Neurotensin is a proinflammatory neuropeptide in colonic inflammation

The neuropeptide neurotensin mediates several intestinal functions, includi ng chloride secretion, motility, and cellular growth. However, whether this peptide participates in intestinal inflammation is not known. Toxin A, an enterotoxin from Clostridium difficile, mediates pseudomembranous colitis i n humans. In animal models, toxin A causes an acute inflammatory response c haracterized by activation of sensory neurons and intestinal nerves and imm une cells of the lamina propria. Here we show that neurotensin and its rece ptor are elevated in the rat colonic mucosa following toxin A administratio n. Pretreatment of rats with the neurotensin receptor antagonist SR-48,692 inhibits toxin A-induced changes in colonic secretion, mucosal permeability , and histologic damage. Exposure of colonic explants to toxin A or neurote nsin causes mast cell degranulation, which is inhibited by SR-48,692. Becau se substance P was previously shown to mediate mast cell activation, we exa mined whether substance P is involved in neurotensin-induced mast cell degr anulation. Our results show that neurotensin-induced mast cell degranulatio n in colonic explants is inhibited by the substance P (neurokinin-l) recept or antagonist CP-96,345, indicating that colonic mast activation in respons e to neurotensin involves release of substance P. We conclude that neuroten sin plays a key role in the pathogenesis of C. difficile-induced colonic in flammation and mast cell activation.