Microbial Monotherapy With Leuconostoc sp LB-P8 Improves Inflammation and Fibrosis in Mouse Primary Sclerosing Cholangitis by Inhibiting Transforming Growth Factor β1/SMAD Signaling

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a prototypical disease with an impaired gut-liver axis, frequently associated with inflammatory bowel disease, and linked to microbial dysbiosis. However, how microbes influence PSC progression remains unclear. We identified a novel L sp. (LB-P8) with potential anti-fibrotic properties via inhibition of transforming growth factor beta-1 (TGF-β)/SMAD signaling and investigated its therapeutic efficacy and mechanisms in mouse PSC models. METHODS: mouse. Hepatic injury, inflammation, and fibrosis were assessed by serum alanine aminotransferase and alkaline phosphatase, histology, immunofluorescence, Picrosirius red staining, and reverse transcription-quantitative polymerase chain reaction. Nanostring GeoMX spatial transcriptomic analysis was performed on DDC-fed liver. LB-P8 was also tested in dextran sodium sulfate (DSS)-induced colitis. RESULTS: and DDC-fed mice, LB-P8 reduced periportal macrophage number (F4/80; ∼30%). GeoMX spatial transcriptomics revealed reduced TGF-β1 in cholangiocyte and myofibroblast regions. Finally, LB-P8 suppressed expression of colonic markers of inflammation and fibrosis in the DSS model of bowel injury. CONCLUSIONS: LB-P8 ameliorates cholestatic liver disease progression by reducing TGF-β-mediated fibroblast activation, and periportal accumulation of macrophages. Targeting the gut-liver axis with LB-P8 may represent a novel therapeutic strategy for PSC.