Microengineered Human Gut‐on‐a‐Chip for Dissecting Intestinal Inflammatory Disease

Human intestinal inflammatory diseases involve debilitating inflammation and mucosal injury caused by complex interactions between gut microbes, intestinal mucosa and immune components. However, it has not been possible to precisely define how these interacting factors contribute to the disease development or to responses to clinical therapies because human‐relevant experimental models that can independently control these factors do not exist. We developed a 'Gut‐on‐a‐Chip' microdevice lined by intestinal villi that mimics the structure and function of living intestine. The physiological microenvironment was recreated by flowing fluid and exerting mechanical cyclic deformations that emulate peristalsis. We used this model to independently vary potential contributors to human intestinal inflammation and epithelial injury. We found that pathological destruction of intestinal villi resulted when the villi were challenged to luminal stimulation such as lipopolysaccharide and immune cells, simultaneously. These intestinal injuries induced secretion of four proinflammatory cytokines that were necessary and sufficient to induce villus injury, which were suppressed by co‐administering probiotic or antibiotic therapy. Our results can lead to the development of a humanized in vitro disease model that faithfully mimics human intestinal pathophysiology observed in IBD patients, which can be used to dissect disease mechanisms and determine the efficacy of new drugs.