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

TLR介导的微生物群-宿主相互作用在调节肠道稳态和炎症中的作用

• 批准号: 237277328
• 负责人: Professor Dr. Manolis Pasparakis
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/237277328?language=en
• 关键词: TLR; mediated; microbiota; host; interaction

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.

肠腔中有数万亿共生细菌，它们提供必要的消化支持，但也影响粘膜和全身免疫反应的调节。宿主细胞和微生物群之间的相互作用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），是病因不明的肠道慢性炎症性疾病。肠道微生物群和宿主免疫系统之间的串扰失调目前被认为是导致IBD的主要因素。单层肠上皮形成了将腔内容物与粘膜分离的机械屏障，但也提供了直接调节微生物群和宿主免疫系统并与其相互作用的主动免疫屏障。肠上皮细胞与微生物群和宿主免疫系统的相互作用被认为是调节肠内稳态的关键，然而调节上皮细胞对肠细菌和粘膜免疫细胞的应答的机制仍然知之甚少。我们以前发现，通过上皮特异性敲除NEMO/IKK γ抑制肠上皮中NF-κB信号传导，触发了严重慢性结肠炎的自发发展。在这些上皮特异性NEMO敲除小鼠中结肠炎的发展取决于MyD 88介导的TLR信号传导和肠道细菌的存在。在这个项目中，我们的目标是解决宿主和微生物群之间TLR介导的串扰在肠道稳态和炎症调节中的作用。在该项目的第一部分，我们将使用遗传小鼠模型来解决TLR信号转导诱导上皮特异性NEMO敲除小鼠慢性结肠炎症发病机制的机制。在该项目的第二部分，我们将使用小鼠模型，允许诱导抑制TLR信号，特别是在肠上皮细胞，以解决上皮TLR信号在肠道微生物群落组成的调节作用。总之，这些研究将提供重要的信息，这些信息将推动当前技术水平的理解TLR介导的控制宿主和微生物群之间的串扰的机制及其在上皮稳态和炎症调节中的影响。