Cellular and molecular gastroenterology and hepatology · 2026
Microbial Monotherapy With Leuconostoc sp LB-P8 Improves Inflammation and Fibrosis in Mouse Primary Sclerosing Cholangitis by Inhibiting Transforming Growth Factor β1/SMAD Signaling.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Park Kihyoun, Kim Joon Yong, Roh Seong Woon, Savaliya Bansi P, Turner Carys A, Pirius Nicholas E, LaRusso Nicholas F, Song Kyoungsub, O'Hara Steven P
Аннотация
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: Human intestinal cells were cultured with or without LB-P8 to assess metabolite profiles (untargeted ultra-performance liquid chromatography-tandem mass spectrometry) and gene expression in co-cultured myofibroblasts and macrophages (reverse transcription-quantitative polymerase chain reaction). LB-P8 was orally gavaged following disease onset in three cholestatic models: bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, and the Mdr2-/- 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: Metabolomic profiling of LB-P8 cultures revealed increased detection of 10 metabolites involved in anti-fibrosis and anti-inflammation. RNA sequencing analysis of hepatic stellate cells showed downregulation of TGF-β, epithelial-mesenchymal transition (EMT,) and integrin signaling pathways. LB-P8 reduced liver fibrosis in BDL, DDC-fed, and Mdr2-/- mouse models as evident by ∼50% lower Picrosirius red staining and decreased expression of Col1a1 and Timp1. In Mdr2-/- 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.
METHODS: Human intestinal cells were cultured with or without LB-P8 to assess metabolite profiles (untargeted ultra-performance liquid chromatography-tandem mass spectrometry) and gene expression in co-cultured myofibroblasts and macrophages (reverse transcription-quantitative polymerase chain reaction). LB-P8 was orally gavaged following disease onset in three cholestatic models: bile duct ligation (BDL), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding, and the Mdr2-/- 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: Metabolomic profiling of LB-P8 cultures revealed increased detection of 10 metabolites involved in anti-fibrosis and anti-inflammation. RNA sequencing analysis of hepatic stellate cells showed downregulation of TGF-β, epithelial-mesenchymal transition (EMT,) and integrin signaling pathways. LB-P8 reduced liver fibrosis in BDL, DDC-fed, and Mdr2-/- mouse models as evident by ∼50% lower Picrosirius red staining and decreased expression of Col1a1 and Timp1. In Mdr2-/- 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.