More than half of patients with inflammatory bowel disease (IBD) do not respond to any given drug in the long term, because the disease varies so much from person to person. The problem is that treatment is still largely one-size-fits-all, even though the underlying biology—the mix of gut microbes, immune cells, and signalling molecules—differs dramatically between patients. This project aims to fix that mismatch by systematically identifying distinct "pathotypes," or biological subtypes of IBD, and then building mouse models that faithfully reproduce each one. The researchers will then use those models to trace how specific cytokines (the chemical messengers that cells use to talk to each other) drive inflammation in each subtype, and test candidate drugs against them. Finally, they will validate the most promising drugs using gut tissue taken from real patients belonging to each pathotype. If successful, this work could transform IBD from a trial-and-error guessing game into a precision medicine approach, where a patient’s pathotype determines which drug they receive first. That would mean fewer failed treatments, fewer relapses, and a clearer biological rationale for choosing therapy—something that does not exist in routine IBD care today.
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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.
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