50] Qiu P, Ishimoto T, Fu L et al. The gut microbiota in inflammatory bowel disease. Front Cell Infect Microbiol 2022;12:733992. https://doi.org/10.3389/fcimb.2022.733992

[51] Lloyd-Price J, Arze C, Ananthakrishnan AN et al. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019;569:655-62. https://doi.org/10.1038/s41586-019-1237-9

[52] Li G, Lin J, Gao X et al. Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease. Gut microbes 2023;15:2257269. https://doi.org/10.1080/19490976.2023.2257269

[53] Zhang Q, Chen LH, Yang H et al. GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages. Acta Pharmacol Sin 2022;43:2042-54. https://doi.org/10.1038/s41401-021-00825-y

[54] Berry D, Schwab C, Milinovich G et al. Phylotype-level 16S rRNA analysis reveals new bacterial indicators of health state in acute murine colitis. ISME J 2012;6:2091-106. https://doi.org/10.1038/ismej.2012.39

[55] Hughes ER, Winter MG, Duerkop BA et al. Microbial respiration and formate oxidation as metabolic signatures of inflammation-associated dysbiosis. Cell Host Microbe 2017;21:208-19. https://doi.org/10.1016/j.chom.2017.01.005

[56] Sokol H, Conway KL, Zhang M et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 2013;145:591-601. e3. https://doi.org/10.1053/j.gastro.2013.05.047

[57] Lamas B, Richard ML, Leducq V et al. CARD 9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med 2016;22:598-605. https://doi.org/10.1038/nm.4102

[58] Tye H, Yu CH, Simms LA et al. NLRP 1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat Commun 2018;9:3728. https://doi.org/10.1038/s41467-018-06125-0

[59] Chen H, Wu X, Xu C et al. Dichotomous roles of neutrophils in modulating pathogenic and repair processes of inflammatory bowel diseases. Precision Clinical Medicine 2021;4:246-57. https://doi.org/10.1093/pcmedi/pbab025

[60] Zhu W, Winter MG, Byndloss MX et al. Precision editing of the gut microbiota ameliorates colitis. Nature 2018;553:208-11. https://doi.org/10.1038/nature25172

[61] Sokol H, Pigneur B, Watterlot L et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:16731-6. https://doi.org/10.1073/pnas.0804812105

[62] Quévrain E, Maubert MA, Michon C et al. Identification of an anti-inflammatory protein from faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. Gut 2016;65:415-25. https://doi.org/10.1136/gutjnl-2014-307649

[63] Crohn BB, Ginzburg L, Oppenheimer GD. Landmark article Oct 15, 1932. Regional ileitis. A pathological and clinical entity. By Burril B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer. JAMA 1984;251:73-9. https://doi.org/10.1001/jama.251.1.73

[64] Giambra V, Pagliari D, Rio P et al. Gut microbiota, inflammatory bowel disease, and cancer: the role of guardians of innate immunity. Cells 2023;12:2654. https://doi.org/10.3390/cells12222654

[65] Ha CWY, Martin A, Sepich-Poore GD et al. Translocation of viable gut microbiota to mesenteric adipose drives formation of creeping fat in humans. Cell 2020;183:666-83. https://doi.org/10.1016/j.cell.2020.09.009

[66] Spencer SP, Sonnenburg JL. When gut microbiota creep into fat, the fat creeps back. Cell 2020;183:589-91. https://doi.org/10.1016/j.cell.2020.10.008

[67] Tanwar H, Gnanasekaran JM, Allison D et al. Unraveling the oral-gut axis: interconnection between periodontitis and IBD, current challenges, and future perspective. Journal of Crohn's & Colitis 2024; 18: 1319-41. https://doi.org/10.1093/ecco-jcc/jjae028

[68] Qian J, Lu J, Huang Y et al. Periodontitis salivary microbiota worsens colitis. J Dent Res 2022;101:559-68. https://doi.org/10.1177/00220345211049781

[69] Atarashi K, Suda W, Luo C et al. Ectopic colonization of oral bacteria in the intestine drives T(H)1 cell induction and inflammation. Science 2017;358:359-65. https://doi.org/10.1126/science.aan4526

[70] Kitamoto S, Nagao-Kitamoto H, Jiao Y et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis. Cell 2020;182:447-62. https://doi.org/10.1016/j.cell.2020.05.048

