Mount Sinai, New York, NY 10029.
J Exp Med. 2014 Mar 10;211(3):457-72. doi: 10.1084/jem.20131587. Epub 2014 Mar 3.
The preferential localization of some neoplasms, such as serrated polyps (SPs), in specific areas of the intestine suggests that nongenetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB-EGF throughout the intestine but developed SPs only in the cecum. Here we show that a host-specific microbiome was associated with SPs and that alterations of the microbiota induced by antibiotic treatment or by embryo transfer rederivation markedly inhibited the formation of SPs in the cecum. Mechanistically, development of SPs was associated with a local decrease in epithelial barrier function, bacterial invasion, production of antimicrobials, and increased expression of several inflammatory factors such as IL-17, Cxcl2, Tnf-α, and IL-1. Increased numbers of neutrophils were found within the SPs, and their depletion significantly reduced polyp growth. Together these results indicate that nongenetic factors contribute to the development of SPs and suggest that the development of these intestinal neoplasms in the cecum is driven by the interplay between genetic changes in the host, an inflammatory response, and a host-specific microbiota.
一些肿瘤（如锯齿状息肉）在肠道的特定区域优先定位，这表明非遗传因素可能对其发生发展很重要。为了验证这一假说，我们利用在整个肠道表达 HB-EGF 但仅在盲肠中发展出锯齿状息肉的转基因小鼠。在这里，我们发现宿主特异性微生物组与锯齿状息肉有关，抗生素治疗或胚胎移植再衍生引起的微生物组改变显著抑制了盲肠中锯齿状息肉的形成。从机制上讲，锯齿状息肉的发生与上皮屏障功能局部下降、细菌入侵、抗菌物质产生以及包括 IL-17、Cxcl2、Tnf-α 和 IL-1 在内的几种炎症因子的表达增加有关。在锯齿状息肉中发现了大量的中性粒细胞，其耗竭显著减少了息肉生长。这些结果表明，非遗传因素有助于锯齿状息肉的发生，并提示这些肠道肿瘤在盲肠中的发展是由宿主遗传改变、炎症反应和宿主特异性微生物组之间的相互作用驱动的。
