Am J Physiol Gastrointest Liver Physiol. 2022 Nov 21. doi: 10.1152/ajpgi.00112.2022. Online ahead of print
Background: Primary Sclerosing Cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes. Methods: FVB/NJ and Mdr2-/- mice were treated with control or ASBT Vivo-Morpholino. We measured (i) ASBT expression and MC presence in liver/ileum; (ii) liver damage/DR; (iii) hepatic fibrosis/inflammation; (iv) biliary inflammation/histamine serum content; and (v) intestinal permeability/hepatic bacterial translocation. TBA/BA composition was measured in cholangiocyte/hepatocyte supernatants, intestine, liver, serum, and feces. Shotgun analysis was performed to ascertain microbiome changes. In vitro, cholangiocytes were treated with BAs +/- ASBT Vivo-Morpholino and histamine content and FXR signaling were determined. Treated cholangiocytes were co-cultured with MCs, and FXR signaling, inflammation, and MC activation measured. Human patients were evaluated for ASBT/MC expression and histamine/TBA content in bile. Control patient- and PSC patient-derived 3D organoids were generated; ASBT, chymase, histamine, and fibroblast growth factor-19 (FGF19) were evaluated. Results: ASBT Vivo-Morpholino in Mdr2-/- mice decreased (i) biliary ASBT expression; (ii) PSC phenotypes; (iii) hepatic TBA; and (iv) intestinal permeability compared to control. We found alterations between WT and Mdr2-/- mice microbiome and ASBT/MC and bile histamine content increased in cholestatic patients. BA-stimulated cholangiocytes increased MC activation/FXR signaling via ASBT, and human PSC-derived 3D organoids secrete histamine/FGF19. Conclusion: Inhibition of hepatic ASBT ameliorates cholestatic phenotypes by reducing cholehepatic BA signaling, biliary inflammation and histamine levels. ASBT regulation of hepatic BA signaling offers a therapeutic avenue for PSC.
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