Capsaicin ameliorates cholestasis through modulation of the FXR-SHP and FXR-FGF15 gut-liver axis in mice

BACKGROUND: Cholestasis, including primary sclerosing cholangitis (PSC), remains a challenging condition with limited treatment options. The gut-liver axis and FXR signaling pathways play critical roles in maintaining bile acid homeostasis and preventing liver injury. Capsaicin, a natural compound with anti-inflammatory properties, has the potential to modulate these pathways and offer therapeutic benefits for cholestasis. PURPOSE: In this study, capsaicin-loaded nanoparticles were developed and evaluated in a PSC mouse model to investigate the therapeutic effects and underlying mechanisms of action. METHODS: Capsaicin-loaded nanoparticles (CAP@NPs) were synthesized via a solvent evaporation method and thoroughly characterized. Using a DDC-induced primary sclerosing cholangitis (PSC) mouse model, we evaluated their therapeutic effects on liver injury through serum biochemistry and histopathology. TRPV1 expression in fibrotic liver tissue was assessed via qRT-PCR, immunohistochemistry, and immunofluorescence. Inflammation, immune responses, and fibrosis were analyzed using molecular, histological, and cytometric techniques. Effects on bile acid metabolism were investigated by profiling hepatic and ileal gene expression, while gut microbiota shifts and colon injury markers were examined to elucidate underlying mechanisms. Biosafety was confirmed by hematological and pathological assessments. RESULTS: Our findings revealed that administration of CAP@NPs attenuated liver injury, inflammation, fibrosis, and bile duct hyperplasia. Mechanistically, CAP@NPs activated hepatic FXR-SHP and ileal FXR-FGF15 pathways to suppress Cyp7A1 expression, modulated gut microbiota composition (increased Clostridia, decreased Bacteroidia), enhanced intestinal barrier integrity, and reduced endotoxin translocation. CONCLUSION: This study represents a novel approach to treating cholestasis through targeted modulation of bile acid metabolism and inflammatory pathways, offering hope for new therapeutic strategies in liver disease.