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

被引：388

作者：

Belcheva, Antoaneta ^{[1
]}

Irrazabal, Thergiory ^{[1
]}

Robertson, Susan J. ^{[1
]}

Streutker, Catherine ^{[2
]}

Maughan, Heather ^{[3
]}

Rubino, Stephen ^{[4
]}

Moriyama, Eduardo H. ^{[5
]}

Copeland, Julia K. ^{[6
]}

Kumar, Sachin ^{[1
]}

Green, Blerta ^{[1
]}

Geddes, Kaoru ^{[1
]}

Pezo, Rossanna C. ^{[7
]}

Navarre, William W. ^{[8
]}

Milosevic, Michael ^{[9
]}

Wilson, Brian C. ^{[5
]}

Girardin, Stephen E. ^{[4
]}

Wolever, Thomas M. S. ^{[10
]}

Edelmann, Winfried ^{[11
]}

Guttman, David S. ^{[6
]}

Philpott, Dana J. ^{[1
]}

Martin, Alberto ^{[1
]}

机构：

[1] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[2] St Michaels Hosp, Dept Lab Med, Toronto, ON M5S 1W8, Canada

[3] Ronin Inst, Montclair, NJ 07043 USA

[4] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON M5S 1A8, Canada

[5] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[6] Univ Toronto, Ctr Anal Genome Evolut & Funct, Toronto, ON M5S 3B2, Canada

[7] Univ Toronto, Dept Med Oncol, Toronto, ON M5S 1A8, Canada

[8] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[9] Princess Margaret Hosp, Dept Radiat Oncol, Toronto, ON M5G 2M9, Canada

[10] Univ Toronto, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada

[11] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA

来源：

CELL | 2014年 / 158卷 / 02期

关键词：

MULTIPLE INTESTINAL NEOPLASIA; DIETARY GLYCEMIC LOAD; COLORECTAL-CANCER; MISMATCH-REPAIR; DNA-DAMAGE; BUTYRATE; TUMORIGENESIS; INFLAMMATION; DEFICIENCY; ACTIVATION;

D O I：

10.1016/j.cell.2014.04.051

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：288 / 299

页数：12

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