Pathogenesis and Therapy of Ulcerative Colitis - From Sequence to Mechanisms

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Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis and presents a chronic intestinal yet incurable disease group. Although the introduction of novel therapies has improved the overall quality of life, there is still a substantial subgroup with an unsatisfactory disease course. Besides a better understanding of the pathogenesis, unmet needs include the detailed dissection of IBD subtypes, the prediction of the disease course as well as causative and disease-specific therapies. In order to fill this knowledge gap, we are developing within the framework of the newly established Collaborative Research Center project "Immune-Epithelial Communication in Inflammatory Bowel Diseases; IEC in IBD" an integrated platform which merges large scale omic-datasets from IBD patients with corresponding clinical disease status, denoted IBDome. The database will be realized on a platform that is similar to already established platforms for solid cancers, where one of the project contributors was mainly involved in. The data will consist of clinical data and biomedical information derived from comprehensive molecular characterization of collected intestinal tissue, peripheral blood and stool using RNA sequencing, exome sequencing, 16s microbiome sequencing, mass cytometry (cytometry by time of flight; CyTOF), and histopathology. Within the framework of the project we are currently establishing a Crohn's disease cohort for IBDome. However, an ulcerative colitis cohort is currently missing. Aim of this project is to complement IBDome by including an ulcerative colitis cohort with three major aims: i) provide a yet lacking in-depth analysis of ulcerative colitis patients with active and inactive disease, ii) identify mechanisms and pathways discriminating ulcerative colitis from Crohn’s disease and iii) identify predictors of response for three treatment strategies, namely TNF-alpha antibodies, anti-integrin antibodies (vedolizumab) as well as the tyrosine kinase inhibitor tofacitinib. The integrated biomolecular, imaging, and clinical data (disease phenotype, disease activity, medication, complications) and its bioinformatics analyses will be made available through a web-based front-end to all researchers within the project in order to enable further exploration of the data and generation of testable hypotheses. We envision to further developing IBDome to a reference database for IBD during the course of the project, which will be populated with a large number of patient samples analyzed using both, deep and broad profiling. Hence, we will provide a central resource platform not only for the project but also for the scientific community and thereby strengthen translational research and enable novel insights into IBD pathogenesis and ultimately the discovery of novel therapeutic strategies.