Sex hormones, blood metabolites and proteins mediating the causal associations between gut microbiota and prostatic diseases: evidences from Mendelian randomization study

Abstract

Background

The causal relationships between the gut microbiota and prostate cancer, prostatitis, and benign prostatic hyperplasia remain uncertain. We intend to identify the causal connections between the gut microbiota and prostatic diseases and investigate the potential mechanisms involved.

Methods

A two-sample Mendelian randomization (MR) analysis was conducted to elucidate the impact of 196 gut microbiota on prostatic diseases risk. Reverse MR, linkage disequilibrium regression score (LDSC), and colocalization analyses were performed to strengthen causal evidence. Phenome-wide MR (Phe-MR) analysis was used to evaluate the potential side effects of targeting the detected gut microbiota. We designed a two-step MR study to assess the mediating effects of sex hormones, blood metabolites, and proteins.

Results

According to the MR analyses, 31 bacterial taxa were causally associated with prostatic diseases, of which 23 types were newly identified. In addition, Alphaproteobacteria restrained prostate cancer, Ruminococcaceae UCG009 prevented prostatitis, and Clostridiales posed a risk for benign prostatic hyperplasia. LDSC and colocalization analyses indicated that the detected associations were not confounded by genetic correlation or LD from common causal loci. In the mediation analysis, we identified 53 mediators linking the gut microbiota to prostatic diseases, with a specific emphasis on the critical roles played by sex hormones and blood metabolites, and identified 34 proteins that may be used as therapeutic targets, especially FGFR1 and XPNPEP1.

Conclusions

Our study represents the first comprehensive exploration of the causal effects of the gut microbiota on prostatic diseases and reveals the mediating effects of sex hormones and blood metabolites on the “gut-prostate axis.”