Dissecting Causal Relationships Between Gut Microbiota, Plasma Metabolites and Bladder Cancer: A Two-Step Mendelian Randomization Study.

BACKGROUND AND AIMS

Previous studies have shown that gut microbiota is associated with bladder cancer. However, the causal relationships and potential mediating factors between the gut microbiota (GM) and bladder cancer (BCa) have not been well defined.

METHODS

To investigate this, we utilized summary statistics from genome-wide association studies of gut microbiota (Dutch Microbiome Project,  = 7738), plasma metabolites (Canadian Longitudinal Study of Aging follows,  = 8096), and BCa (FinnGen Biobank R9, 2053 cases and 287,137 controls). We then conducted bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between GM and BCa, and employed a two-step MR approach to identify potential mediating metabolites.

RESULTS

Our study revealed that three taxa, Species Bacteroides dorei, Genus Streptococcus Species and Bacteroides salyersiae, were associated with BCa, while no association was found between BCa on these three taxa. Additionally, we identified 5 plasma metabolites that were simultaneously associated with BCa and the above three taxa. Mediation analysis showed that the associations between Species Bacteroides salyersiae and BCa were mediated by N-methylproline and X-19299, accounting for 11.6% and 28.56% of the total effect, respectively. Furthermore, Species Bacteroides dorei, Genus Streptococcus Species and Bacteroides salyersiae potentially affected BCa through 2,3-dihydroxypyridine, N-palmitoyl-sphinganine and N-methylproline, respectively.

CONCLUSIONS

Overall, our study dissected the causal relationships between GM and BCa, potentially mediated by plasma metabolites. Our study identified potential targets for treatment of bladder cancer.