Probiotic Lactobacillus rhamnosus mitigates ductular reaction in Mcpip1-deficient mice via modulation of gut-liver crosstalk
Primary biliary cholangitis (PBC), a chronic autoimmune liver disease characterized by progressive cholestasis and biliary destruction, remains incompletely understood in its pathogenesis, particularly regarding the interplay between gut dysbiosis, immune dysregulation, and hepatic injury. Current therapies, including ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), exhibit limited efficacy in advanced disease, necessitating novel therapeutic strategies targeting the gut-liver axis. Here, we investigate the therapeutic potential of Lactobacillus rhamnosus (Lbr) in a murine model of PBC using Mcpip1fl/flAlbCre mice, which develop autoimmune cholangitis due to liver-specific deletion of the Zc3h12a gene (encoding Mcpip1), recapitulating human PBC features such as bile acid dysregulation, autoantibodies, cholangiocyte hyperplasia and fibrosis.Six-week-old male Mcpip1fl/fl (wild-type) and Mcpip1fl/flAlbCre (knockout) mice were randomized into five treatment groups for six weeks: (1) corn oil (control), (2) Lbr, (3) UDCA, (4) UDCA + Lbr, and (5) UDCA + OCA. Liver and gut pathology, serum biomarkers, transcriptomic profiles, and microbiome composition were analyzed post-treatment.Control knockout mice exhibited severe cholangiocyte proliferation, fibrosis, elevated serum total IgM, bile acids, and anti-PDC-E2 autoantibodies, alongside gut pathology marked by intraepithelial lymphocyte infiltration and mucosal hypertrophy. NGS of liver tissue revealed enrichment of humoral immune responses and T cell activation pathways in knockouts, all of which were significantly attenuated by Lbr monotherapy. Lbr treatment also restored gut architecture, reduced inflammation, and modulated the microbiome, increasing the Firmicutes/Bacteroidetes ratio and enriching butyrate-producing Lachnospiraceae. While UDCA and UDCA+OCA improved cholestasis, Lbr uniquely ameliorated both hepatic and intestinal pathology, suggesting gut-microbiome-immune crosstalk as a pivotal disease mechanism.This study demonstrates that probiotic intervention with Lbr disrupts the gut-liver axis-driven vicious cycle in PBC, attenuating autoimmune and fibrotic progression. These findings highlight microbiome modulation as a promising adjunctive therapy for cholestatic liver diseases.