Ethyl Gallate Ameliorates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Suppressing Inflammation and Modulating the Gut Microbiota-Intestinal Barrier Axis

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder with rising global prevalence, yet effective therapeutic options remain limited. Chronic inflammation and gut microbiota dysbiosis are key contributors to NAFLD progression. Ethyl gallate (EG), a natural polyphenolic compound, exhibits anti-inflammatory and antioxidant properties. However, its therapeutic potential and underlying mechanisms in NAFLD remain unclear. This study aimed to evaluate the effects of EG in a high-fat diet (HFD)-induced NAFLD mouse model. Mice were fed an HFD for 12 weeks, with EG administered (10 or 20 mg/kg) from week 3 to week 12. The impact of EG was assessed through histopathological examination, serum biochemical analysis, glucose tolerance and insulin sensitivity tests, hepatic and systemic pro-inflammatory cytokine measurements, 16 S rRNA gene sequencing and intestinal tight junction protein evaluation. EG treatment markedly alleviated hepatic steatosis, improved serum lipid profiles, and enhanced glucose tolerance and insulin sensitivity. Moreover, EG significantly reduced hepatic and systemic levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. Gut microbiota analysis revealed that EG reversed HFD-induced increases in Firmicutes and Actinobacteria and the reduction in Bacteroidetes, partially restoring microbial diversity. Notably, EG suppressed the overgrowth of Faecalibaculum and Dubosiella while restoring Ligilactobacillus and Alistipes abundance. Furthermore, EG enhanced intestinal barrier integrity by upregulating tight junction proteins Claudin-1, Occludin and ZO-1, thereby reducing endotoxin translocation. Collectively, EG effectively ameliorates HFD-induced NAFLD by suppressing inflammation, modulating gut microbiota composition, and reinforcing intestinal barrier function. These findings highlight the potential of EG as a promising therapeutic candidate for the prevention and treatment of NAFLD.