Gut microbial metabolism drives transformation of msh2-deficient colon epithelial cells

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

Research output: Contribution to journalArticle

195 Scopus citations

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 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. PaperClip

Original languageEnglish (US)
Pages (from-to)288-299
Number of pages12
JournalCell
Volume158
Issue number2
DOIs
StatePublished - Jul 17 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Belcheva, A., Irrazabal, T., Robertson, S. J., Streutker, C., Maughan, H., Rubino, S., Moriyama, E. H., Copeland, J. K., Kumar, S., Green, B., Geddes, K., Pezo, R. C., Navarre, W. W., Milosevic, M., Wilson, B. C., Girardin, S. E., Wolever, T. M. S., Edelmann, W., Guttman, D. S., ... Martin, A. (2014). Gut microbial metabolism drives transformation of msh2-deficient colon epithelial cells. Cell, 158(2), 288-299. https://doi.org/10.1016/j.cell.2014.04.051