MICA: Tissue ecology in IBD-development and pathophysiological function

The intestine is one of the largest immune organs in the body. In health, a complex communication network ensures intestinal immune cells peacefully co-exist with the large number of microbes that inhabit the gut. To maintain this tolerance, epithelial cells that form the intestinal wall, underlying immune cells and fibroblasts constantly process signals from their environment. These signals can originate from the sensing of bacteria, or from molecules called cytokines that cells use to communicate with each other. Long-term disruption to any of these communication pathways can result in the development of chronic inflammation and disease.

Inflammatory bowel diseases (IBDs) are characterised by a damaging inflammation of the intestinal wall. There is no cure for IBD and patients go through unpredictable periods of relapse and remission. Genes, diet and other environmental factors result in a host-microbial dialogue that is highly individualised across patients. As a consequence, IBDs are highly variable in terms of disease behaviour, location and the response to therapies. Personalised therapies, however, are not standard practise for IBD, reflected by high failure rates of each of the different drugs, with more than 1 out of 2 patients not responding to treatment in the long-term.

In recent studies, we grouped patients with IBD that do not respond well to current therapies based on their cellular and molecular characteristics or 'pathotype'. In the proposed programme, we will characterise these IBD pathotypes in more detail and discover new ones. We will examine the cell types, microbes, signalling molecules and clinical features of each pathotype and develop mouse models that accurately reflect disease in these different patient groups. Using these mouse models, we will look at how cytokines control communication between epithelial cells, immune cells and fibroblasts to contribute to disease. Information gained from these studies will be used to design and test candidate therapies. Finally, we will validate the most promising drug candidates in experiments using gut tissues derived from IBD patients belonging to the different pathotypes.

Overall, we will generate new information about of the diversity of pathologic processes that drive inflammation in the intestine that can be used as a biological evidence-based guide for improving and personalized therapies in IBD.

IBD is a complex multifactorial disease involving maladaptation of the host microbe interface and ensuing relapsing and remitting chronic inflammation of the gastrointestinal tract. Encompassing Crohn's disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDu), IBD is extremely heterogeneous in disease phenotype, behaviour, location and response to therapy limiting our ability to direct new biological therapies to those most likely to benefit. In recent work we mapped distinct cellular and molecular pathways to discreet intestinal tissue niches termed pathotypes that underlie treatment non-response in IBD. Building on these results we will employ a multi-disciplinary approach, iterating between mouse models and study of human IBD tissue to provide mechanistic insight into pathotype development and function. Bulk and single cell sequencing alongside spatial transcriptomics and proteomics on human IBD tissue will be used to further characterise established pathotypes, as well as to identify new ones related to disease outcome measures. Mechanistic analysis will be performed using disease positioned mouse models that reproduce tissular pathotypes to identify upstream microbial drivers and sensing pathways triggering pathotype development, including the contribution of inflammasome and autophagy pathways to epithelial cell responses. In parallel, we will assess the contribution of cytokine networks and fibroblasts to the formation of pathotype-specific inflammatory tissue niches. Finally, pathologic processes identified in mouse models will be validated functionally in ex vivo patient tissue assays, and assessed for therapeutic utility. By generating new understanding of the diversity of tissular processes that underlie IBD heterogeneity, we aim to provide a biological evidence-based strategy for the therapeutic management of IBD.