Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Its major risk factors are prematurity and the introduction of enteric feedings. The severe necrotizing inflammation of the distal small intestine occurs at the time of initial colonization. Accordingly, we have hypothesized that NEC is an age-related disease that results from an inappropriate, immature enterocyte response to initial bacterial colonization after the introduction of oral feedings. In the previous granting period we have reported that intestinal microvillus membrane glycosylation (glycoconjugate bacterial receptors) is developmentally regulated via glycosyltransferases and that pathologic colonization and translocation occur more readily in immature than mature small intestine. We have also shown that fetal human enterocytes and intestinal biopsies respond excessively (inappropriately) to endotoxin (LPS IL-8 response) and exotoxin (cholera toxin secretory response) than do mature enterocytes and intestine. We have also shown that commensal bacteria elicit an inflammatory (IL-8) response in immature but not mature intestine. Collectively these observations provide strong evidence to support this hypothesis. Using established human fetal intestinal models which include two fetal small intestinal cell lines, organ culture of biopsies, a micro Ussing chamber technique and a fetal small intestinal transplant into scid/scid mice, we plan: (1) to determine the role of developmental regulation of microvillus surface glycosylation in microbial colonization and it's cellular mechanism(s); (2) define the cellular mechanisms of exotoxin interaction and endotoxin tolerance with the developing gut; and (3) devise strategies to correct these inappropriate immature intestinal responses using hormones and protective nutrients. Based on these studies, we should be able to consider future clinical trials using protective nutrients to prevent this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK070260-12
Application #
7046690
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
1994-05-01
Project End
2010-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
12
Fiscal Year
2006
Total Cost
$372,910
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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