[71] Jia L, Jiang Y, Wu L et al. Porphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/treg cell balance axis. Nat Commun 2024;15:1617. https://doi.org/10.1038/s41467-024-45473-y

[72] Gao X, Sun R, Jiao N et al. Integrative multi-omics deciphers the spatial characteristics of host-gut microbiota interactions in Crohn's disease. Cell Reports Medicine 2023;4:101050. https://doi.org/10.1016/j.xcrm.2023.101050

[73] Vujkovic-Cvijin I, Welles HC, Ha CWY et al. The systemic anti-microbiota IgG repertoire can identify gut bacteria that translocate across gut barrier surfaces. Sci Transl Med 2022;14:eabl3927. https://doi.org/10.1126/scitranslmed.abl3927

[74] Ning L, Zhou YL, Sun H et al. Microbiome and metabolome features in inflammatory bowel disease via multi-omics integration analyses across cohorts. Nat Commun 2023;14:7135. https://doi.org/10.1038/s41467-023-42788-0

[75] Gao S, Gao X, Zhu R et al. Microbial genes outperform species and SNVs as diagnostic markers for Crohn's disease on multicohort fecal metagenomes empowered by artificial intelligence. Gut microbes 2023;15:2221428. https://doi.org/10.1080/19490976.2023.2221428

[76] Kang DY, Park JL, Yeo MK et al. Diagnosis of Crohn's disease and ulcerative colitis using the microbiome. BMC Microbiol 2023;23:336. https://doi.org/10.1186/s12866-023-03084-5

[77] Pascal V, Pozuelo M, Borruel N et al. A microbial signature for Crohn's disease. Gut 2017;66:813-22. https://doi.org/10.1136/gutjnl-2016-313235

[78] Gao H, He Q, Xu C et al. The development and validation of anti-paratuberculosis-nocardia polypeptide antibody [Anti-pTNP] for the diagnosis of Crohn's Disease. Journal of Crohn's & Colitis 2022;16:1110-23. https://doi.org/10.1093/ecco-jcc/jjac008

[79] Chen W, Wang D, Deng X et al. Bile acid profiling as an effective biomarker for staging in pediatric inflammatory bowel disease. Gut microbes 2024;16:2323231. https://doi.org/10.1080/19490976.2024.2323231

[80] Mu C, Zhao Q, Zhao Q et al. Multi-omics in Crohn's disease: new insights from inside. Comput Struct Biotechnol J 2023;21:3054-72. https://doi.org/10.1016/j.csbj.2023.05.010

[81] Machiels K, Sabino J, Vandermosten L et al. Specific members of the predominant gut microbiota predict pouchitis following colectomy and IPAA in UC. Gut 2017;66:79-88. https://doi.org/10.1136/gutjnl-2015-309398

[82] Mondot S, Lepage P, Seksik P et al. Structural robustness of the gut mucosal microbiota is associated with Crohn's disease remission after surgery. Gut 2016;65:954-62. https://doi.org/10.1136/gutjnl-2015-309184

[83] Wang C, Gu Y, Chu Q et al. Gut microbiota and metabolites as predictors of biologics response in inflammatory bowel disease: A comprehensive systematic review. Microbiol Res 2024;282:127660. https://doi.org/10.1016/j.micres.2024.127660

[84] Franzin M, Stefančič K, Lucafò M et al. Microbiota and drug response in inflammatory bowel disease. Pathogens (Basel, Switzerland) 2021;10:211. https://doi.org/10.3390/pathogens10020211

[85] Mah C, Jayawardana T, Leong G et al. Assessing the relationship between the gut microbiota and inflammatory bowel disease therapeutics: A systematic review. Pathogens (Basel, Switzerland) 2023;12:262. https://doi.org/10.3390/pathogens12020262

[86] Lee JWJ, Plichta D, Hogstrom L et al. Multi-omics reveal microbial determinants impacting responses to biologic therapies in inflammatory bowel disease. Cell Host Microbe 2021;29:1294304. e4. https://doi.org/10.1016/j.chom.2021.06.019

[87] Wang Y, Gao X, Zhang X et al. Microbial and metabolic features associated with outcome of infliximab therapy in pediatric Crohn's disease. Gut Microbes 2021;13:1-18. https://doi.org/10.1080/19490976.2020.1865708

