The epithelial cells lining the intestine control responses to gut bacteria, limiting intestinal damage in Crohn’s disease. A critical gene in this pathway is DUOX2, which is up-regulated in response to bacteria, and helps maintain intestinal health. We discovered that Crohn’s disease patients who carry genetic variants in DUOX2 are more likely to progress to fibrotic disease complications requiring surgery. We tested an intestinal gene signature for refractory pediatric Crohn’s disease in a database containing 2000 small molecules, identifying 140 which might be more effective therapies. Our studies will now utilize a novel Human Intestinal Organoid, or “mini-gut” model system for refractory pediatric Crohn’s disease that we have developed informed by genetic factors like DUOX2. We have prepared stem cells from pediatric Crohn’s disease patients who did or did not have DUOX2 genetic variants, and will differentiate them into white blood cells and human intestinal organoids. This novel model system will be used to test ways to modulate pathways linked to fibrosis in patients, by screening the top small molecules which we have identified as potentially beneficial. Our studies will advance precision medicine, by developing a platform to screen new therapies in patient-derived intestinal organoids with clinically important genetic variants.