From Metformin to Microbiome: The Missing Links in Metabolic Modulation

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose metabolism. Emerging evidence suggests that gut microbiota plays a pivotal role in the pathogenesis and management of T2DM. Metformin, the first-line therapy for T2DM, exerts its glucose-lowering effects not only through classical mechanisms of enhancing insulin sensitivity and reducing hepatic gluconeogenesis but also by modulating the gut microbiota. Metformin-induced alterations in gut flora, including an increase in beneficial species such as Bifidobacterium and Akkermansia, contribute to improved glucose metabolism, enhanced gut barrier integrity, reduced inflammation, and increased GLP-1 secretion. Animal studies have demonstrated that metformin-modified microbiota can improve glycemic control when transferred to germ-free mice, highlighting the therapeutic relevance of microbiome modulation. However, most existing evidence stems from animal models, with limited large-scale, long-term human trials available. Further research employing multi-omics approaches is essential to elucidate specific microbial species' roles and their clinical implications. Understanding the metformin–microbiome interaction could pave the way for novel microbiota-targeted therapies in T2DM management.