Carcinogen metabolism and bladder cancer: role of gut microbiota in disease and prevention

Bladder cancer remains a significant global health concern, with environmental carcinogen exposure-particularly from tobacco-derived compounds such as aromatic amines, polycyclic aromatic hydrocarbons (PAHs), and nitrosamines-recognized as a primary etiological factor. These carcinogens undergo complex metabolic activation in the liver, bladder epithelium, and gut microbiota, generating reactive intermediates that initiate DNA damage, oxidative stress, and pro-tumorigenic signaling. This review synthesizes emerging evidence on how carcinogen-induced metabolic reprogramming contributes to bladder cancer initiation and progression, emphasizing the roles of key genetic pathways and metabolic enzymes involved in xenobiotic detoxification, DNA repair, and redox regulation. In parallel, we examine the influence of gut microbiota on carcinogen bioactivation and biotransformation, highlighting its dual role as both a metabolic modulator and a potential preventive target. We critically evaluate human observational data linking microbiome dysbiosis to bladder cancer risk, while addressing limitations such as small cohort sizes and confounders like diet and age. Finally, we discuss promising strategies for risk mitigation, including microbiome-directed interventions, dietary modulation, and chemopreventive agents that counteract carcinogenic effects. By integrating molecular oncology, toxicogenomics, and host-microbiome interactions, this review provides a mechanistic framework for understanding bladder cancer etiology and identifies novel opportunities for preventive and precision interventions.