Epigenetics, bacterial metabolites and type 2 diabetes: a new view of gut-genome interactions

Type 2 diabetes (T2D) is traditionally viewed as a disorder of glucose homeostasis, yet growing evidence suggests that its pathogenesis is deeply influenced by interactions between the gut microbiota and host gene regulation. Bacterial metabolites have emerged as key molecular mediators capable of linking environmental exposures, metabolism and epigenetic control of gene expression. These insights are reshaping current understanding of how microbial signals contribute to metabolic disease. This review examines the emerging role of bacterial metabolites as modulators of host epigenetic landscapes in T2D. We discuss how short-chain fatty acids (SCFAs), particularly butyrate and propionate, regulate chromatin accessibility through histone deacetylase inhibition and changes in histone acetylation. Beyond SCFAs, we highlight additional classes of microbiota-derived metabolites, including tryptophan-derived indoles such as indole-3-propionic acid, polyamines such as spermidine and aromatic amino acid derivatives, that expand the microbiota-epigenetic axis through mechanisms involving DNA methylation, transcriptional regulation, mitochondrial function and inflammatory signaling. These effects occur in a tissue-specific manner across metabolically relevant organs including the colon, liver, pancreatic β-cells and adipose tissue, reflecting differences in metabolite exposure and cellular metabolic context. We further discuss emerging evidence suggesting that microbial metabolites may contribute to intergenerational metabolic programming, linking maternal diet, microbiota composition and offspring epigenetic trajectories. Finally, we examine therapeutic perspectives targeting this axis, including dietary strategies, microbiota-directed interventions and metabolite-based therapies. Collectively, discussed works support a conceptual shift in our understanding of T2D biology: gut microbial metabolites are active regulators of chromatin architecture and metabolic gene networks that influence the risk, development and progression of T2D. Understanding these gut-epigenome interactions may provide new opportunities to identify biomarkers of metabolic risk and to develop mechanism-based strategies for diabetes prevention and treatment.