Causal relationship between bladder cancer and gut microbiota contributes to the gut-bladder axis: A two-sample Mendelian randomization study.

Background: Recent studies have underscored a potential link between gut microbiota and urological tumors, yet the causal relationship with bladder cancer (BCa) and the role of metabolic pathways remain unclear.

Methods: Instrumental variables (IVs) for gut microbiota were obtained from genome-wide association studies (GWAS) conducted by the MiBioGen consortium (n = 18,340). GWAS data for BCa were sourced from a comprehensive genome-wide meta-analysis encompassing 23 cohorts. Mendelian randomization (MR) was employed to investigate the causal relationship between gut microbiota and BCa, utilizing inverse variance weighted (IVW) as the primary MR method. Additionally, metabolic pathways associated with these microbiota were analyzed to understand their functional roles in BCa pathogenesis. Sensitivity analyses were conducted to validate all MR results.

Results: The MR analysis identified five gut microbiota taxa with a causal association with BCa, with the genus Bilophila notably promoting BCa. Metabolic pathway analysis revealed significant associations between specific pathways and BCa, suggesting that changes in amino acid and NAD metabolism might influence BCa development. Sensitivity analyses indicated no significant heterogeneity or horizontal pleiotropy among the IVs.

Conclusion: This study revealed the significant causal relationship between gut microbiota and BCa, particularly identifying Bilophila as a key pathogenic initiator. These findings elucidated the potential impact of metabolic pathways, especially amino acid and NAD metabolism, on the pathogenesis of BCa. They not only laid the foundation for innovative therapeutic strategies but also highlighted the immense potential of microbiota-based interventions in the prevention and treatment of BCa, paving the way for new directions in precision medicine.