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However, the precise mechanisms linking these conditions remain unclear. In this study, we established a murine model of experimental sclerosing cholangitis (eSC) using a DDC (3,5\u2010diethoxycarbonyl 1,4\u2010dihydrocollidine) diet. We then demonstrated that eSC mice exhibited increased susceptibility to DSS\u2010induced colitis, accompanied by severe intestinal pathology. Further integrated analyses revealed that eSC disrupted bile acid metabolism and gut microbiota composition, notably increasing Th17\u2010inducing bacteria and altering bile acid profiles. Single\u2010cell and bulk RNA\u2010seq analyses identified a marked expansion of colonic Th17 cells and a loss of immune homeostasis in eSC mice. Therapeutically, rectal administration of lithocholic acid (LCA) and its derivative, 3\u2010Oxo\u20105\u03b2\u2010cholanoic acid (3\u2010O\u2010LCA), was found to restore farnesoid X receptor (FXR) signaling, reduce Th17 cell proportions, and alleviate liver and intestinal injury. Mechanistic studies show that LCA and 3\u2010O\u2010LCA modulate macrophage polarization and Th17 differentiation via FXR. These findings highlight the central role of the gut\u2013liver axis, bile acid signaling, and Th17 responses in PSC\u2013IBD pathogenesis, and suggest that targeting bile acid metabolism offers a promising therapeutic strategy. This work advances our understanding of PSC\u2013IBD and provides a foundation for novel interventions in high\u2010risk patients.<\/jats:p>","DOI":"10.1002\/mco2.70429","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T07:38:37Z","timestamp":1759995517000},"source":"Crossref","is-referenced-by-count":8,"title":["Disruption of Bile Acid Metabolism in the Gut\u2013Liver Axis Predisposes Mice to Inflammatory Bowel Disease"],"prefix":"10.1002","volume":"6","author":[{"given":"Hui","family":"Chang","sequence":"first","affiliation":[{"name":"College of Life Sciences and Department of Genetic and Metabolic Disease The Children's Hospital Zhejiang University School of Medicine National Clinical Research Center for Child Health Zhejiang University Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Life Sciences and Department of Genetic and 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