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Published on: September 7, 2013
Melanin-concentrating hormone (MCH) modulates C difficile toxin A-mediated enteritis in mice
E Kokkotou1, D O Espinoza, D Torres
1Division of Gastroenterology, Dana 501, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ekokkoto@bidmc.harvard.edu
Objective:
Melanin-concentrating hormone (MCH) is a hypothalamic orexigenic neuropeptide that regulates energy balance. However, the distribution of MCH and its receptor MCHR1 in tissues other than brain suggested additional, as yet unappreciated, roles for this neuropeptide. Based on previous paradigms and the presence of MCH in the intestine as well as in immune cells, its potential role in gut innate immune responses was examined.
Methods:
In human intestinal xenografts grown in mice, changes in the expression of MCH and its receptors following treatment with Clostridium difficile toxin A, the causative agent of antibiotic-associated diarrhoea in hospitalised patients, were examined. In colonocytes, the effect of C difficile toxin A treatment on MCHR1 expression, and of MCH on interleukin 8 (IL8) expression was examined. MCH-deficient mice and immunoneutralisation approaches were used to examine the role of MCH in the pathogenesis of C difficile toxin A-mediated acute enteritis.
Results:
Upregulation of MCH and MCHR1 expression was found in the human intestinal xenograft model, and of MCHR1 in colonocytes following exposure to toxin A. Treatment of colonocytes with MCH resulted in IL8 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 epithelial cells in the intestine.
Insights
Melanin-concentrating hormone (MCH) plays a role in gut inflammation. MCH deficiency or blocking MCH signaling reduces inflammation caused by Clostridium difficile toxin A.
Area of Science:
- Neuroendocrinology
- Gastroenterology
- Immunology
Background:
- Melanin-concentrating hormone (MCH) is a neuropeptide primarily known for regulating energy balance.
- MCH and its receptor (MCHR1) are found in the gut and immune cells, suggesting roles beyond the brain.
- The role of MCH in gut innate immunity, particularly in response to pathogens, was unexplored.
Purpose of the Study:
- To investigate the role of MCH in the innate immune response of the intestine.
- To examine the involvement of MCH and MCHR1 in Clostridium difficile toxin A-induced enteritis.
Main Methods:
- Human intestinal xenografts were used to study MCH and MCHR1 expression changes after exposure to Clostridium difficile toxin A.
- Colonocytes were treated with toxin A and MCH to assess MCHR1 and interleukin 8 (IL8) expression.
- MCH-deficient mice and immunoneutralization were employed to evaluate MCH's role in C. difficile toxin A-mediated enteritis.
Main Results:
- Clostridium difficile toxin A upregulated MCH and MCHR1 expression in the intestinal xenograft model and in colonocytes.
- MCH treatment of colonocytes led to increased IL8 expression, indicating a link to inflammatory pathways.
- MCH-deficient mice and mice treated with anti-MCH or anti-MCHR1 antibodies exhibited reduced intestinal inflammation and secretion.
Conclusions:
- Melanin-concentrating hormone (MCH) acts as a mediator in Clostridium difficile-associated enteritis.
- MCH may contribute to inflammation in the gut by acting on intestinal epithelial cells.
- These findings suggest MCH could be involved in the pathogenesis of other gut pathogens.
