Vancomycin enriches Parabacteroides goldsteinii in the gut and promotes reconstruction of the hepatobiliary system in cholestasis

Abstract

Impaired bile secretion disrupts the gut microbiome and perpetuates cholestatic liver injury. Vancomycin (VCM) has been shown to improve cholestasis in human patients, but its biological effects remain unclear. This study aimed to investigate the therapeutic effects of VCM on microbiome modulation and the restoration of liver function. VCM was administered in a modified Abcb11 knockout (KO) mice model with pre‐existing cholestasis to examine its therapeutic effects and microbiome changes. After 2 weeks of treatment, VCM significantly decreased serum bilirubin while maintaining stable transaminase in the KO mice. Three‐dimensional imaging of pan‐CK expression by immunofluorescence revealed improvement of the disrupted biliary epithelium and interconnected bile duct network, as evidenced by increased coverage and cumulative duct length in the liver. Gene expression and hepatic bile acid profiling demonstrated that VCM enhanced canalicular/sinusoidal bile acid export while repressing bile acid synthesis, with a reduction in tauro‐β‐muricholic acid, the predominant bile acid in mice, in KO livers. Fecal microbial analysis using next‐generation sequencing identified Parabacteroides goldsteinii (PG) as the predominant species after VCM treatment. KO mice fed PG demonstrated improved cholestasis, with significantly reduced direct bilirubin, alkaline phosphatase, total bile acids in serum, as well as fewer reactive ductules in the liver. In vitro culture of ductal organoids suggested that PG directly promoted the growth of cholangiocytes. RNA sequencing results suggested that PG suppressed pro‐inflammatory Lyz1 (mouse orthologous gene of human LYZ) and Aqp4 and increased pro‐proliferative Muc6 and Chrm3. This study highlights the therapeutic potential of VCM in cholestasis by enriching PG in the gut and improving biliary structures in the liver, identifying PG as a potential probiotic with beneficial effects in cholestasis. © 2026 The Pathological Society of Great Britain and Ireland.