Intestinal Organoids as a Patient-Specific Model System for Congenital Diarrheal Disorders

Without our intestines, we would not survive. They extract nutrients from our food, and take-up electrolytes and water from what we eat and drink. To regulate all of these processes, the intestinal wall produces a mixture of substances which are needed to get this done. Furthermore, the intestine is the first line of defense against pathogens which enter our digestive system as well. All of this complex machinery is largely regulated by a single sheet of cells, the intestinal epithelium. If, despite everything, this epithelium still gets damaged, it is usually quickly restored by rapidly dividing stem cells. Sometimes, however, a child is born with a genetic defect which results in an inability of the epithelium to establish or restore its balance. In severe cases this causes vomiting, diarrhea, and a shortage of nutrients and water. Sometimes this defect is unfortunately severe enough to become life-threatening to the child. Since these disorders occur only rarely, we often do not know exactly what mechanically goes wrong, let alone how we can treat such a disease. Luckily, a technology was developed in Utrecht about ten years ago which made it possible to grow living intestinal stem cells in the laboratory, as so-called mini-guts. This development enabled us for the first time to study live intestinal cells with rare genetic defects in the lab. My thesis describes how we used these mini-guts to study intestines of children with three rare intestinal disorders. Our research led to a better understanding of the detailed mechanism of disease, and with that might bring us one step closer to a treatment for these rare diseases.