The Mismatch Repair System Control Proliferation and Differentiation of Colon Epithelial Cells by Sensing Microbial Induced Oxidative DNA Damage

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 found 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 fuels hyperproliferation of MSH2-/- colon epithelial cells. Further, we provided evidence that the mismatch repair pathway has a role in regulating β-catenin. Although colon epithelial cells (CECs) use butyrate to proliferate, the increased proliferation observed in MMR-deficient CECs was not expected, suggesting a unique interaction between MMR genes within CECs and the cell’s environment. Therefore, we investigated why MSH2-deficient cells hyperproliferate in the presence of butyrate. We show that MMR-deficient CECs have higher basal levels of reactive oxygen species than MMR-proficient CECs. Butyrate further increases oxidative stress in CECs, inducing DNA damage that arrests CEC proliferation in MMR-proficient but not in MMR-deficient CECs. Indeed, scavenging ROS increases proliferation only in MMR-proficient CECs. Our results uncover a mechanism by which gut microbiota control cell proliferation and differentiation in conjunction with the MMR system. The protective effect imparted by MMR in CECs allows for utilization of butyrate and maintenance of a healthy hypoxic environment.Ph.D.2020-11-19 00:00:0