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

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.

Intestinal inflammation is carefully regulated to enable clearance of pathogens while avoiding excessive responses against harmless challenges such as resident microbes and food. Although immune cells lie at the heart of this process, the specific cell types involved and the core mechanisms they employ are not completely understood. It is clear that commensal microbes and their products can influence almost every aspect of host health, including immune cell and cytokine networks, and promotion or regulation of mucosal inflammation. However, the mechanistic basis for this impact of the microbiota on intestinal health has not yet been defined. Our work will address the fundamental question of how barrier immunity is regulated by the microbiota from a novel perspective, using tissue-damaging helminth infection in mice to establish an inflamed yet 'regulated' intestinal environment. Using cutting edge approaches including multiparameter flow cytometry, imaging mass cytometry, shotgun metagenomics and metabolomics, we will define the immune, microbial and tissue repair features that are hallmarks of controlled intestinal inflammation. Guided by these results, we will use culturomics, faecal transplants, germ-free and transgenic mice to identify the role and importance of candidate bacteria, immune cells and mediators in regulation of intestinal inflammation and repair.

This innovative project will tackle the fundamental question of how barrier immunity is regulated from a novel perspective, linking together immune cell function and the microbiota to reveal core mechanisms that promote or regulate colonic inflammation and disease in the context of a relevant murine model of intestinal damage and repair. In addition to discovery in this important area, the information gained from this work will provide a platform for future research addressing mechanisms that regulate human inflammatory disease in the intestines, as well as in other mucosal sites such as the lung.