284P - Gut microbiota mediates the protective effects of resveratrol against the intestinal barrier dysfunction in non-alcoholic steatohepatitis induced by high-fat diet

Background

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally. We investigate the ameliorative effects of resveratrol (RSV) in a high fat diet (HFD)-induced NASH rat model, focusing on the gut microbiota and cannabinoid receptor type 1 (CB1) in the maintenance of gut barrier integrity.

Methods

Male Sprague Dawley (SD) rats were fed HFD with or without RSV for 6 weeks. For the depletion of gut microbiota test, the rats were subjected to HFD with or without RSV for 6 weeks, followed by an administration of broad-spectrum antibiotic cocktail solution for 4 weeks. For the study of the CB1 function in vivo, the rats were fed HFD with RSV for 6 weeks, followed by the administration with the CB1 agonist ACEA (1 mg/kg·day) or vehicle, intraperitoneally for an additional 4 weeks. We characterised the gut microbiota by 16s rRNA gene sequencing, lipopolysaccharide measurements and phylogenetic reconstruction of unobserved states (PICRUSt) analysis.

Results

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 CB1 mRNA in the colon. The RSV-induced benefits regarding enhanced gut barrier integrity and reduced intestinal permeability were abrogated with a CB1 agonist, ACEA. Moreover, microbiota depletion using a cocktail of antibiotics was sufficient to block RSV-induced reduction in intestinal permeability, as well as the altered mRNA expressions of CB1 in the distal colon.

Conclusions

These data indicate that the expressions of CB1, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.