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<p>Primary sclerosing cholangitis (PSC) represents the prototypical disorder of the gut–liver axis, characterized by complex interactions among bile acids, the intestinal microbiome, and immune regulation. Dysbiosis and disruption of the enterohepatic circulation alter the bile acid composition, impair farnesoid X receptor (FXR)- and Takeda&#xa0;G protein-coupled receptor 5 (TGR5)-mediated signaling and promote inflammatory and fibrogenic processes within the liver. The close association with ulcerative colitis, observed in up to 80% of patients with PSC, underscores the relevance of mucosal immune–microbial interactions in disease pathogenesis. Clinically, disease progression is primarily driven by strictures of the large bile ducts, whereas an exclusively intrahepatic variant generally follows a&#xa0;more favorable course. Regular surveillance and endoscopic management of dominant strictures have shown to improve outcomes. Modulation of the bile acid pool constitutes a&#xa0;central therapeutic strategy. Ursodeoxycholic acid (UDCA) at moderate doses can improve biochemical surrogate markers, although it has not shown to prolong transplant-free survival. Norucholic acid (NCA) demonstrated significant improvements in cholestatic parameters and liver histology in a&#xa0;phase&#xa0;III trial and is currently under regulatory review. In parallel, microbiome-targeted interventions, including fecal microbiota transplantation (FMT) and antibiotic therapy, are emerging as novel approaches, though their long-term efficacy and safety remain to be determined. Nuclear receptor-directed therapies also show promise: FXR and peroxisome proliferator-activated receptor (PPAR) agonists improve hepatic biochemistry in clinical trials, while ileal bile acid transporter (iBAT) inhibitors effectively reduce cholestasis-associated pruritus. In conclusion, PSC remains a&#xa0;heterogeneous cholestatic liver disease with substantial unmet therapeutic need. Targeted modulation of the gut–liver axis through interventions affecting bile acid metabolism, the intestinal microbiome, and nuclear receptor signaling offer promising therapeutic avenues that are currently being evaluated in advanced clinical trials.</p>

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Die primär sklerosierende Cholangitis als cholestatische Lebererkrankung und Modellerkrankung einer gestörten Darm-Leber-Achse

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Philipp Dignus,
  • Jörg Albert,
  • Jan G. Hengstler,
  • Christian Trautwein

摘要

Primary sclerosing cholangitis (PSC) represents the prototypical disorder of the gut–liver axis, characterized by complex interactions among bile acids, the intestinal microbiome, and immune regulation. Dysbiosis and disruption of the enterohepatic circulation alter the bile acid composition, impair farnesoid X receptor (FXR)- and Takeda G protein-coupled receptor 5 (TGR5)-mediated signaling and promote inflammatory and fibrogenic processes within the liver. The close association with ulcerative colitis, observed in up to 80% of patients with PSC, underscores the relevance of mucosal immune–microbial interactions in disease pathogenesis. Clinically, disease progression is primarily driven by strictures of the large bile ducts, whereas an exclusively intrahepatic variant generally follows a more favorable course. Regular surveillance and endoscopic management of dominant strictures have shown to improve outcomes. Modulation of the bile acid pool constitutes a central therapeutic strategy. Ursodeoxycholic acid (UDCA) at moderate doses can improve biochemical surrogate markers, although it has not shown to prolong transplant-free survival. Norucholic acid (NCA) demonstrated significant improvements in cholestatic parameters and liver histology in a phase III trial and is currently under regulatory review. In parallel, microbiome-targeted interventions, including fecal microbiota transplantation (FMT) and antibiotic therapy, are emerging as novel approaches, though their long-term efficacy and safety remain to be determined. Nuclear receptor-directed therapies also show promise: FXR and peroxisome proliferator-activated receptor (PPAR) agonists improve hepatic biochemistry in clinical trials, while ileal bile acid transporter (iBAT) inhibitors effectively reduce cholestasis-associated pruritus. In conclusion, PSC remains a heterogeneous cholestatic liver disease with substantial unmet therapeutic need. Targeted modulation of the gut–liver axis through interventions affecting bile acid metabolism, the intestinal microbiome, and nuclear receptor signaling offer promising therapeutic avenues that are currently being evaluated in advanced clinical trials.