From gene to function: unraveling the BSH1-mediated mechanism of Lactobacillus in alleviating intrahepatic cholestasis

Intrahepatic cholestasis is associated with gut microbiota dysbiosis and excessive accumulation of bile acids (BAs). Bile salt hydrolase (BSH)–mediated deconjugation represents the first and rate-limiting step of microbial BA metabolism, and distinct BSH subtypes exhibit markedly different enzymatic activities and substrate preferences. Through comparative genomic analysis, we identified and genetically subtyped BSH-harboring Lactobacillus strains. In vitro bile salt co-culture assays demonstrated that BSH activity was determined by genotype rather than gene copy number, with BSH1-encoding strains showing significantly higher activity. In vivo, BSH1-positive strains markedly reduced serum liver enzymes and TBAs, alleviating liver injury in cholestatic mice, whereas BSH1-deficient strains showed minimal effects. Lactiplantibacillus plantarum CCFM242 exhibited the strongest therapeutic efficacy, which was completely abolished by BSH1 knockout. Mechanistically, BSH1 reshaped gut microbiota composition, increased Bacillota abundance, regulated BA profiles, modulated the FXR–FGF15 axis, enhanced hepatic BSEP expression to promote BA excretion, and suppressed ileal ASBT expression to reduce BA reabsorption, thereby facilitating fecal BA elimination. Consistently, metagenomic analysis of fecal samples from patients with intrahepatic cholestasis of pregnancy revealed reduced Bacillota and BSH abundance, with a BSH1-homologous protein enriched in healthy controls. These findings highlight the central role of BSH1 in maintaining BA homeostasis globally.