The pathology of intestinal motility disturbances often involves inflammatory processes. A good example thereof if the pathogenesis of surgery-induced Postoperative ileus (POI), which is a common consequence of abdominal surgery that increases morbidity and hospitalization. Intestinal handling and manipulation during surgery leads to specific recruitment in inflammatory infiltrates to the smooth muscle layer in the intestine. Previously we showed in a mouse models and human samples taken after surgery that intestinal manipulation leads to inflammation of the muscularis externa and motility disturbances. This was independent of toll-like receptor or TRIF signaling, yet dependent on MyD88, pointing to a crucial role for IL-1R-type-I (IL1R1) in POI. Both IL1α and IL1β were secreted from ME explants following IM, but surprisingly, IL1α or -β production was independent of canonical inflammasome as ASC-deficient mice were not protected from POI. We have further demonstrated that IL-1R signaling leading to POI occurs in the non-hematopoietic cell compartment, and involved IL1R1 activation on enteric glial cells within the myenteric plexus. Human small bowel cross-sections confirmed IL1R1 immunoreactivity within ganglia of the myenteric plexus. I will discuss the implications of these findings for inflammation-induced disturbances in intestinal motility, and epithelial barrier disruption, and involve the potential treatment options to intervene with this pathways.