Cyanidin-3-<i>O</i>-glucoside alleviates non-alcoholic fatty liver disease through modulation of the gut microbiota

Abstract Non-alcoholic fatty liver disease (NAFLD) is closely linked to gut microbiota dysbiosis. Cyanidin-3-O-glucoside (C3G) shows therapeutic potential in multiple diseases. It regulates gut microbiota composition and metabolic homeostasis bidirectionally. This study investigates the potential of C3G in alleviating high-fat diet (HFD)-induced NAFLD, with a specific focus on genus_Eubacterium_coprostanoligenes, a gut microbe exhibiting a significant negative correlation with metabolic dysfunction in mice. Phenotypic evaluations demonstrated that C3G mitigated the high-fat diet (HFD)-induced increases in body weight, liver weight, and liver-to-body weight ratio. Microbiota analyses revealed that HFD disrupted gut homeostasis. These analyses included taxonomic profiling, Linear Discriminant Analysis Effect Size (LEfSe), and functional predictions. Key microbial taxa showed altered abundances, with increased Firmicutes and Desulfobacterota. Remarkably, g_Eubacterium_coprostanoligenes, which was negatively correlated with metabolic dysfunction, showed increased abundance following C3G treatment. C3G modulated pathways associated with g_Eubacterium_coprostanoligenes, including cholesterol metabolism and short-chain fatty acid synthesis, while reversing HFD-induced impairments in biotin biosynthesis and cell wall homeostasis. This study identifies g_Eubacterium_coprostanoligenes as a key regulatory node in C3G-mediated NAFLD attenuation. It provides a microbiota-focused foundation for potential therapeutic strategies.