Gut Microbial Metabolism Drives Transformation of Msh2-Deficient Colon Epithelial Cells

The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APCMin/+MSH2−/− mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2−/− colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. [Display omitted] [Display omitted] •Gut microbiota induce colon cancer in genetically sensitized MSH2-deficient mice•Reduced dietary carbohydrates decreased polyp frequency in APCMin/+MSH2−/− mice•The carbohydrate metabolite butyrate induces colon cancer in APCMin/+MSH2−/− mice•MSH2 regulates β-catenin activity and/or transit-amplifying cell differentiation Carbohydrate metabolites, produced by gut microbes, can directly induce hyperproliferation and transformation of genetically susceptible colon epithelial cells. This process is independent of inflammation or production of DNA mutagens and provides a mechanism for interaction of microbiota, diet, and mismatch repair deficiency in colorectal cancer induction.