Microbiota-Driven Gut–Liver Axis Dysregulation in Primary Sclerosing Cholangitis–Ulcerative Colitis Comorbidity: A Narrative Review

Primary sclerosing cholangitis (PSC) often coexists with inflammatory bowel disease (IBD), especially ulcerative colitis (UC). PSC-UC differs clinically from PSC or UC alone, with right-sided colonic predominance, relative rectal sparing, increased risk of colorectal neoplasia, and liver transplantation intestinal inflammation recurrence. The existing microbiota, bile acid, and immune studies have been mostly derived from mixed PSC-IBD cohorts; direct PSC-UC data remain limited. We propose a working model in which PSC is associated with reduced α-diversity, enrichment of proinflammatory and oral-derived bacteria, and depletion of butyrate-producing and putative protective commensals; IBD further modifies the mucosal niche. Direct PSC-UC evidence remains limited; most mechanistic inferences are derived from mixed PSC-IBD cohorts, PSC-only studies, and experimental models. Evidence from mixed PSC-IBD and limited PSC-UC studies suggests in the ileum, ascending colon and rectum and are linked to local immune and epithelial reprogramming. Experimental and translational evidence suggests that bacterial translocation and outer membrane vesicles activate TLR4-NLRP3-GSDMD-IL-1β; the monocyte-IL-1β-Th17 axis, IL-17/IL-22 signaling, Treg/Th17 imbalance, epithelial stem cell reprogramming, and MAdCAM-1/CCL25/VAP-1-dependent aberrant lymphocyte homing connect dysbiosis to biliary inflammation and fibrosis. Direct PSC-UC causal evidence remains limited. Bile acid–microbiota interactions, including FXR/TGR5 signaling, altered primary/secondary bile acid ratios, and immunomodulatory metabolites (DCA, LCA, 3-oxoLCA, and isoalloLCA), form a positive feedback loop amplifying pathology. Thus, PSC-UC is a gut-liver axis ecotype dominated by PSC, modified by IBD, amplified by spatial heterogeneity, and driven by bile acid–microbiota–immune feedback; treatment should shift from single-disease extrapolation to comorbidity-specific stratified intervention. In this review, evidence is categorized as: (i) direct PSC-UC evidence from cohorts that explicitly report UC subtype; (ii) mixed PSC-IBD evidence, in which UC is predominant but not fully stratified; (iii) PSC-only evidence; and (iv) experimental model evidence. When direct PSC-UC data are unavailable, conclusions are explicitly labeled as extrapolated from mixed PSC-IBD or PSC-only studies.