Probiotic Lactobacillus rhamnosus mitigates PBC-like features in Mcpip1-deficient mice via modulation of gut-liver crosstalk.

Abstract

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive biliary destruction and cholestasis. Current therapies, including ursodeoxycholic acid (UDCA), exhibit limited efficacy in advanced disease. In this study, we investigate the therapeutic potential of microbial intervention using Lactobacillus rhamnosus (Lbr) in the Mcpip1Albknockout mouse model of PBC, which we described previously. Knockout mice develop human PBC-like features such as bile acid dysregulation, autoantibodies, cholangiocyte hyperplasia and fibrosis. METHODS: Six-week-old Mcpip1(wild-type) and Mcpip1Alb(knockout) mice were treated with Lactobacillus rhamnosus supplementation, UDCA (15 mg/kg/day), UDCA + Lbr, and UDCA + OCA (obeticholic acid, 10 mg/kg/day) for six weeks. Treatment response was characterized by liver and gut pathology, serum biomarkers, transcriptomic profiles, and microbiome composition. RESULTS: Treatment of Mcpip1Albanimals with Lbr decreased serum bile acids and reduced pathological cholangiocyte dysplasia in the liver, decreased leukocyte infiltration and fibrosis. RNAseq 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. Gut pathology marked by increased intraepithelial lymphocyte infiltration and mucosal hypertrophy, was also normalized upon Lbr administration. Finally, probiotic treatment modulated the microbiome by increasing the Firmicutes/Bacteroidetes ratio and enriching butyrate-producing Lachnospiraceae. Administration of UDCA and UDCA+OCA had less pronounced effects: only decreased serum bile acids was detected in both groups. CONCLUSIONS: Probiotic intervention with Lbr represents a feasible strategy to attenuate fibrotic progression in a mouse model of autoimmune cholestatic disease by modulation of the gut-microbiome-immune crosstalk.