Abstract
BACKGROUND: Dysbiosis of the gut microbiota (GM) has been reported to be associated with cancers, including bladder cancer (BLCA). However, the specific causal relationship between GM and BLCA, as well as the mediating role of circulating metabolic biomarkers (CMBs), has remained unclear. Therefore, we aimed to elucidate the causal relationship among GM, CMBs, and BLCA, through a mendelian randomization (MR) approach. METHOD: The summary statistics of 473 GM (n = 5959) and 233 CMBs (n = 136,016) from the NHGRI-EBI GWAS Catalog, and BLCA (cases n = 2053 and controls n = 287,137) from the FinnGen study were leveraged for our research. Bidirectional MR analysis was conducted to investigate the causal link between GM and BLCA, and two-step MR (TSMR) was employed to identified potential mediating CMBs. The inverse-variance weighted (IVW) was primarily utilized for effect estimation. Additionally, the Cochrane's Q test was used to evaluate heterogeneity, and the MR-Egger method was employed to evaluate pleiotropy. RESULT: The study revealed that 15 GM and 12 CMBs were causally associated with BLCA (p < 0.05). Specially, dorea was found to significantly increase the risk of developing BLCA (OR = 2.20, 95% CI: 1.29-3.75). Furthermore, TSMR analysis indicated that total cholesterol levels in small HDL and cholesterol esters in small HDL mediate the causal relationship between dorea and BLCA, with mediated proportions of 2.46% and 2.14%, respectively. CONCLUSION: The findings of this study provide compelling evidence supporting the mediating role of CMBs in the causal relationship on GM and BLCA.