Gut Microbiota and DNA Methylation: Mechanistic Insights into the Development and Microbiota-Based Modulation of Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is a multifactorial metabolic disease that arises from the intricate interplay between genetic predisposition and environmental factors. Beyond traditional risk factors, substantial evidence points to the gut microbiota (GM) as a critical regulator of host metabolism through epigenetic processes, specifically DNA methylation. Microbial metabolites, including short-chain fatty acids (SCFAs), methyl-donor precursors, and inflammatory mediators, modulate DNA methyltransferase activity, chromatin accessibility, and metabolic gene expression. These microbiota-derived signals modulate gene expression programs involved in insulin secretion, insulin sensitivity, inflammation, and energy homeostasis. This review summarizes current knowledge on the interplay between GM dysbiosis and DNA methylation in the development and progression of T2D. We emphasize the role of SCFAs, one-carbon metabolism, inflammatory signaling, and metabolic memory in shaping the diabetic epigenome. Furthermore, we critically examine microbiota-targeted interventions, including prebiotics, probiotics, fecal microbiota transplantation, antibiotics and dietary modulation, as potential strategies to restore epigenetic balance and improve metabolic outcomes. Understanding the microbiota-epigenome axis may redefine T2D as not only a metabolic disease but also a disorder of maladaptive epigenetic programming.