Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment
Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment
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DOI：
10.1093/infdis/jiw069
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发表时间：
2016-07-01
影响因子：
6.4
通讯作者：
Sears, Cynthia L.
中科院分区：
文献类型：
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作者：
Shields, Christina E. DeStefano;Van Meerbeke, Sara W.;Sears, Cynthia L.
背景慢性炎症和结肠微生物群的组成与人类结直肠癌有关。人肠道致炎性脆弱拟杆菌（ETBF）与炎症性肠病和结直肠癌有关，在我们的小鼠模型中，它会引起白细胞介素17 A（IL-17 A）依赖性结肠肿瘤。在这些研究中，我们假设ETBF的持续定植是肿瘤发生所必需的。我们建立了一种用抗生素头孢西丁清除小鼠ETBF的方法。在实验期间用ETBF定殖多发性肠肿瘤小鼠或在5或14天后清除感染。然后评价大体肿瘤和/或微腺瘤。同时，在野生型同窝仔中评估IL-17 A表达。头孢西丁治疗导致ETBF定植的完全和持久清除。我们观察到，在头孢西丁治疗前，随着ETBF定植持续时间的增加，结肠肿瘤中位数逐渐增加。ETBF根除也显著降低了粘膜IL-17 A的表达。ETBF清除的时间深深地影响结肠腺瘤形成，定义了在该鼠模型中结肠对IL-17 A依赖性肿瘤发生敏感的时期。该模型系统可用于研究促成IL-17 A依赖性结肠肿瘤起始的微生物群依赖性和分子机制。
Background. Chronic inflammation and composition of the colon microbiota have been associated with colorectal cancer in humans. The human commensal enterotoxigenic Bacteroides fragilis (ETBF) is linked to both inflammatory bowel disease and colorectal cancer and, in our murine model, causes interleukin 17A (IL-17A)-dependent colon tumors. In these studies, we hypothesized that persistent colonization by ETBF is required for tumorigenesis.Methods. We established a method for clearing ETBF in mice, using the antibiotic cefoxitin. Multiple intestinal neoplasia mice were colonized with ETBF for the experiment duration or were cleared of infection after 5 or 14 days. Gross tumors and/or micro-adenomas were then evaluated. In parallel, IL-17A expression was evaluated in wild-type littermates.Results. Cefoxitin treatment resulted in complete and durable clearance of ETBF colonization. We observed a stepwise increase in median colon tumor numbers as the duration of ETBF colonization increased before cefoxitin treatment. ETBF eradication also significantly decreased mucosal IL-17A expression.Conclusions. The timing of ETBF clearance profoundly influences colon adenoma formation, defining a period during which the colon is susceptible to IL-17A-dependent tumorigenesis in this murine model. This model system can be used to study the microbiota-dependent and molecular mechanisms contributing to IL-17A-dependent colon tumor initiation.