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

点击翻译按钮获取中文摘要

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.