547 Effects of Substance P on Pro and Anti-Inflammatory Responses of Human Mesenteric Preadipocytes Isolated From IBD Patients

Abstract

Oxytocin (OT) is best known for its hormonal roles in milk let down and parturition. It has also been found in neurons that project within the brain and plays roles in mediating the central effects of nurturing stimuli. We have recently demonstrated that a subset of enteric neurons expresses OT and that about 70% of adult enteric neurons express the oxytocin receptor (OTR). OTR expression, which is developmentally regulated, also occurs in crypt epithelial cells where it concentrates at junctional complexes, particularly at the crypt-villus boundary. We tested hypotheses that endogenous enteric OT signaling affects intestinal motility, inflammation, and mucosal homeostasis. Dry stool mass and fecal water content were found to be greater in mice lacking OTR (OTRKO) than in WT mice. Total gastrointestinal transit time in OTRKO animals was also faster than that of WT animals; however, the time OTRKO mice required to expel glass beads inserted into their rectum was greater than that of WT animals. The severity of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in OTRKO mice was more severe compared to that in WT animals. Clinical scores (aggregating weight loss, stool blood and consistency), histological damage scores, and abundance of transcripts encoding pro-inflammatory cytokines and chemokines, were all significantly greater in OTRKO than in WT mice. Administration of exogenous OT, moreover, ameliorated TNBS-induced colitis in WT mice. Absorption of FITC-dextran was greater in OTRKO than in WT, suggesting that intestinal macromolecular permeability is increased in the absence of OT signaling. Exudative enteropathy, however, did not occur in OTRKO mice and following its intravenous infusion, horseradish peroxidase was found to be trapped at tight junctions between enterocytes. Villus height and crypt depth were each smaller in the intestines of OTRKO than WT mice, suggesting that signaling by crypt epithelial OTR plays a role in mucosal homeostasis. The current study supports the idea that enteric oxytocinergic signaling is physiologically significant; it slows intestinal propulsion, modulates inflammation, dampens macromolecular permeability, and contributes to the maintenance mucosal homeostasis. Observations are consistent with an overarching hypothesis that oxytocinergic signaling counterbalances effects of other molecules, such as corticotrophin releasing hormone, which mediate effects of stress. If so, then congenital or acquired defects in enteric oxytocinergic signaling may decrease resistance to stress and thus contribute to the pathophysiology of intestinal disorders, such as irritable bowel syndrome or inflammatory bowel disease. Development of means of initiating or enhancing oxytocinergic signaling may also be useful in treating stress-related disorders.