Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
J Exp Med. 2019 Oct 7;216(10):2378-2393. doi: 10.1084/jem.20181939. Epub 2019 Jul 29.
Chronic inflammation and gut microbiota dysbiosis, in particular the bloom of genotoxin-producing 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 strains in the azoxymethane/dextran sulfate sodium colitis model was driven by molybdoenzyme-dependent metabolic pathways. Oral administration of sodium tungstate inhibited molybdoenzymes and selectively decreased gut colonization with genotoxin-producing 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, -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.
慢性炎症和肠道微生物群落失调，特别是产遗传毒素菌株的过度生长，是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落代谢和组成的精确编辑是否可以降低结肠炎相关结直肠癌（CAC）小鼠模型中肿瘤发展的风险。在氧化偶氮甲烷/葡聚糖硫酸钠结肠炎模型中，实验引入的菌株的扩张是由钼酶依赖性代谢途径驱动的。口服钨酸钠抑制钼酶，并选择性地减少产遗传毒素的和其他肠杆菌科的肠道定植。限制肠杆菌科的过度生长可减少肠道炎症，并降低两种 CAC 模型（氧化偶氮甲烷/葡聚糖硫酸钠结肠炎模型和氧化偶氮甲烷处理的 Apc 缺陷小鼠）中结肠肿瘤的发生率。我们得出结论，在慢性炎症期间对产促肿瘤性肠杆菌科进行代谢靶向是预防由肠道微生物群落失调引起的恶性肿瘤发展的一种合适策略。
