Tissue destruction and healing in Celiac Disease

PROJECT SUMMARY Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by dietary gluten in HLA-DQ2+ and/or HLA-DQ8+ individuals, which currently affects 1% of the global population. A gluten-free diet (GFD) is, to this date, the treatment of choice for CeD. However, 50% of CeD patients are unable to effectively adhere to a diet that sustainably excludes gluten, with many patients suffering from inadvertent gluten exposure. Moreover, over 30% of CeD patients have persistent high symptom burdens, resulting from continued mucosal damage, despite adhering to a GFD. Persistent mucosal damage on a GFD is associated with several severe complications, including malignancies, especially lymphomas and bone diseases. In addition, patients with active CeD display a wide range of clinical presentations, including metabolic defects (vitamins, iron, and cholesterol) that are not correlated to the degree of tissue damage. Although much progress has been made in understanding CeD, major gaps remain, notably regarding the biological mechanisms involved in different clinical presentations and the inconsistent healing process. For instance, it is poorly understood why, independently from the degree of villous atrophy, certain patients display nutrient and lipid deficiencies, whereas others have normal levels of vitamins, cholesterol, and iron. Furthermore, while there is evidence for a role of the microbiome in CeD, we lack information on small-intestinal mucosal microbiota in human CeD (which is more likely to have metabolic effects and directly interact with the immune system). Finally, we have little knowledge about interactions between gluten, intestinal epithelial cells (IECs), immune cells, and the microbiota, and how they are linked to the different CeD clinical phenotypes. Our RC2 proposal will test the hypothesis that CeD is a heterogeneous disorder, while attempting to define interactions between IECs, microbiota, immune system, and genetics that underlie differences in clinical presentation, severity of tissue destruction, and the ability to heal. It will also address critical gaps in our understanding of CeD pathogenesis and clinical presentations, and develop tools for non-invasive monitoring of CeD patients. We have assembled a team of internationally recognized experts in the field of CeD, epithelial cell biology, mucosal immunology, microbiome, and chemistry. The RC2 proposal is anchored around multi-omics studies performed in the context of cross-sectional and interventional gluten challenge and de-challenge studies, on 445 well-characterized adult and pediatric patients. The proposed specific aims are: 1) Developing an approach to precision medicine in CeD; 2) Deciphering the mechanisms associated with tissue destruction and healing in CeD, 3) Developing non-invasive tools for monitoring CeD patients, and 4) Developing research resources for the scientific and medical community to advance patient care as well as discovery-based and hypothesis-generating science. This application aims to generate the much- needed knowledge base and resources to further our understanding of CeD pathogenesis and its heterogeneity, improve individualized patient care and follow-up, and develop new therapeutic and preventive targets.