{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T14:20:27Z","timestamp":1788272427675,"version":"build-2803163510"},"reference-count":114,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Fibrosis is a common end-stage pathological change across multiple chronic organ injuries and a primary driver of global organ failure and high mortality. Accumulating evidence indicates that the gut microbiota and its metabolites can bidirectionally regulate fibrosis progression through the gut\u2013organ axis; however, a unified and systematic theoretical framework remains lacking. This review synthesizes evidence from six major organs\u2014the liver, biliary tract, intestine, lung, heart, and skin\u2014and proposes a \u201cshared core pathway\u2013organ-specific differentiation\u201d dual-layer theoretical framework for microbiota-mediated multiorgan fibrosis. In this shared layer, short-chain fatty acid signaling, the tryptophan\u2013AhR pathway, intestinal barrier disruption with microbial translocation, and bile acid metabolic disorders constitute the common metabolic\u2013immune basis across organs. Animal intervention studies, including germ-free colonization, metabolite reconstitution, and gene knockout experiments, have established the causal regulatory effects of these four pathways, whereas human cross-sectional and cohort studies can reveal only statistical associations between metabolites and fibrosis stage without establishing causality. At the specific layer, organs differ in their anatomical exposure patterns, resident cell types, and local microenvironments, leading to divergent responses to identical microbial signals and the formation of organ-specific signature pathways: the hepatobiliary system features the bile acid\/FXR axis as its core regulatory mechanism; the heart possesses a unique TMAO\u2013JAK2\u2013STAT3 profibrotic axis; the lung utilizes palmitoylethanolamide as a specific protective mediator; and the skin integrates circulating metabolic signals with Piezo1 mechanosensation to form a dual regulatory network. This dual-layer framework provides a unified explanation for the divergent effects of identical metabolites across organs, offering both theoretical support for broad-spectrum microbiota-based antifibrotic interventions and new perspectives for precision stratified diagnosis and treatment of fibrosis in individual organs. Future studies should move beyond observational research by leveraging large-scale prospective cohorts and standardized randomized controlled trials to complete causal validation, thereby translating microbiota-targeted strategies from animal-based mechanistic research into clinical practice for the precision prevention and treatment of multiorgan fibrosis.<\/jats:p>","DOI":"10.3389\/fmicb.2026.1893651","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:49:35Z","timestamp":1788270575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut microbiota-derived metabolites and host interactions in fibrotic diseases: mechanisms, cross-organ signatures, and therapeutic opportunities"],"prefix":"10.3389","volume":"17","author":[{"given":"Yang","family":"Pan","sequence":"first","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Shu","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Mei","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueping","family":"Qiu","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luo","family":"Fang","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s12876-024-03424-3","article-title":"The effect of probiotic supplementation on non-alcoholic fatty liver disease (NAFLD) fibrosis score in patients attending a tertiary hospital clinic in Cairo, Egypt: a randomized controlled trial","volume":"24","author":"Abd El Hamid","year":"2024","journal-title":"BMC Gastroenterol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.chom.2024.11.012","article-title":"Intestinal E. coli-produced yersiniabactin promotes pro-fibrotic macrophages in Crohn's disease","volume":"33","author":"Ahn","year":"2025","journal-title":"Cell Host Microbe"},{"key":"B3","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/j.jhep.2019.10.003","article-title":"The gut\u2013liver axis in liver disease: pathophysiological basis for therapy","volume":"72","author":"Albillos","year":"2020","journal-title":"J. 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