Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process for a wide variety of injury and inflammatory conditions of the gut. Despite extensive investigation of inflammation-induced epithelial repair processes, currently there is a lack of epithelial targeted therapies for IBD. Patient-derived stem cell organoids provide a powerful physiological 3D model to study stem cell injury and repair, lineage and innate responses, barrier integrity and its interactions with the micro-environment.

Using 3D intestinal organoids, my study showed for the first time that there is an inherent stem cell-dependent developmental defect in the epithelium and barrier function of organoids derived from IBD patients. We show, subsequently, that intestinal organoids are an excellent tool to model the effect of chemically induced IBD agents on epithelial stem cell regulation. In parallel studies, we reveal novel mechanisms through which TNF signalling is essential for the proper specification and stem-cell niche function of colonic mesenchymal cells; providing new insights into why anti-TNF therapies fail for many IBD patients. My current study shows how the key bacterial metabolite, butyrate regulates innate responses of the intestinal epithelium in Crohn’s disease through a novel Type I Interferon signalling pathway, helping develop new target to predict response in non-responder IBD patients.

Thus, overall, we show that intestinal organoids are an excellent tool to model the many ways in which the epithelium contributes to mucosal healing in IBD and offers the potential for development as a tool for personalized medicine for screening therapeutics for inflammatory intestinal diseases.