Unveiling the causal relationships between gut microbiota, circulating metabolic biomarkers, and benign prostate...

The complex roles of gut microbiome (GM) dysbiosis and circulating metabolites in benign prostatic hyperplasia (BPH) pathogenesis have been widely hypothesized but lacked causal evidence. Critically, no Mendelian randomization (MR) study has established whether GM and metabolites exert direct causal effects or act through mediating pathways in BPH development. Using genome-wide association studies data, we conducted comprehensive 2-sample and mediation MR analyses. Causal effects were estimated via inverse-variance weighted methods with sensitivity analyses. Six bacterial phyla/genera showed significant causal links to BPH, including Actinobacteria (genus Bifidobacterium), Bacteroidetes (genus Bacteroides), Firmicutes (genera Blautia, Holdemania), and Proteobacteria (genus Comamonas). Additionally, 2 circulating metabolites - the mean diameter of low-density lipoprotein (LDL) particles and the free cholesterol to total lipids ratio in small very LDL - were significantly associated with BPH. However, no mediation effect was found for any circulating metabolites on BPH. In summary, our 2-sample and mediation MR analysis revealed 18 GM and 2 circulating metabolites significantly linked to BPH, highlighting their potential as risk factors. While no mediation effects for circulating metabolites were detected, these findings enhance our understanding of preventive strategies for BPH, emphasizing the intricate relationship between GM dysbiosis, circulating lipid metabolites, and disease onset.