Multiomics reveals metformin's dual role in gut microbiome remodeling and hepatic metabolic reprogramming for MAFLD intervention.

Metabolic Associated Fatty Liver Disease (MAFLD), previously known as Non-Alcoholic Fatty Liver Disease, is a growing global health issue associated with obesity, type 2 diabetes, and metabolic syndrome. This study investigates the potential of metformin, a common anti-diabetic drug, to slow the progression of MAFLD using a multi-omics approach. Male Wistar rats were fed a choline-deficient diet to induce MAFLD and treated with metformin through their drinking water for 48 weeks. We conducted a comprehensive analysis including liver histology, untargeted metabolomics, lipidomics, and gut microbiome profiling to assess the effects of metformin on liver and gut metabolic patterns. Metformin administration led to significant changes in gut microbiome diversity and the abundance of specific microbial species in MAFLD rats. Histological analysis showed that metformin-treated rats had reduced lipid accumulation and fibrosis in the liver compared to untreated MAFLD rats. Metabolomic and lipidomic analyses revealed that metformin corrected abnormal lipid metabolism patterns, reduced hepatic fat deposition, and influenced key metabolic pathways associated with MAFLD progression. Our findings suggest that metformin has a protective role against MAFLD by modulating gut microbiota and liver metabolism, thereby slowing the progression of hepatic fibrosis. This study provides insights into the therapeutic potential of metformin for MAFLD by addressing metabolic pattern disorders and abnormal changes in gut microbial diversity, highlighting its impact on lipid metabolism and gut-liver axis interactions.