Epigenetic Regulation and Gut Microbiota Dysbiosis in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Beyond the classical pathogenetic pathways, increasing evidence suggests that epigenetic regulation and the gut-retina axis may substantially contribute to AMD development and progression. This review synthesizes current evidence on two increasingly recognized and interconnected domains of AMD pathogenesis: epigenetic regulation and gut microbiota dysbiosis. Epigenetic processes, such as DNA methylation, histone modifications, and non-coding RNAs, can influence gene function involved in oxidative stress responses, complement regulation, angiogenesis, and inflammation, while several related markers have emerged as potential diagnostic and prognostic biomarkers. Moreover, growing evidence suggests a functional gut-retina axis, in which alterations in the gut microbiota impair intestinal barrier function and facilitate the systemic passage of bacteria and microbial metabolites, potentially affecting retinal inflammation and immune responses. Furthermore, several microbial metabolites, including short-chain fatty acids, lipopolysaccharide, bile acids, tryptophan derivatives, and trimethylamine-N-oxide, may have either protective or harmful effects on retinal and choroidal homeostasis, with altered circulating and fecal concentrations reported in patients with AMD compared with controls. These findings support AMD as a systemically and molecularly interconnected disorder, while further longitudinal, mechanistic, and multi-omics studies are required to establish causality, define interactions between epigenetic and microbiome-related pathways, and clarify their potential utility as biomarkers and therapeutic targets.