Immune:microbiota cross-talk in regulation and repair of intestinal inflammation

免疫系统是维持我们身体和环境之间屏障的核心，肠道在这方面提出了特别的挑战，因为它们经常接触微生物、食物，甚至感染。然而，肠道细胞的类型和它们用来维持免疫健康，同时防止感染和限制过度炎症造成的损害的核心机制还不完全清楚。由于肠炎性疾病可能是严重的，并危及生命，因此迫切需要更好地从机制上了解这些过程。炎症性肠病(包括溃疡性结肠炎和克罗恩病)提供了一个突出的例子，说明了调节屏障部位免疫的重要性，以及当这种免疫失衡时会发生什么。这些慢性、复发的疾病伴随着巨大的痛苦，据估计，英国每250人中就有1人受到影响。因此，更好地了解调节屏障部位炎症的过程对于未来开发新的治疗方法以预防影响全球数百万人的一系列疾病至关重要。哺乳动物肠道含有数万亿种共生或常驻微生物，微生物组成的变化直接与各种慢性炎症条件有关，包括炎症性肠道疾病的出现、寿命和严重程度。然而，对这些微生物如何在肠道疾病期间影响免疫、炎症和组织修复的了解仍然极其有限。生活在肠道中的寄生虫在组织中迁移和破裂时往往会造成重大损害。因此，这类寄生虫进化出了有效的策略，以确保肠道炎症得到“控制”，促进受损组织的快速有效修复，同时防止肠道内容物危险地扩散到底层组织和循环中。这些属性使寄生虫感染成为揭示调节肠道炎症和组织损伤的重要机制的理想实验系统。本项目旨在使用小鼠寄生虫感染的实验系统来显著增加我们对宿主免疫细胞和驻留微生物之间的相互作用的了解，以及这种对话在控制肠道炎症和损伤方面的重要性。更具体地说，我们的目标是发现管理这种相互作用的新机制，定义“受调控的”肠炎和组织修复的关键特征，这些特征可能成为未来开发针对广泛疾病的新疗法的候选者。

The immune system is central to maintaining the barrier between our bodies and the environment, with the intestines presenting a particular challenge in this regard given their constant exposure to microbes, food, and even infections. However, the intestinal cell types and the core mechanisms they employ to maintain immune health while protecting against infection and limiting damage caused by excessive inflammation are not completely understood. As inflammatory diseases of the intestine can be severe and life-threatening, better mechanistic understanding of these processes is urgently required. Inflammatory bowel diseases (including ulcerative colitis and Crohn's disease) provide a striking example of the importance of regulated barrier site immunity, and what can happen when this becomes unbalanced. These chronic, relapsing conditions are accompanied by significant suffering, with an estimated 1 in 250 people affected in the UK. Thus, better understanding of the processes that regulate inflammation at barrier sites is vital to enable future development of novel therapies to prevent a wide range of diseases that affect millions of people worldwide.Mammalian intestines contain trillions of 'commensal' or resident microbes, and alterations in microbial composition have been directly implicated in a variety of chronic inflammatory conditions, including emergence, longevity and severity of inflammatory bowel diseases. However, understanding of how these microbes influence immunity, inflammation and tissue repair during intestinal disease is still extremely limited.Parasitic worms that live in the intestines often cause significant damage as they migrate and rupture through tissues. Consequently, such parasites have evolved potent strategies to ensure 'regulated' intestinal inflammation, promoting rapid and effective repair of damaged tissues, while preventing the dangerous spread of gut contents into the underlying tissues and circulation. These attributes make parasitic worm infections ideal experimental systems to uncover vital mechanisms responsible for regulation of intestinal inflammation and tissue damage.This project aims to use an experimental system of parasitic worm infection in mice to dramatically increase our understanding of cross-talk between host immune cells and resident microbes, and the importance of this dialogue in controlling intestinal inflammation and damage. More specifically, we aim to discover novel mechanisms governing this interplay, to define key features of 'regulated' intestinal inflammation and tissue repair that could be candidates for future development of new therapies against a wide range of diseases.