Intestinal epithelial cells: Central coordinators in Inflammatory Bowel Disease and targets for treatment

Many patients with inflammatory bowel diseases (IBD) experience frequent relapses and prolonged periods of severe symptoms while various drugs are tested through a trial-and-error approach. Treatments for IBD range from classic anti-inflammatory agents to antibodies and small molecules that more specifically target parts of the immune system. However, these treatments do not offer a cure and their effects can be unpredictable. Medications are mainly used as induction therapy to reduce inflammation and achievie mucosal healing, and as maintenance therapy to sustain remission and prevent relapses. Since IBD manifests as inflammatory diseases, most IBD research has focused on immune cell-mediated mechanisms. Our understanding of intestinal epithelial cells as target for treatments has been limited, particular regarding mechanisms related to promoting mucosal healing and maintaining remission. There are few, if any, drugs designed to target intestinal epithelial cells in IBD, and we do not know whether drugs developed to affect immune cells have positive or negative effects on epithelial functions. The main aim for this project is to is to provide insights into IBD pathobiology and bring forward detailed mechanistic knowledge about the role of epithelial cells in IBD that can facilitate precision medicine for this patient group. We use advanced 3D organoid technology to gain mechanistic understanding of the mode of action of approved and emerging IBD drugs on epithelium, identify whether drugs designed against immune cell show adverse effects in epithelial cells, and identify novel treatment options targeting intestinal epithelial cells. Organoids derived from patient-derived intestinal biopsies ("mini-guts") recapitulate important features of epithelium in a donor-specific manner. In a collaborative work within the CAG-IBD (https://www.ntnu.edu/cag-ibd/), we published a paper in August 2024 that demonstrates that patient-derived organoids can be a useful physiologically relevant model to study the impact of genetics and single nucleotide polymorphisms (SNPs) on inflammation in IBD. Since the project’s inception in December 2023, we have established organoids from a well-characterised anti-TNF patient cohort, which are now used alongside other samples in our extensive IBD biobank for drug-screening experiments.

We hypothesize that intestinal epithelial cells (IECs) are significantly more central in gut inflammation than previously acknowledged and challenge the view that immune cells should be the main target for treatment for Inflammatory Bowel Diseases (IBD). Every IBD patient presents with a unique disease and treatment history, and their own hereditary and environmental backdrop. This IBD cohort heterogeneity can only be captured through combinatory analyses of clinical information and laboratory results from real-life biological material or patient-derived ex vivo models faithfully reproducing the heterogeneity. Therefore, the proposed project has a genuine translational approach focusing on systematic clinical observations in parallel with research on patient specific epithelial organoids (“mini-guts”) that can reproduce patient heterogeneity. We will perform state-of the art functional studies and evaluate approved and investigational IBD-drugs as treatment options targeting observed physical, biochemical, and immunological intestinal epithelial dysfunctions. Since research into IBD pathobiology has mainly focused on immune cell-mediated mechanisms there is very limited information about how the drugs commonly used in IBD affect epithelial functions in health and disease. The American Crohn’s & Colitis Foundation (ACCF) recently highlighted that “understanding the essential role of the intestinal epithelium in IBD is paramount, particularly since mucosa healing has become major endpoint in clinical management of patients”. The present project will directly answer important questions regarding IEC biology and meet challenges as stated by ACCF. The ambition for the project is to bring forward detailed mechanistic knowledge about the role of IECs in IBD that can facilitate precision medicine.