Objective. Melanin Concentrating Hormone (MCH) is a hypothalamic orexigenic neuropeptide which regulates energy balance. However, the distribution of MCH and its receptor MCHR1 in tissues other than brain suggested additional, yet unappreciated, roles for this neuropeptide. Based on previous paradigms and the presence of MCH in the intestine as well as in immune cells, we examined its potential role in gut innate immune responses.
Methods. In human intestinal xenografts grown in mice, we examined changes in the expression of MCH and its receptors following treatment with C. difficile toxin A, the causative agent of antibiotic-associated diarrhea in hospitalized patients. In colonocytes, we examined the effect C. difficile toxin A treatment on MCHR1 expression, and of MCH on IL-8 expression. We used MCH-deficient mice and immunoneutralization approaches to examine the role of MCH in the pathogenesis of C.difficile toxin A-mediated acute enteritis.
Results. We found upregulation of MCH and MCHR1 expression in the human intestinal xenograft model, and of MCHR1 in NCM460 cells following exposure to toxin A. Treatment of colonocytes with MCH resulted in IL-8 transcriptional upregulation, implying a link between MCH and inflammatory pathways. In further support of this view, MCH deficient mice developed attenuated toxin A-mediated intestinal inflammation and secretion, as did wild-type mice treated with an antibody against MCH or MCHR1
Conclusion. These findings signify MCH as a mediator of C.difficile-associated enteritis and possibly of additional gut pathogens. MCH may mediate its proinflammatory effects at least in part by acting on intestinal epithelial cells.
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