Disruption of Bile Acid Metabolism in the Gut–Liver Axis Predisposes Mice to Inflammatory Bowel Disease

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is frequently associated with inflammatory bowel disease (IBD). 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-diethoxycarbonyl 1,4-dihydrocollidine) diet. We then demonstrated that eSC mice exhibited increased susceptibility to DSS-induced colitis, accompanied by severe intestinal pathology. Further integrated analyses revealed that eSC disrupted bile acid metabolism and gut microbiota composition, notably increasing Th17-inducing bacteria and altering bile acid profiles. Single-cell and bulk RNA-seq 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-Oxo-5β-cholanoic acid (3-O-LCA), 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-O-LCA modulate macrophage polarization and Th17 differentiation via FXR. These findings highlight the central role of the gut–liver axis, bile acid signaling, and Th17 responses in PSC–IBD pathogenesis, and suggest that targeting bile acid metabolism offers a promising therapeutic strategy. This work advances our understanding of PSC–IBD and provides a foundation for novel interventions in high-risk patients.

Keywords

primary sclerosing cholangitis / bile acid / gut–liver axis / immune cell homeostasis / susceptibility to IBD

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