[88] Chen L, Lu Z, Kang D et al. Distinct alterations of fecal microbiota refer to the efficacy of adalimumab in Crohn's disease. Front Pharmacol 2022;13:913720. https://doi.org/10.3389/fphar.2022.913720

[89] Blesl A, Wurm P, Waschina S et al. Prediction of response to systemic corticosteroids in active UC by microbial composition-A prospective multicenter study. Inflamm Bowel Dis 2024;30:9-19. https://doi.org/10.1093/ibd/izad126

[90] Palmieri O, Bossa F, Castellana S et al. Deciphering microbial composition in patients with inflammatory bowel disease: implications for therapeutic response to biologic agents. Microorganisms 2024;12:1260. https://doi.org/10.3390/microorganisms12071260

[91] Koh YC, Chang YC, Lin WS et al. Efficacy and mechanism of the action of live and heat-killed Bacillus coagulans BC198 as potential probiotic in ameliorating dextran sulfate sodiuminduced colitis in mice. ACS Omega 2024;9:10253-66. https://doi.org/10.1021/acsomega.3c07529

[92] Suez J, Zmora N, Segal E et al. The pros, cons, and many unknowns of probiotics. Nat Med 2019;25:716-29. https://doi.org/10.1038/s41591-019-0439-x

[93] Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease. J Allergy Clin Immunol 2020;145:1627. https://doi.org/10.1016/j.jaci.2019.11.003

[94] Zhang XF, Guan XX, Tang YJ et al. Clinical effects and gut microbiota changes of using probiotics, prebiotics or synbiotics in inflammatory bowel disease: a systematic review and metaanalysis. Eur J Nutr 2021;60:2855-75. https://doi.org/10.1007/s00394-021-02503-5

[95] Liang X, Dai N, Sheng K et al. Gut bacterial extracellular vesicles: important players in regulating intestinal microenvironment. Gut Microbes 2022;14:2134689. https://doi.org/10.1080/19490976.2022.2134689

[96] Ma L, Shen Q Lyu W et al. Clostridium butyricum and its derived extracellular vesicles modulate gut homeostasis and ameliorate acute experimental colitis. Microbiol Spectr 2022;10:e0136822. https://doi.org/10.1128/spectrum.013 68-22

[97] Martyniak A, Medyńska-Przęczek A, Wędrychowicz A et al. Prebiotics,probiotics, synbiotics, paraprobiotics and postbiotic compounds in IBD. Biomolecules 2021;11:1903. https://doi.org/10.3390/biom11121903

[98] Feng Z, Hua J, Guo F et al. A retrospective analysis of vitamin B6 deficiency and associated changes of gut microbes in Crohn's disease. Eur J Clin Nutr 2023;77:1034-43. https://doi.org/10.1038/s41430-023-01324-5

[99] Wu J, Huang H, Wang L et al. A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation. Gut Microbes 2024;16:2316575. https://doi.org/10.1080/19490976.2024.2316575

[100] Cao F, Jin L, Gao Y et al. Artificial-enzymes-armed bifidobacterium longum probiotics for alleviating intestinal inflammation and microbiota dysbiosis. Nat Nanotechnol 2023;18:617-27. https://doi.org/10.1038/s41565-023-01346-x

[101] Zhou J, Li M, Chen Q et al. Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective oral delivery. Nat Commun 2022;13:3432. https://doi.org/10.1038/s41467-022-31171-0

[102] Seida I, Al Shawaf M, Mahroum N. Fecal microbiota transplantation in autoimmune diseases-an extensive paper on a pathogenetic therapy. Autoimmun Rev 2024;23:103541. https://doi.org/10.1016/j.autrev.2024.103541

[103] Haneishi Y, Furuya Y, Hasegawa M et al. Inflammatory bowel diseases and gut microbiota. Int J Mol Sci 2023;24:3817. https://doi.org/10.3390/ijms24043817

[104] Li G, Wu X, Gao X et al. Long-term exclusive enteral nutrition remodels the gut microbiota and alleviates TNBS-induced colitis in mice. Food & Function 2022;13:1725-40. https://doi.org/10.1039/d1fo03579g

[105] Sugihara K, Kamada N. Diet-microbiota interactions in inflammatory bowel disease. Nutrients 2021;13:1533. https://doi.org/10.3390/nu13051533