TY - JOUR
T1 - Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer
AU - Zhu, Wenhan
AU - Miyata, Naoteru
AU - Winter, Maria G.
AU - Arenales, Alexandre
AU - Hughes, Elizabeth R.
AU - Spiga, Luisella
AU - Kim, Jiwoong
AU - Sifuentes-Dominguez, Luis
AU - Starokadomskyy, Petro
AU - Gopal, Purva
AU - Byndloss, Mariana X.
AU - Santos, Renato L.
AU - Burstein, Ezra
AU - Winter, Sebastian E.
N1 - Funding Information:
We thank Dr. R. Balfour Sartor (University of North Carolina, Chapel Hill, NC) and Dr. Mark Goulian (University of Pennsylvania, Philadelphia, PA) for providing E. coli strains. Work in S.E. Winter's laboratory was funded by the National Institutes of Health (AI118807 and AI128151), the Welch Foundation (I-1969-20180324), the Burroughs Wellcome Fund (1017880), and an American Cancer Society Research Scholar Grant (RSG-17-048-01-MPC). W. Zhu was supported by a Research Fellows Award from the Crohn's and Colitis Foundation of America (454921). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding agencies. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. S.E. Winter is listed as an inventor on patent application WO2014200929A1, which describes a treatment to prevent the inflammation-associated expansion of Enterobacteriaceae. The other authors declare no additional competing financial interests.
Funding Information:
Work in S.E. Winter’s laboratory was funded by the National Institutes of Health (AI118807 and AI128151), the Welch Foundation (I-1969-20180324), the Burroughs Wellcome Fund (1017880), and an American Cancer Society Research Scholar Grant (RSG-17-048-01-MPC). W. Zhu was supported by a Research Fellows Award from the Crohn’s and Colitis Foundation of America (454921). Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the funding agencies. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© 2019 Zhu et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019
Y1 - 2019
N2 - Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.
AB - Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing E. coli strains, are risk factors for the development of colorectal cancer. Here, we sought to determine whether precision editing of gut microbiota metabolism and composition could decrease the risk for tumor development in mouse models of colitis-associated colorectal cancer (CAC). Expansion of experimentally introduced E. coli strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited E. coli molybdoenzymes and selectively decreased gut colonization with genotoxin-producing E. coli and other Enterobacteriaceae. Restricting the bloom of Enterobacteriaceae decreased intestinal inflammation and reduced the incidence of colonic tumors in two models of CAC, the azoxymethane/dextran sulfate sodium colitis model and azoxymethane-treated, Il10-deficient mice. We conclude that metabolic targeting of protumoral Enterobacteriaceae during chronic inflammation is a suitable strategy to prevent the development of malignancies arising from gut microbiota dysbiosis.
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U2 - 10.1084/jem.20181939
DO - 10.1084/jem.20181939
M3 - Article
C2 - 31358565
AN - SCOPUS:85072993886
SN - 0022-1007
VL - 216
SP - 2378
EP - 2393
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -