{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:23:01Z","timestamp":1787678581091,"version":"build-2784847793"},"reference-count":233,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010265","name":"Guizhou Medical University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Inflammatory bowel disease (IBD), comprising Crohn\u2019s disease (CD) and ulcerative colitis (UC), arises from complex interactions among host susceptibility, microbial dysbiosis, altered metabolite profiles, and dysregulated mucosal immune responses. Interleukin-22 (IL-22), a cytokine that acts primarily on non-hematopoietic cells, contributes to epithelial antimicrobial defense, survival, and tissue repair, but may also amplify inflammation under specific chronic or co-inflammatory conditions. This review evaluates the evidence linking major microbiota-associated metabolites\u2014including short-chain fatty acids (SCFAs), bile acids (BAs), tryptophan (Trp) -derived metabolites, and the trimethylamine (TMA)\/trimethylamine N-oxide (TMAO) pathway\u2014to IL-22 production, bioavailability, and function in IBD. Relatively direct mechanistic support is available for SCFA-mediated and Trp-Aryl hydrocarbon receptor (AhR) -dependent regulation of IL-22, whereas bile acid effects appear metabolite-, receptor-, and context-dependent. In contrast, the proposed relationship between TMA\/TMAO and IL-22 is currently supported mainly by indirect evidence and should be considered an emerging hypothesis. We further incorporate IL-22-binding protein (IL-22BP) as a determinant of local IL-22 bioavailability and distinguish upstream regulation of IL-22 production from downstream signaling initiated through the epithelial IL-22R1\/IL-10R2 receptor complex. Particular attention is given to canonical JAK1\/TYK2-STAT3 signaling and its context-dependent interactions with NF-\u03baB, PI3K-AKT-mTOR, and MAPK pathways. We propose that the duration and magnitude of IL-22 exposure, its cellular source, the IL-22\/IL-22BP balance, epithelial target-cell state, concurrent inflammatory signals, and disease context collectively determine whether IL-22 promotes mucosal repair or contributes to inflammatory amplification. By separating established mechanisms from associative, extrapolated, and hypothesis-generating evidence, this review provides a more evidence-calibrated framework for investigating the microbiota-metabolite-IL-22 network in UC and CD.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1891172","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:48:40Z","timestamp":1787676520000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut microbiota-derived metabolites and IL-22 signaling in inflammatory bowel disease: context-dependent regulation of mucosal repair and inflammation"],"prefix":"10.3389","volume":"17","author":[{"given":"Peixin","family":"Shi","sequence":"first","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weisong","family":"Pan","sequence":"additional","affiliation":[{"name":"Wuhan Institute for Drug and Medical Device Control","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingmei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of 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