Genistein ameliorates non-alcoholic fatty liver disease in mice by modulating gut microbiota and hepatic macrophage polarization.

Genistein (GEN) exhibits diverse biological activities. This study is conducted to explore the effect of GEN on metabolic dysfunction-associated steatotic liver disease (MASLD) mice. MASLD was induced in mice by a high-fat diet (HFD). The results indicated that GEN significantly reduced HFD-induced body weight and improved lipid homeostasis and glucose tolerance in HFD-fed mice. Furthermore, GEN intervention markedly ameliorated hepatic pathological changes, hepatic dysfunction, and macrophage polarization. Meanwhile, GEN had a beneficial significant impact on colonic pathological changes and the expression of tight junction-related proteins. The results of gut microbiota showed that high-dose GEN intervention was able to down-regulate Firmicutes and Proteobacteria and increase Bacteroidota at the phylum level. At the genus level, GEN intervention increased Lactobacillus, Muribaculum, and Muribaculaceae_unclassified in MASLD mice, and decreased Ruminococcus, Allobaculum, and Helicobacter. In conclusion, GEN attenuated lipid metabolism disorders and hepatic inflammatory reaction via regulating the composition of the gut microbiota and hepatic macrophage polarization in MASLD mice.