| Literature DB >> 25036629 |
Antoaneta Belcheva1, Thergiory Irrazabal1, Susan J Robertson1, Catherine Streutker2, Heather Maughan3, Stephen Rubino4, Eduardo H Moriyama5, Julia K Copeland6, Anu Surendra6, Sachin Kumar1, Blerta Green1, Kaoru Geddes1, Rossanna C Pezo7, William W Navarre8, Michael Milosevic9, Brian C Wilson5, Stephen E Girardin4, Thomas M S Wolever10, Winfried Edelmann11, David S Guttman6, Dana J Philpott1, Alberto Martin12.
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(-/-) 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. PAPERCLIP:Entities:
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Year: 2014 PMID： 25036629 DOI： 10.1016/j.cell.2014.04.051
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582