Gut microbiota carcinogen metabolism causes distal tissue tumours

Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development. Similar to drug molecules, pollutants are typically metabolised in the body, which can change their carcinogenic potential and impact tissue distribution through altered toxicokinetics. Although recent studies demonstrated that human-associated microbes can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota dramatically reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice, which affects the toxicokinetics of nitrosamines. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine-carcinogens. Altogether, these results suggest gut microbiota carcinogen metabolism as a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.