Speaker
Description
Background: Cholestasis is a clinical syndrome of toxic bile acid accumulation due to impaired bile flow, categorized as intrahepatic or extrahepatic, with limited treatment options. Emerging evidence implicates gut microbiota dysregulation in cholestatic liver disease, although its precise mechanistic role remains unclear.
Methods: Intrahepatic and extrahepatic cholestasis models were established in C57BL/6 mice and subjected to gut microbiota intervention with an antibiotic cocktail (vancomycin, neomycin sulfate, metronidazole and ampicillin) or individual antibiotics. The effects and mechanisms of antibiotic treatment were evaluated by biochemical and histological assessments combined with multi-omics analyses.
Results: Treatment with an antibiotic cocktail or individual antibiotics alleviated intrahepatic cholestasis but exacerbated extrahepatic cholestasis in mice. Antibiotic treatment markedly altered the profile of bile acid and gut microbiota in intrahepatic cholestasis mice. Among these changes, Prevotella melaninogenica (P. melaninogenica) and taurodeoxycholic acid (TDCA) were identified as potential factors that aggravate intrahepatic cholestasis. Mechanistically, we found that antibiotic treatment inhibited STAT3 activation in hepatic stellate cells, thereby alleviating liver fibrosis and inflammation, which are key pathological drivers of disease progression in cholestasis.
Conclusion: This study demonstrates that antibiotics exert opposing effects on intrahepatic and extrahepatic cholestasis. Our results highlight the critical role of the gut–liver axis in cholestatic liver disease and suggest that interventions targeting the intestinal microbiota may represent a promising therapeutic strategy.
