TY - JOUR
T1 - Gut microbial metabolism drives transformation of msh2-deficient colon epithelial cells
AU - Belcheva, Antoaneta
AU - Irrazabal, Thergiory
AU - Robertson, Susan J.
AU - Streutker, Catherine
AU - Maughan, Heather
AU - Rubino, Stephen
AU - Moriyama, Eduardo H.
AU - Copeland, Julia K.
AU - Kumar, Sachin
AU - Green, Blerta
AU - Geddes, Kaoru
AU - Pezo, Rossanna C.
AU - Navarre, William W.
AU - Milosevic, Michael
AU - Wilson, Brian C.
AU - Girardin, Stephen E.
AU - Wolever, Thomas M.S.
AU - Edelmann, Winfried
AU - Guttman, David S.
AU - Philpott, Dana J.
AU - Martin, Alberto
N1 - Funding Information:
We are thankful to Drs. M. Shulman, M. Ohh, J. Mogridge, J. Danska, J. Carlyle, J. Gommerman, R. Bruce, and the Martin laboratory for helpful discussions and for reading the manuscript. We thank Maribel Berru and Kervan Rivera-Rufner for technical help. We acknowledge Becas Chile and DFATD Canada for sponsoring T.I. This research is supported by a CIHR grant to D.S.G. and to W.W.N. (MOP-86683, MSH-87729) and by a Cancer Research Society grant (MOP66965) and the Lotte & John Hecht Memorial Foundation grant of the Canadian Cancer Society (#702027) to A.M., who is supported by a Canada Research Chair award.
PY - 2014/7/17
Y1 - 2014/7/17
N2 - 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
AB - 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
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U2 - 10.1016/j.cell.2014.04.051
DO - 10.1016/j.cell.2014.04.051
M3 - Article
C2 - 25036629
AN - SCOPUS:84904543667
SN - 0092-8674
VL - 158
SP - 288
EP - 299
JO - Cell
JF - Cell
IS - 2
ER -
