Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer

Wenhan Zhu, Naoteru Miyata, Maria G. Winter, Alexandre Arenales, Elizabeth R. Hughes, Luisella Spiga, Jiwoong Kim, Luis Sifuentes-Dominguez, Petro Starokadomskyy, Purva Gopal, Mariana X. Byndloss, Renato L. Santos, Ezra Burstein, Sebastian E. Winter

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3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2378-2393
Number of pages16
JournalJournal of Experimental Medicine
Volume216
Issue number10
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Zhu, W., Miyata, N., Winter, M. G., Arenales, A., Hughes, E. R., Spiga, L., Kim, J., Sifuentes-Dominguez, L., Starokadomskyy, P., Gopal, P., Byndloss, M. X., Santos, R. L., Burstein, E., & Winter, S. E. (2019). Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer. Journal of Experimental Medicine, 216(10), 2378-2393. https://doi.org/10.1084/jem.20181939