Clostridial-dominated gut microbiota promotes 7α-dehydroxylation of obeticholic acid to lithocholic acid in cholestasis treatment.

Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist used in the treatment of liver diseases associated with cholestasis, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). However, its clinical utility is limited by dose-dependent hepatotoxicity, and the precise mechanism underlying OCA toxicity remains unclear. In this study, we investigated the mechanistic link between cholestasis-induced gut dysbiosis and OCA-associated hepatotoxicity. Cholestasis induces a significant shift in the gut microbiota composition, leading to a dysbiotic state dominated by the genera Clostridium, Bacteroides, and Lactobacillus. Crucially, the upregulation of bile acid inducible (bai) operon-encoded 7α-dehydroxylase in gut microbiota potently drives the metabolic conversion of OCA to lithocholic acid (LCA), a highly hepatotoxic secondary bile acid. This accelerated biotransformation of OCA to LCA provides a mechanistic explanation for the dose-dependent hepatotoxicity observed with OCA treatment, thereby elucidating the underlying cause of OCA-induced liver injury. These findings establish a direct causal link between cholestasis-driven gut dysbiosis, enhanced microbial 7α-dehydroxylation, and the bioactivation of OCA to its toxic metabolite, LCA. Consequently, this study underscores the gut microbiome as a critical determinant governing both the therapeutic efficacy and the adverse toxicity profile of bile acid-based therapeutics like OCA. Importantly, the results suggest that targeted modulation of the gut microbiota composition represent promising therapeutic strategies to mitigate OCA-associated hepatotoxicity and improve its clinical safety profile.