European Bilberry Extract Ameliorates Dietary Advanced Glycation End Products-Induced Non-Alcoholic Steatohepatitis in Rats via Gut Microbiota and Its Metabolites.

Background: Gut dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) caused by diets rich in advanced glycation end products (AGEs). European bilberry extract (EBE) exerts a regulatory effect on gut microbiota. Nevertheless, it is still unknown whether EBE influences NASH via gut microbiota and their metabolites. This study aimed to investigate the effects and underlying mechanisms of EBE on NASH caused by a long-term AGEs diet. Methods: Rats fed with a high-AGE diet were orally administered with EBE for 80 weeks, and NASH was measured. 16S rRNA analysis and targeted metabolomics were used to detect gut microbiota and SCFA, respectively. The hepatic expression of SCFA receptors and that of the HMGB1/RAGE/NF-κB signaling pathway were detected to investigate the possible molecular mechanism. Results: EBE reduced the accumulation of AGEs in the circulation and liver of high-AGE diet-fed rats. EBE also ameliorated impaired glucose tolerance and insulin sensitivity, liver inflammation, steatosis, fibrosis, and dysfunction in high-AGE-fed rats. EBE reshaped high-AGE diet-induced gut dysbiosis by increasing short-chain fatty acid (SCFA)-producing bacteria and SCFA levels and reducing deleterious bacteria. Mechanistically, EBE promoted the activation of GPR43 and inhibited the activation of downstream HDAC3 and HMGB1/RAGE/NF-κB signaling pathway in the liver of high-AGE diet-fed rats. Additionally, EBE decreased the levels of TNF-α, IL-1β, and IL-6 and increased the level of IL-10 in the liver of high-AGE diet-fed rats. Conclusions: EBE promoted the production of SCFA, which might engage with the GPR43 receptor and inhibited the activation of HDAC3 and HMGB1/RAGE/NF-κB signaling pathway, ultimately alleviating NASH caused by a high-AGE diet.