Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota
Of Microbes and Cancer
Inflammation is a well-established driver of tumorigenesis. For example, patients with inflammatory bowel disease have an elevated risk of developing colorectal cancer (CRC). Whether the gut microbiota also contributes to the development of CRC is less well understood. Arthur et al. (p. 120, published online 16 August; see the Perspective by Schwabe and Wang) now show that the microbiota does indeed promote tumorigenesis in an inflammation-driven model of CRC in mice. Although germ-free mice were protected against developing cancer, colonization of mice with Escherichia coli was sufficient to drive tumorigenesis.
Abstract
Inflammation alters host physiology to promote cancer, as seen in colitis-associated colorectal cancer (CRC). Here, we identify the intestinal microbiota as a target of inflammation that affects the progression of CRC. High-throughput sequencing revealed that inflammation modifies gut microbial composition in colitis-susceptible interleukin-10–deficient (Il10−/−) mice. Monocolonization with the commensal Escherichia coli NC101 promoted invasive carcinoma in azoxymethane (AOM)–treated Il10−/− mice. Deletion of the polyketide synthase (pks) genotoxic island from E. coli NC101 decreased tumor multiplicity and invasion in AOM/Il10−/− mice, without altering intestinal inflammation. Mucosa-associated pks+ E. coli were found in a significantly high percentage of inflammatory bowel disease and CRC patients. This suggests that in mice, colitis can promote tumorigenesis by altering microbial composition and inducing the expansion of microorganisms with genotoxic capabilities.
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Science
Volume 338 | Issue 6103
5 October 2012
5 October 2012
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Copyright © 2012, American Association for the Advancement of Science.
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Received: 17 May 2012
Accepted: 1 August 2012
Published in print: 5 October 2012
Acknowledgments
We thank M. Bower and S. Tonkonogy of the National Gnotobiotic Rodent Resource Center at University of North Carolina (UNC) and North Carolina State University for assistance with gnotobiotic mice (NIH P40 R018603). Histology was performed at the Center for Gastrointestinal Biology and Diseases histology core (P30 DK034987). This work was supported by funding from NIH T32 DK007737 (J.C.A.), R01 DK73338 (C.J.), R01 DK47700 (C.J.), R01 CA136887 (T.O.K.), R01 DK53347-11 (K.W.S./A.B.S.), the American Institute for Cancer Research (C.J.), UNC University Cancer Research Fund (C.J.), New York Presbyterian/Weill Cornell Medical College (K.W.S.), Crohn’s and Colitis foundation UK (B.J.C.), the NIH Research Specialist Biomedical Research Center in Microbial Disease (J.M.R.), the North West Cancer Research Fund UK (B.J.C.), and the Canadian Institutes of Health Research MOP#114872 (A.S.). T.A. is supported by a scholarship from King Abdulaziz University, through the Saudi Arabian Cultural Bureau in Canada. J.M.R. is a member of advisory boards for Atlantic, Procter and Gamble, and Falk and has received speaking honoraria from Abbott, Falk, Ferring, GlaxoSmithKline, Procter and Gamble, Schering Plough, Shire, and Wyeth. All data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Illumina sequencing data are deposited in National Center for Biotechnology Information’s (NCBI’s) sequence read archive (SRA) and are accessible under SRA055272. Inflammation PCR array data are deposited in NCBI’s Gene Expression Omnibus (GEO) and are accessible through GEO series accession no. GSE39085. This work is in the memory of Mathieu Jobin, Lyne Gauthier, and Janine Drysdale.
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