TLR-mediated microbiota-host interaction in the regulation of intestinal homeostasis and nflammation

肠腔被数以万亿计的共生细菌定植，这些细菌提供必要的消化支持，但也影响粘膜和系统免疫反应的调节。宿主细胞和微生物区系之间的串扰现在被认为是胃肠道健康和疾病的主要决定因素。炎症性肠病(IBD)，包括克罗恩病(CD)和溃疡性结肠炎(UC)，是一种病因不明的慢性肠道炎症性疾病。肠道微生物区系和宿主免疫系统之间的串扰解除管制目前被认为是导致IBD的主要因素。单层肠上皮形成机械屏障，将腔内容物与粘膜隔开，但也提供主动的免疫屏障，直接调节微生物区系和宿主免疫系统并与其相互作用。肠道上皮细胞与微生物区系和宿主免疫系统之间的相互作用被认为是调节肠道内环境平衡的关键，然而调控上皮细胞对肠道细菌和粘膜免疫细胞反应的机制仍然知之甚少。我们之前的研究表明，上皮特异性敲除NEMO/κγ基因抑制了肠上皮细胞中的NF-IKB信号，从而触发了严重的慢性结肠炎的自发发展。在这些上皮特异性NEMO基因敲除小鼠中，结肠炎的发展依赖于MyD88介导的TLR信号和肠道细菌的存在。在这个项目中，我们的目标是解决TLR介导的宿主和微生物区系之间的串扰在调节肠道内稳态和炎症中的作用。在该项目的第一部分，我们将使用遗传小鼠模型来解决TLR信号诱导上皮特异性NEMO基因敲除小鼠慢性结肠炎的发病机制。在项目的第二部分，我们将使用小鼠模型，允许对TLR信号的诱导抑制，特别是在肠道上皮，以解决上皮TLR信号在调节肠道微生物群落组成中的作用。总之，这些研究将提供重要的信息，有助于了解TLR介导的控制宿主和微生物区系之间的串扰的机制以及它们在调节上皮内稳态和炎症方面的影响。

The intestinal lumen is colonised by trillions of commensal bacteria that provide essential digestive support but also influence the regulation of mucosal and systemic immune responses. The cross talk between host cells and the microbiota is now believed to be the major determinant of health and disease in the gastrointestinal tract. Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory conditions of the intestine with unclear aetiology. Deregulation of the cross talk between the intestinal microbiota and the host immune system is currently believed to be the main factor contributing to IBD. The single-layered intestinal epithelium forms a mechanical barrier separating the luminal contents from the mucosa but also provides an active immunological barrier directly regulating and interacting with both the microbiota and the host immune system. The cross-talk of intestinal epithelial cells with the microbiota and with the host immune system is believed to be critical for the regulation of intestinal homeostasis, however the mechanisms regulating epithelial responses to intestinal bacteria and mucosal immune cells remain poorly understood. We showed previously that inhibition of NF-κB signalling in the intestinal epithelium by epithelial specific knockout of NEMO/IKKgamma triggered the spontaneous development of severe chronic colon inflammation. The development of colitis in these epithelial-specific NEMO knockout mice depends on MyD88-mediated TLR signalling and on the presence of intestinal bacteria. In this project we aim to address the role of the TLR-mediated cross talk between the host and the microbiota in the regulation of intestinal homeostasis and inflammation. In the first part of the project we will use genetic mouse models to address the mechanisms by which TLR signalling induces the pathogenesis of chronic colon inflammation in mice with epithelial-specific NEMO knockout. In the second part of the project we will use mouse models allowing the inducible inhibition of TLR signalling specifically in the intestinal epithelium in order to address the role of epithelial TLR signalling in the regulation of the composition of the intestinal microbial communities. Together, these studies will provide important information that will advance the current state of the art in understanding the TLR-mediated mechanisms controlling the cross-talk between the host and the microbiota and their impact in the regulation of epithelial homeostasis and inflammation.