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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI043472-01
Application #
2679049
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1998-08-01
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Takedachi, Masahide; Qu, Dongfeng; Ebisuno, Yukihiko et al. (2008) CD73-generated adenosine restricts lymphocyte migration into draining lymph nodes. J Immunol 180:6288-96
Sanderson, Ian R (2007) Dietary modulation of GALT. J Nutr 137:2557S-2562S
Sanderson, Ian R; Bustin, Stephen A; Dziennis, Suzan et al. (2004) Age and diet act through distinct isoforms of the class II transactivator gene in mouse intestinal epithelium. Gastroenterology 127:203-12
Ohtsuka, Yoshikazu; Sanderson, Ian R (2003) Dextran sulfate sodium-induced inflammation is enhanced by intestinal epithelial cell chemokine expression in mice. Pediatr Res 53:143-7
Naik, S; Kelly, E J; Meijer, L et al. (2001) Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium. J Pediatr Gastroenterol Nutr 32:449-53
Ohtsuka, Y; Lee, J; Stamm, D S et al. (2001) MIP-2 secreted by epithelial cells increases neutrophil and lymphocyte recruitment in the mouse intestine. Gut 49:526-33
Pender, S L; Quinn, J J; Sanderson, I R et al. (2000) Butyrate upregulates stromelysin-1 production by intestinal mesenchymal cells. Am J Physiol Gastrointest Liver Physiol 279:G918-24
Fusunyan, R D; Quinn, J J; Fujimoto, M et al. (1999) Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation. Mol Med 5:631-40
Siafakas, C G; Anatolitou, F; Fusunyan, R D et al. (1999) Vascular endothelial growth factor (VEGF) is present in human breast milk and its receptor is present on intestinal epithelial cells. Pediatr Res 45:652-7
Sanderson, I R (1998) Dietary regulation of genes expressed in the developing intestinal epithelium. Am J Clin Nutr 68:999-1005