Evidence for Genetic Causal Association Between the Gut Microbiome, Derived Metabolites, and Age-Related Macular Degeneration: A Mediation Mendelian Randomization Analysis

<b>Background/Objectives</b>: Despite substantial research, the causal relationships between gut microbiota (GM) and age-related macular degeneration (AMD) remain unclear. We aimed to explore these causal associations using Mendelian randomization (MR) and elucidate the potential mechanisms mediated by blood metabolites. <b>Methods</b>: We utilized the 211 GM dataset (n = 18,340) provided by the MiBioGen consortium. AMD outcome data were sourced from the MRC Integrated Epidemiology Unit (IEU) OpenGWAS Project. We performed bidirectional MR, two mediation analyses, and two-step MR to assess the causal links between GM and different stages of AMD (early, dry, and wet). <b>Results</b>: Our findings indicate that the <i>Bacteroidales S24.7</i> group and genus <i>Dorea</i> are associated with an increased risk of early AMD, while <i>Ruminococcaceae UCG011</i> and <i>Parasutterella</i> are linked to a higher risk of dry AMD. Conversely, <i>Lachnospiraceae UCG004</i> and <i>Anaerotruncus</i> are protective against dry AMD. In the case of wet AMD, <i>Intestinimonas</i> and <i>Sellimonas</i> increase risk, whereas <i>Anaerotruncus</i> and <i>Rikenellaceae RC9</i> reduce it. Additionally, various blood metabolites were implicated: valine, arabinose, creatine, lysine, alanine, and apolipoprotein A1 were associated with early AMD; glutamine and hyodeoxycholate-with a reduced risk of dry AMD; and androsterone sulfate, epiandrosterone sulfate, and lipopolysaccharide-with a reduced risk of wet AMD. Notably, the association between family <i>Oxalobacteraceae</i> and early AMD was mediated by valine, accounting for 19.1% of the association. <b>Conclusions</b>: This study establishes causal links between specific gut microbiota and AMD, mediated by blood metabolites, thereby enhancing our understanding of the gut-retina axis in AMD pathophysiology.