Gut Immune Homeostasis of Plays an Essential Role in the Maintenance Epithelial Cell-Intrinsic Notch Signaling

Intestinal epithelial cells (IECs) have important functions as the first line of defense against diverse microorganisms on the luminal surface. Impaired integrity of IEC has been implicated in increasing the risk for inflammatory disorders in the gut. Notch signaling plays a critical role in the maintenance of epithelial integrity by regulating the balance of secretory and absorptive cell lineages, and also by facilitating epithelial cell proliferation. We show in this article that mice harboring IEC-specific deletion of Rbpj (RBP-J DIEC), a transcription factor that mediates signaling through Notch receptors, spontaneously develop chronic colitis characterized by the accumulation of Th17 cells in colonic lamina propria. Intestinal bacteria are responsible for the development of colitis, because their depletion with antibiotics prevented the development of colitis in RBP-J DIEC mice. Furthermore, bacterial trans-location was evident in the colonic mucosa of RBP-J DIEC mice before the onset of colitis, suggesting attenuated epithelial barrier functions in these mice. Indeed, RBP-J DIEC mice displayed increase in intestinal permeability after rectal administration of FITC-dextran. In addition to the defect in physical barrier, loss of Notch signaling led to arrest of epithelial cell turnover caused by downregulation of Hes1, a transcriptional repressor of p27 Kip1 and p57 Kip2. Thus, epithelial cell-intrinsic Notch signaling ensures integrity and homeostasis of IEC, and this mechanism is required for containment of intestinal inflammation. T he mucosal surface of the gastrointestinal tract is continuously exposed to a profusion of foreign Ags including food Ags, food-borne pathogens, and commensal bacteria. A single layer of columnar epithelial cells covering the intestinal mucosa serves as a barrier to protect the host from invasion by potential pathogens, as well as a sentinel to warn of their presence. Epithelial stem cells located at the crypt bottom continuously divide to produce transit-amplifying cells, which can then divide several times before creating terminally differentiated epithelial cell lin-eages: absorptive enterocytes and three types of secretory epithelial cells, namely, goblet cells, enteroendocrine cells, and Paneth cells. Under physiological conditions, the cellular composition of the intestinal epithelium is kept in balance; however, disruption of this homeostatic state has been associated with various gastrointestinal diseases including ulcerative colitis (UC) (1), experimental colitis induced by dextran sodium sulfate (DSS) (2), and an infection model with Citrobacter rodentium (3, 4). These findings raise the possibility that the balanced composition of the four types of intestinal epithelial cells (IECs) is essential for the maintenance of intestinal homeostasis …