Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.,Journal of Experimental Medicine

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Editing of the gut microbiota reduces carcinogenesis in mouse models of colitis-associated colorectal cancer.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2019-07-29 , DOI: 10.1084/jem.20181939
Wenhan Zhu ₁ , Naoteru Miyata _{2,

3} , Maria G Winter ₁ , Alexandre Arenales ₄ , Elizabeth R Hughes ₁ , Luisella Spiga ₁ , Jiwoong Kim ₅ , Luis Sifuentes-Dominguez ₆ , Petro Starokadomskyy ₂ , Purva Gopal ₇ , Mariana X Byndloss ₈ , Renato L Santos ₄ , Ezra Burstein _{9,

10} , Sebastian E Winter ₁₁

Affiliation

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
Digestive Disease Center, International University of Health and Welfare, Mita Hospital, Japan.
Departamento de Clinica e Cirurgia Veterinarias, Escola de Veterinaria, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Department of Clinical Science, Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX

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.

中文翻译：

肠道微生物群的编辑减少了结肠炎相关大肠癌小鼠模型的致癌作用。

慢性炎症和肠道微生物群失调，特别是产生基因毒素的大肠杆菌菌株大量繁殖，是导致结直肠癌发展的危险因素。在这里，我们试图确定肠道微生物群代谢和组成的精确编辑是否可以降低结肠炎相关大肠癌（CAC）小鼠模型中肿瘤发展的风险。乙二氧甲烷/葡聚糖硫酸盐钠结肠炎模型中实验引入的大肠杆菌菌株的扩展是由钼酶依赖的代谢途径驱动的。钨酸钠的口服抑制了大肠杆菌的钼酵素，并选择性地降低了产生基因毒素的大肠杆菌和其他肠杆菌科细菌对肠道的定殖。在两种CAC模型中，限制肠杆菌科细菌的开花减少了肠道炎症，并降低了结肠肿瘤的发生率，这两种模型分别是乙氧基甲烷/葡聚糖硫酸盐钠结肠炎模型和乙氧基甲烷治疗的Il10缺陷型小鼠。我们得出的结论是，在慢性炎症过程中以代谢性靶向前列腺癌菌是预防肠道微生物群营养不良引起的恶性肿瘤发展的合适策略。

更新日期：2019-10-07

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