Unlike the full term vaginally delivered infant, the premature infant is unprepared to deal with initial colonizafion of the gut because of an underdeveloped mucosal immune system and thus is more suscepfible to age-related gastrointesfinal infiammatory diseases (e.g., necrofizing enterocolifis [NEC]). Accordingly a major research need is defining how these immaturities affect colonizing bacterial-intestinal """"""""crosstalk"""""""". We have studied immaturifies in intesfinal host defense using established in vitro and ex vivo human models of intesfinal development and have published that human fetal enterocytes respond with excessive (IL-8/IL-6) inflammafion to sfimuli (LPS, IL-1[3) and to both commensal and pathogenic bacteria. Recently we suggest that excessive inflammation may be due to a developmentally inappropriate expression of the enterocyte NFKB/MyD88 innate immune response genes and that intrauterine cortisone and postpartum probiofics may lessen the excessive IL-8 response by sfimulafing maturafion of these genes. Accordingly, our overall hypothesis is that inappropriate/immature enterocyte inflammafion in prematures after inifial bacterial colonizafion may be caused by a developmentally disrupted expression of innate immune response genes and may be prevented by the trophic factor corticosteroids (HC) and/or anti-inflammatory secreted factor(s) in probiofics. To address this hypothesis, we will confirm that fetal primary enterocyte inflammafion is due to a developmental expression of NFKB/MyD88 genes, determine if other inflammatory sfimuli (TNF-a, IL-1p) and inflammatory pathways (e.g., NFKB/TRIF, etc.) are affected and if other known negative regulators of inflammafion, sfimulated by commensal bacteria, are underexpressed. We will then determine if HC affects these developmentally underexpressed genes specifically or has a generalized effect on enterocyte development and if clinically-proven probiofic secrefions have an effect. This proposal in human models should provide the mechanisfic basis for excessive inflammation in prematures and in vitro evidence for prevenfion leading eventually to an acceptable regime for prevenfing NEC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK033506-27
Application #
8380327
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
27
Fiscal Year
2012
Total Cost
$269,974
Indirect Cost
$117,396
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Walker, W Allan (2017) The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health. Pediatr Res 82:387-395
Saslowsky, David E; Thiagarajah, Jay R; McCormick, Beth A et al. (2016) Microbial sphingomyelinase induces RhoA-mediated reorganization of the apical brush border membrane and is protective against invasion. Mol Biol Cell 27:1120-30
Giannogonas, Panagiotis; Apostolou, Athanasia; Manousopoulou, Antigoni et al. (2016) Identification of a novel interaction between corticotropin releasing hormone (Crh) and macroautophagy. Sci Rep 6:23342
Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang et al. (2016) A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun 7:12225
Hoffman, Jill M; Baritaki, Stavroula; Ruiz, Jonathan J et al. (2016) Corticotropin-Releasing Hormone Receptor 2 Signaling Promotes Mucosal Repair Responses after Colitis. Am J Pathol 186:134-44
Gregory, Katherine E; Samuel, Buck S; Houghteling, Pearl et al. (2016) Influence of maternal breast milk ingestion on acquisition of the intestinal microbiome in preterm infants. Microbiome 4:68
Ganguli, Kriston; Collado, Maria C; Rautava, Jaana et al. (2015) Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut. Pediatr Res 77:528-35
Houghteling, Pearl D; Walker, W Allan (2015) Why is initial bacterial colonization of the intestine important to infants' and children's health? J Pediatr Gastroenterol Nutr 60:294-307
Rodriguez, Jorge A; Huerta-Yepez, Sara; Law, Ivy Ka Man et al. (2015) Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling. Cell Mol Gastroenterol Hepatol 1:610-630
Hallstrom, Kelly N; Srikanth, C V; Agbor, Terence A et al. (2015) PERP, a host tetraspanning membrane protein, is required for Salmonella-induced inflammation. Cell Microbiol 17:843-59

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