title: Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells.
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:
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Belcheva
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Thergiory
authors.initials: T
authors.lastname: Irrazabal
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Department of Laboratory Medicine, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Streutker
authors.affiliation: Ronin Institute, Montclair, NJ 07043, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Maughan
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Rubino
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Moriyama
authors.affiliation: Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, ON M5S 3B2, Canada.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Copeland
authors.affiliation: Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, ON M5S 3B2, Canada.
authors.forename: Anu
authors.initials: A
authors.lastname: Surendra
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Sachin
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Blerta
authors.initials: B
authors.lastname: Green
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Geddes
authors.affiliation: Department of Medical Oncology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Rossanna C
authors.initials: RC
authors.lastname: Pezo
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Navarre
authors.affiliation: Department of Radiation Oncology, Princess Margaret Hospital, Toronto, ON M5G 2M9, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Toronto, ON M5G 1L7, Canada.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
authors.affiliation: Department of Nutritional Sciences, University of Toronto, Toronto, ON M5S 3E2, Canada.
authors.forename: Thomas M S
authors.initials: TMS
authors.lastname: Wolever
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
authors.affiliation: Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, ON M5S 3B2, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Guttman
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: alberto.martin@utoronto.ca.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003111:Colonic Polyps / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D053843:DNA Mismatch Repair; D004040:Dietary Carbohydrates / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D025601:Adenomatous Polyposis Coli Protein; D002087:Butyrates; D004040:Dietary Carbohydrates; C501485:Mlh1 protein, mouse; D009687:Nuclear Proteins; D051176:beta Catenin; C497173:Msh2 protein, mouse; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein