Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system

Background & aims This study aims to investigate the ameliorative effects of resveratrol (RSV) in a high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) rat model, focusing on the gut endocannabinoid system (ECS), regulated by RSV, in the maintenance of gut barrier integrity and inhibition of gut inflammation. Methods and results Male Sprague–Dawley (SD) rats were fed HFD with or without RSV for 6 weeks. The HFD caused increase in body weight, liver index, hepatic lipid accumulation, and inflammation, which was inhibited by RSV. RSV also attenuated gut microbial dysbiosis, with an increase in Akkermansia muciniphila, Ruminococcaceae, and Lachnospiraceae, and a decrease in Desulfovibrio. Moreover, RSV led to a reduction of metabolic endotoxemia and colon inflammation in HFD-fed rats. This was indicated by a decrease in bacterial invasion and translocation along with up-regulation of the mRNA levels of occludin, ZO1, claudin1, and down-regulation of FAK, MyD88, and IRAK4 in the distal colon. Furthermore, RSV inhibited HFD-induced elevation in the expression of cannabinoid receptor type 1 (CB1) mRNA and suppressed CB2 mRNA levels in the colon. The RSV-induced benefits regarding enhanced gut barrier integrity and reduced intestinal permeability were abrogated with a CB1 agonist, ACEA, whereas the inhibitory effect of RSV on the intestinal inflammation was abolished by a CB2 antagonist, AM630. Moreover, microbiota depletion using a cocktail of antibiotics was sufficient to block RSV-induced reduction in intestinal permeability and gut inflammation, as well as the altered mRNA expressions of CB1 and CB2 in the distal colon. Conclusions These data indicate that the ECS, particularly the expressions of CB1 and CB2, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation.