Human commensal bacteria produce novel genotoxic metabolites and exacerbate colorectal cancer

Microbiota-derived metabolites that elicit DNA damage can contribute to intestinal tumorigenesis. However, the full spectrum of genotoxic chemicals produced by indigenous gut microbes remains to be defined. We established a pipeline to systematically evaluate the genotoxicity of a large collection of human gut commensals and identified isolates from divergent phylogenies whose small molecule metabolites caused DNA damage. Using comparative metabolomics and bioactivity-guided natural product-discovery techniques, we discovered a previously undescribed family of genotoxic metabolites—termed the indolimines—produced by the colorectal cancer (CRC)-associated species Morganella morganii. The synthesis of indolimines was catalyzed by aspartate aminotransferase with IAld and amino acids as precursors. Finally, we found that indolimine-producing M. morganii exacerbated CRC in gnotobiotic mice. These studies reveal the existence of a previously unexplored universe of genotoxic small molecules from the human microbiome and imply a broader role for microbiota-derived genotoxins in CRC.