IDDF2024-ABS-0031 Sex hormones and blood metabolites mediating the causal associations between gut microbiota and prostate cancer: evidence from mendelian randomization study

<h3>Background</h3> The gut microbiota has been recognized as tumor biomarkers for various cancers, and specific tumor markers can be discovered through causal relationships. The causal relationships between gut microbiota and prostate cancer remained uncertain. We intend to identify the causal connections between gut microbiota and prostate cancer and investigate the potential underlying mechanisms. <h3>Methods</h3> A two-sample Mendelian randomization (MR) analysis was conducted to elucidate the impact of 196 gut microbiota on prostate cancer (IDDF2024-ABS-0031 Figure 1). The reverse MR, linkage disequilibrium regression score (LDSC), and colocalization analyses were performed to strengthen causal evidence. A phenome-wide MR (Phe-MR) analysis evaluated potential side effects targeting the detected gut microbiota. We designed a two-step MR study to assess the mediation effects of circulating cytokines, sex hormones, and blood metabolites. <h3>Results</h3> In the MR analyses, 11 bacterial taxa were causally associated with prostate cancer (IDDF2024-ABS-0031 Figure 2 (a,b)). In these bacterial taxa, <i>Alphaproteobacteria</i> (OR = 0.87 95% CI, 0.76-0.96, P = 0.004) restrained prostate cancer and <i>Paraprevotella</i> (OR = 1.08 95% CI, 1.00-1.17, P = 0.044) had a risk effect on prostate cancer. In reverse MR analysis, gut microbiota abundance was unaffected by prostate cancer. LDSC and colocalization analyses indicated that the detected associations would not be confounded by genetic correlation or LD from common causal loci (IDDF2024-ABS-0031 Figure 2 (c)). The Phe-MR analysis showed no apparent tox or side effects on the identified gut microbiota. In the mediation analysis, we found 7 mediators linking gut microbiota to prostate cancer, with a specific emphasis on the critical roles played by sex hormones and blood metabolites (IDDF2024-ABS-0031 Figure 3). <h3>Conclusions</h3> Our study represented the first comprehensive exploration of the gut microbiota’s causal effects on prostate cancer and revealed the mediating effects of sex hormones and blood metabolites in the ‘gut-prostate axis.’ Our study has contributed to the discovery of tumor biomarkers in the gut microbiota for prostate cancer, providing a basis for early screening and treatment of the disease.