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

A. Belcheva | Zendy; Thergiory Irrazábal | Zendy; Susan J. Robertson | Zendy; Catherine Streutker | Zendy; Heather Maughan | Zendy; Stephen Rubino | Zendy; Eduardo H. Moriyama | Zendy; Julia K. Copeland | Zendy; Anu Surendra | Zendy; Sachin Kumar | Zendy; Blerta Green | Zendy; Kaoru Geddes | Zendy; Rossanna C. Pezo | Zendy; William Wiley Navarre | Zendy; Michael Milosevic | Zendy; Brian C. Wilson | Zendy; Stephen E. Girardin | Zendy; Thomas M.S. Wolever | Zendy; Winfried Edelmann | Zendy; David S. Guttman | Zendy; Dana J. Philpott | Zendy; Alberto Martín | Zendy

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

Author(s) -

A. Belcheva,

Thergiory Irrazábal,

Susan J. Robertson,

Catherine Streutker,

Heather Maughan,

Stephen Rubino,

Eduardo H. Moriyama,

Julia K. Copeland,

Anu Surendra,

Sachin Kumar,

Blerta Green,

Kaoru Geddes,

Rossanna C. Pezo,

William Wiley Navarre,

Michael Milosevic,

Brian C. Wilson,

Stephen E. Girardin,

Thomas M.S. Wolever,

Winfried Edelmann,

David S. Guttman,

Dana J. Philpott,

Alberto Martín

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.04.051

Subject(s) - biology , transformation (genetics) , microbiology and biotechnology , metabolism , microbial metabolism , epithelium , genetics , bacteria , biochemistry , gene

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:

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