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Pathogenesis and Therapy of Ulcerative Colitis - From Sequence to Mechanisms

Subject Area Gastroenterology
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 418055832
 
Final Report Year 2024

Final Report Abstract

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), remains a major clinical challenge, affecting over 400,000 people in Germany. While advances like anti-TNFα antibodies and Janus kinase inhibitors have improved outcomes, many patients still require surgery, and predicting disease progression or selecting optimal treatments remains difficult. Emerging genetic research suggests IBD is a continuum of disorders, with dis-ease location playing a significant role, highlighting the need for reclassification using clinical, imaging, and molecular data. Omics technologies, particularly next-generation sequencing (NGS), have revolutionized our understanding of IBD by revealing genetic predispositions, mo-lecular signatures, and immune responses. However, integrating these insights with clinical data remains a challenge. The TRR 241 consortium developed the IBDome platform to ad-dress this. IBDome organizes large-scale omics data alongside clinical information. IBDome aims to become the largest IBD-related database in Germany, identifying new therapeutic targets and predictive biomarkers. This proposal focused on sequencing samples from distinct patient cohorts at the Universitätsklinikum Erlangen and the Charité – Universitätsmedizin Berlin, creating a unique resource for generating hypotheses on IBD-related genes, proteins, and pathways. These sequencing data generated during the funding period contributed to several publications that advanced the understanding of IBD pathomechanisms. For example, Horn et al. (2024) analyzed expression data in IBD patients treated with vedolizumab using mass cytometry and single-cell RNA sequencing. They identified significant changes in immune cell populations and T cell receptor diversity, uncovering a T cell signature linked to non-response, emphasizing the importance of predictive signatures for personalized treatments. Similarly, Lehmann et al. (2024) conducted the first multiplexed single-cell analysis of immune cells in CD fistulas, finding altered MMP9 expression correlated with matrix remodeling and a strong association between MMP9+ neutrophils and cytotoxic T cells in fistulas and colitis. Schulze et al. (2023) compared ontamalimab and vedolizumab, the first one currently in clinical trials, the latter approved for IBD treatment. Ontamalimab induced internalization of the MAdCAM-1 complex and inhibited T cell adhesion like vedolizumab but also uniquely blocked L-selectin-dependent immune cell rolling. Single-cell RNA sequencing revealed specific clusters in on-tamalimab-treated lamina propria cells, suggesting activation of redundant adhesion pathways. Further exploring immunometabolism, Schulz-Kuhnt et al. (2024) examined ACLY in mucosal T cells. ACLY, essential for metabolism and proinflammatory function, was downregulated in inflamed lamina propria cells. ACLY-deficient CD4+ T cells showed reduced inflammation and impaired cytokine production. Erkert et al. (2024) identified presenilin genes Psen1 and Psen2 as critical for intestinal homeostasis. Deleting these genes in mice caused rapid weight loss, spontaneous inflammation, and epithelial barrier disruption. Microbiota depletion prevented colitis but not weight loss, indicating that inflammation and wasting disease are independent processes. These findings underscore the vital role of presenilins in gut health.

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