Schisantherin A alleviates non-alcoholic fatty liver disease by restoring intestinal barrier function

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is intricately linked to dysregulation of the gut–liver axis, and correlated with intestinal inflammation and barrier disruption. OBJECTIVES: To investigate the protective effects and possible molecular mechanism of Schisantherin A (Sin A) in a high-fat diet (HFD) induced NAFLD mouse model. METHODS: HFD-fed NAFLD mice were treated with the vehicle and 80 mg/kg Sin A every day for 6 weeks. The gut permeability of the NAFLD mice was assessed by intestinal permeability assays in vivo and transepithelial electrical resistance (TEER) measurements in vitro were also used to evaluate the function of the gut barrier. TLR4 inhibitor was then used to investigate the impact of Sin A in the LPS- TLR4 signaling pathway. Alternatively, the composition of the microbiome was assessed using 16S rRNA amplification. Finally, the experiment of antibiotic treatment was performed to elucidate the roles of the gut microbiome mediating Sin A induced metabolic benefits in the NAFLD mice. RESULTS: We found that Sin A potently ameliorated HFD-induced hepatic steatosis and inflammation, alleviated gut inflammation, and restored intestinal barrier function. We also observed that Sin A improved gut permeability and reduced the release of lipopolysaccharide (LPS) into circulation and further found that Sin A can suppress LPS-TLR4 signaling to protect against HFD-induced NAFLD. Sin A treatment altered the composition of the microbiome in NAFLD mice compared to vehicle controls. CONCLUSIONS: Sin A is an effective and safe hepatoprotective agent against HFD-induced NAFLD by partly ameliorating gut inflammation, restoring intestinal barrier function, and regulating intestinal microbiota composition.