Exploring the Regional Characteristics of Intestinal Drug Metabolism and Fibrogenesis

The intestine plays an important role in the absorption of, among others, nutrients and water, and intestinal malfunctioning will lead to a systemic imbalance of these components. This thesis focused on intestinal fibrosis, a pathological process that is characterized by the excessive accumulation of extracellular matrix proteins in the intestine, which will ultimately result in loss of function. Intestinal fibrosis is predominantly found in patients with Crohn’s disease. To this day, there remains an urgent need to find an effective therapy for intestinal fibrosis. This thesis delineates the use of precision-cut intestinal slice (PCIS) as a tool to study the pathophysiology of intestinal fibrosis, as well as a drug-screening platform. We successfully used this model to test the antifibrotic potential of putative drugs. Furthermore, we studied regional differences in fibrogenesis and drug metabolism. Essentially, the human PCIS model, which is highly efficient and relatively easy to use, may become an effective tool in exploring new antifibrotic drug candidates. Finally, PCIS are in good compliance with the 3Rs (replacement, reduction, and refinement), most notably with reduction, because the number of animals needed for research can be considerably reduced when using PCIS. In the future, human PCIS will hopefully fully replace animal studies for intestinal fibrosis research.