Gut-derived Klebsiella pneumoniae in primary biliary cholangitis patients translocates to liver and induces hepatic inflammation

Although gut dysbiosis is recognized as a key environmental factor, the mechanisms by which specific members of the microbiota drive primary biliary cholangitis (PBC) progression by impacting hepatic immunity and metabolism remains incompletely understood. We established a PBC-fecal microbiota transplantation (FMT) mouse model by fecal transplantation. Liver injury and gut barrier integrity were assessed using serological, histological, and molecular metrics. The microbiota was analyzed by 16 S rDNA sequencing, and K. pneumoniae was tracked by culture, fluorescence in situ hybridization (FISH), and PCR. Spearman correlation analysis was used to evaluate microbiota-clinical correlations and profile the hepatic transcriptome via RNA-seq. K. pneumoniae pathogenicity was tested by mono-colonization, and the effect of metronidazole was evaluated in the PBC-FMT model. PBC-FMT successfully induced cholestatic liver injury, anti-mitochondrial antibody production, and pericholangitis in mice. Model mice exhibited altered gut microbiota composition, characterized by reduced beneficial bacteria, enrichment of potentially pathogenic bacteria (e.g., Bacteroides and Aeromonas ), and intestinal barrier damage. Liver RNA-seq revealed a significant activation of immune-inflammatory pathways and suppression of various metabolic pathways in the PBC-FMT group. K. pneumoniae colonization was detected in the livers of both model mice and patients with PBC, and its abundance was positively correlated with liver function indices. Mono-colonization experiments confirmed that K. pneumoniae can disrupt the intestinal barrier, translocate to the liver, and induce liver injury and metabolic pathway disturbances. Metronidazole (MNZ) intervention partially alleviated liver injury in PBC-FMT mice and reversed some transcriptional pathways related to K. pneumoniae . Gut microbiota from patients with PBC can drive PBC-like liver injury, with gut-liver translocation of K. pneumoniae constituting an important event. This bacterium likely contributes to disease progression by impairing metabolic functions such as bile acid metabolism.