Unveiling the causal relationships between gut microbiota, circulating metabolic biomarkers, and benign prostate hyperplasia: A Mendelian randomization study.

Six bacterial phyla/genera showed significant causal links to BPH across four phyla.

• Causal associations were identified in Actinobacteria (genus Bifidobacterium), Bacteroidetes (genus Bacteroides), Firmicutes (genera Blautia, Holdemania), and Proteobacteria (genus Comamonas).
• Causal effects were estimated via inverse-variance weighted (IVW) methods as the primary analytical approach.
• Sensitivity analyses were conducted to validate findings.
• The study used genome-wide association studies (GWAS) data in a 2-sample MR framework.

A total of 18 gut microbiota taxa were significantly linked to BPH in the overall analysis.

• The abstract specifies 18 GM taxa as significantly associated with BPH.
• The six bacterial phyla/genera highlighted represent those with significant causal links specifically identified among the 18.
• The analysis used comprehensive 2-sample MR methods with GWAS summary data.
• Inverse-variance weighted methods were used as the primary causal estimation approach.

Two circulating metabolites were significantly associated with BPH: mean diameter of LDL particles and free cholesterol to total lipids ratio in small very LDL.

• The mean diameter of low-density lipoprotein (LDL) particles was identified as significantly associated with BPH.
• The free cholesterol to total lipids ratio in small very low-density lipoprotein (VLDL) was the second significantly associated circulating metabolite.
• Both metabolites are lipid-related circulating biomarkers.
• These associations were identified through 2-sample MR analysis using GWAS data.

No mediation effect was found for any circulating metabolites on the causal pathway between gut microbiota and BPH.

• Mediation MR analyses were conducted to assess whether circulating metabolites mediated GM effects on BPH.
• Despite significant direct associations of both GM and circulating metabolites with BPH, no mediating pathway through circulating metabolites was detected.
• This finding suggests gut microbiota and circulating lipid metabolites may exert independent rather than sequential effects on BPH.
• The absence of mediation was identified despite testing across the 2 significantly associated circulating metabolites.

Gut microbiome dysbiosis and circulating metabolites had been widely hypothesized but lacked causal evidence in BPH pathogenesis prior to this study.

• No prior Mendelian randomization study had established whether GM and metabolites exert direct causal effects or act through mediating pathways in BPH development.
• The study addresses this gap using a Mendelian randomization framework, which uses genetic variants as instrumental variables to infer causality.
• GWAS summary data were used to enable 2-sample MR analyses.