Work

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

Year: 2025

Type: article

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.

Source: MedComm

DOI: 10.1002/mco2.70429