Abstract SY43-02: Mismatch repair, gut microbiota, and the etiology of colon cancer

Abstract

Abstract 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 APC(Min/+)Msh2-/- and APC(Min/+)Mlh1-/- 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 fuels hyperproliferation of Msh2-/- and Mlh1-/- colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and potentially modulating the differentiation of transit-amplifying cells in the colon. These data show that mismatch repair deficiency sensitizes colon epithelial cells to transformation by gut microbiota, and thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. Citation Format: Alberto Martin. Mismatch repair, gut microbiota, and the etiology of colon cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY43-02. doi:10.1158/1538-7445.AM2015-SY43-02