Abstract
BACKGROUND: While the relationship between gut microbiota and erectile dysfunction (ED) has been reported, the specific pathways involved remain unclear. AIM: This study aims to investigate the causal relationship between gut microbiota and ED, and to identify the potential role of plasma metabolites as mediators. METHODS: Utilizing aggregated genome-wide association study (GWAS) data, a comprehensive two-sample Mendelian randomization (MR) analysis was performed involving 196 gut microbiota taxa, 1400 plasma metabolites and ED. Causal relationships between gut microbiota, plasma metabolites and ED were explored. In addition, mediation analysis was applied to identify the pathway from gut microbiota to ED mediated by plasma metabolites. OUTCOMES: This study reveals that plasma metabolites act as mediators regulating the influence of gut microbiota on ED. RESULTS: MR analysis identified causal relationships between six gut microbial taxa and ED, with Butyrivibrio increasing the risk of ED, while Alistipes, Prevotella 9, Dialister, Marvinbryantia, and LachnospiraceaeUCG010 exhibited protective effects. Additionally, 45 plasma metabolites demonstrated causal associations with ED. Finally, mediation analysis revealed four mediation relationships. Sensitivity analysis indicated no heterogeneity or pleiotropy in this study. CLINICAL IMPLICATIONS: Modulating gut microbiota or targeting specific metabolites may offer new therapeutic approaches for ED, highlighting the potential for microbiome-based interventions. STRENGTHS AND LIMITATIONS: The MR approach and large-scale GWAS data provide robust causal evidence, but the findings are limited by their focus on European populations and lack of experimental validation. Further studies are needed to confirm these mechanisms in diverse cohorts and functional models. CONCLUSION: This study establishes a causal link between gut microbiota, plasma metabolites, and ED, identifying specific microbial taxa and metabolites as key contributors to ED risk. The mediating role of plasma metabolites highlights potential therapeutic strategies, such as probiotics or dietary interventions targeting harmful metabolites.