The microbiome-epigenome axis: Regulation of host genome function across development and disease

The gut microbiome is increasingly recognized as a metabolically active regulator of host gene expression, translating environmental exposures-particularly diet-into epigenetic signals that shape development, immunity, metabolism, and disease susceptibility. This narrative review synthesizes current evidence for a microbiome-epigenome axis in which microbial metabolites and regulatory molecules modulate DNA methylation, histone modifications, non-coding RNA networks, RNA epitranscriptomic marks, and higher-order chromatin organization. Short-chain fatty acids act as histone deacetylase inhibitors, acyl-CoA donors, and regulators of histone acetyltransferase activity; microbially derived B vitamins influence one-carbon metabolism and S-adenosylmethionine availability; and bile acids, indoles, trimethylamine-N-oxide, and extracellular vesicle cargo signal through host metabolic, immune, and transcriptional pathways. Evidence from germ-free and recolonization models, genetic perturbation studies, in vitro systems, and human cohorts indicates that microbial signals exert particularly strong effects during developmental windows of heightened epigenetic plasticity, contributing to immune tolerance, trained innate immunity, and long-term metabolic programming. Dysbiosis may disrupt these regulatory circuits and promote inflammatory bowel disease, colorectal cancer, cardiometabolic and atherosclerotic disorders, and neurodevelopmental or neurodegenerative conditions. By integrating microbial metabolism with chromatin regulation, RNA-based control, and genome topology, this review highlights the microbiome as a dynamic epigenetic interface between environment and host physiology. Key challenges include establishing causality in humans, resolving temporal and tissue-specific mechanisms, and developing longitudinal multi-omics studies with functional validation. Targeted microbiome modulation may ultimately restore epigenetic homeostasis and support precision prevention and therapy.