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

作者：Belcheva Antoaneta; Irrazabal Thergiory; Robertson Susan J; Streutker Catherine; Maughan Heather; Rubino Stephen; Moriyama Eduardo H; Copeland Julia K; Kumar Sachin; Green Blerta; Geddes Kaoru; Pezo Rossanna C; Navarre William W; Milosevic Michael; Wilson Brian C; Girardin Stephen E; Wolever Thomas M S; Edelmann Winfried; Guttman David S; Philpott Dana J; Martin Alberto^*

来源：Cell, 2014, 158(2): 288-299.

DOI：10.1016/j.cell.2014.04.051

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(-/-) 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 beta-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.

• 出版日期2014-7-17