L6H21 stabilizing gut barrier improves EtOH-LPS-induced hepatic steatosis and injury in mice.

This study aimed to investigate the role of (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21) in alcoholic liver disease (ALD) by considering the connection among alcohol intake, gut microbiota-related intestinal endothelial barrier dysfunction, and ALD. Male C57BL/6J mice (8 weeks old) were randomly assigned to 8 experimental groups (n = 5/group), including those fed a control isocaloric liquid diet (Control), a Lieber-DeCarli liquid alcohol diet with 5% ethanol (EtOH group), and mice in the EtOH + LPS group or LPS group receiving LPS on Day 10. Other four groups (L6H21 group, LPS + L6H21 group, EtOH + L6H21 group, EtOH + LPS + L6H21 group) received L6H21 treatment at 10 mg/kg body weight/day via oral gavage starting from the experiment's onset. Histological analysis (liver and ileum) and biochemical assays (serum and hepatic tissues) were performed in mice, while real-time PCR, Western blots, and immunofluorescence staining were used to investigate underlying mechanisms. In mice, EtOH-LPS induction led to significant increases in hepatic steatosis, hepatic inflammation, and serum ALT and AST levels. L6H21 treatment significantly reversed these changes. Furthermore, L6H21 treatment also reduced serum total cholesterol and hepatic triglyceride levels. In the intestine, L6H21 suppressed alcohol- and LPS-induced mucosal lesions and bacterial translocation, restored tight junction protein function, inhibited inflammation, and attenuated ROS production. L6H21 represents a promising therapeutic candidate for the intervention of ALD.