Microbial Metabolites of Flavanols in Urine Are Associated with Enhanced Anti-Proliferative Activity in Bladder Cancer Cells In Vitro

Flavanols are metabolized by the gut microbiota to bioavailable metabolites, and the absorbed fraction is excreted primarily via urine. Uroepithelial cells are thus a potential site of activity due to exposure to high concentrations of these compounds. Chemoprevention by flavanols may be partly due to these metabolites. In Vitro work in this area relies on a limited pool of commercially available microbial metabolites, and little has been done in bladder cancer. The impact of physiologically relevant mixtures of flavanols and their metabolites remains unknown. Rats were fed various flavanols and urine samples, approximating the bioavailable metabolome, were collected. Urines were profiled by UPLC-MS/MS, and their anti-proliferative activities were assayed In Vitro in four bladder cancer models. Significant interindividual variability was observed for composition and proliferation. Microbial metabolite concentrations (valerolactones, phenylalkyl acids and hippuric acids) were positively associated with reduced bladder cancer proliferation In Vitro, while native flavanols were poorly correlated with activity. These results suggest that microbial metabolites may be responsible for chemoprevention in uroepithelial cells following flavanol consumption. This highlights the potential to use individual genetics and microbial metabotyping to design personalized dietary interventions for cancer prevention and/or adjuvant therapy to reduce bladder cancer incidence and improve outcomes.