Soybean genistin-driven gut microbiota-derived butyrate synthesis activates the SIRT1 signaling pathway to ameliorate metabolic fatty liver

Genistin (Gen), an isoflavone derived from soybeans, possesses lipid-lowering and anti-metabolic syndrome properties. Nonetheless, its impact on mitigating metabolic dysfunction-associated fatty liver disease (MAFLD) is insufficiently researched. We assessed the impact of GEN on lipid metabolism using a rat MAFLD model and an in vitro model of cellular lipid accumulation. The results indicated that Gen alleviated liver injury in MAFLD by reducing inflammation, lowering lipid levels, and normalizing liver function indicators. The diversity of harmful gut microbiota was significantly affected by Gen, which also boosted the abundance of beneficial bacteria such as Bacteroidetes and notably promoted the production of short-chain fatty acids (SCFAs). Butyrate, in particular, demonstrated a significant association with MAFLD biomarkers like triglyceride, total cholesterol, LDL-C, and TNF-α. In vitro experiments showed that butyrate counteracted sodium oleate's effects by restoring mitochondrial membrane potential, reducing active ROS levels and cell apoptosis, increasing SIRT1 protein and mRNA expression, and decreasing AKT1, PTGS2, and MAOA protein and mRNA levels. Additionally, sodium butyrate improved the expression of lipid-related genes, reversing changes in PPARα, SREBP1, ACACA, and FASN. Our study suggests that genistein activates the SIRT1 signaling pathway by enhancing gut microbiota-derived butyrate production, thereby improving liver function and lipid metabolism in MAFLD rats. In conclusion, soy-derived Gen shows promise as a supplementary dietary option for enhancing MAFLD management. • Genistin significantly mitigates the symptoms of MAFLD induced by a high-fat diet in rats. •Genistin enhances gut microbiota composition and short-chain fatty acid levels in MAFLD rats. •Genistin promotes butyrate production to activate the SIRT1 pathway, thereby ameliorating lipid metabolism disorders. •Genistin alleviates oxidative stress and promotes the stability of mitochondrial membrane potential.