The environment of the intestinal lumen changes rapidly within the first month of life. The neonatal intestine must therefore adapt from birth. Immunosurveillance of molecules in the lumen is a central feature of this process. The rapid increase in short chain fatty acids, particularly butyrate, reflects the changes due to bacterial colonization and the introduction of diet. Butyrate molecules therefore carry information about the intestinal milieu. Appropriate immunological responses to their uptake by the intestinal epithelium constitute an example of innate immunity. This proposal will study the hypothesis that short chain fatty acids regulate the expression of enterocyte molecules that act on the mucosal immune system. Preliminary data has shown that butyrate up-regulates the secretion of the alpha- chemokines, IL-8 and macrophage inflammatory protein-2 by epithelial cells stimulated with IL-1 while down-regulating the beta-chemokine, monocyte chemoattractant protein-1. In addition, butyrate alters the profile of IGF binding proteins constitutively secreted by epithelial cells. First, the mechanisms by which short chain fatty acids alter chemokine expression in epithelial cells will be examined. The proposal will study both chromosomal regulation and regulation by regulatory proteins that bind to promoter DNA. Accessibility of DNA to DNase I will show if butyrate directly alters histones attached to chemokine genes in cultured epithelial cells; interruption of protein synthesis will demonstrate if butyrate acts through the synthesis of nuclear binding proteins. The effect of histone acetylation on chemokine expression in vivo will be examined in mice. Second, the ontogeny of histone acetylation will be related to IGF binding protein expression in vivo. The intermediate metabolite(s) of butyrate responsible for regulating IGF binding protein secretion will be investigated, using blockers of butyrate uptake and non-metabolizable analogues. Third, the proposal will study the effect of enhancing chemokine expression in epithelial cells, by linking a chemokine to an epithelial cell-specific promoter in transgenic mice. The luminal milieu is a major factor in the development of necrotizing enterocolitis. A study of how luminal molecules regulate intestinal immune function will help our understanding of the pathogenesis of this condition.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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General Medicine A Subcommittee 2 (GMA)
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Massachusetts General Hospital
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