Biological aging phenotypes mediate gut microbiota effects on age-related macular degeneration subtype progression: genetic causality by mendelian randomization and mediation analysis.

The mechanisms driving age-related macular degeneration (AMD) progression into two major but distinct vision-threatening subtypes, geographic atrophy (GA) and choroidal neovascularization (CNV), are unclear. This study identifies causal gut microbiota (GM) taxa involved in AMD and their connections to biological aging phenotypes, including epigenetic clock acceleration, telomere length, mitochondrial DNA copy number, 731 immune cell traits, and 91 inflammatory proteins through genetic prediction. Analyzing 207 GM taxa and 205 functional pathways alongside AMD progression GWAS data, we found that class_Gammaproteobacteria significantly influences both CNV and GA, and a bidirectional gut-retina axis involving Erysipelotrichaceae was also identified. Genus_Flavonifractor, species_Ruminococcus_obeum, and species_Streptococcus_thermophilus may attenuate AMD progression. Mediation analysis revealed pathways linking Ruminococcus obeum to GA progression via SSC-A expression on CD4 + T cells, and a CNV-associated pathway mediated by CD33dim HLA-DR + CD11b- cell counts. This study provides novel genetic evidence linking GM to dynamic AMD progression, offering genetic insights for future experimental research and clinical strategies.