Unlike the full term vaginally delivered infant, the premature infant is unprepared to deal with initial colonization of the gut because of an underdeveloped mucosal immune system and thus is more susceptible to age-related gastrointestinal inflammatory diseases (e.g., necrotizing enterocolitis [NEC]). Accordingly a major research need is defining how these immaturities affect colonizing bacterial-intestinal "crosstalk". We have studied immaturities in intestinal host defense using established in vitro and ex vivo human models of intestinal development and have published that human fetal enterocytes respond with excessive (IL-8/IL-6) inflammation to stimuli (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 probiotics may lessen the excessive IL-8 response by stimulating maturation of these genes. Accordingly, our overall hypothesis is that inappropriate/immature enterocyte inflammation in prematures after initial bacterial colonization 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 probiotics. To address this hypothesis, we will confirm that fetal primary enterocyte inflammation is due to a developmental expression of NFKB/MyD88 genes, determine if other inflammatory stimuli (TNF-a, IL-1p) and inflammatory pathways (e.g., NFKB/TRIF, etc.) are affected and if other known negative regulators of inflammation, simulated by commensal bacteria, are underexpressed. We will then determine if HC affects these developmentally under expressed genes specifically or has a generalized effect on enterocyte development and if clinically-proven probiotic secretions have an effect. This proposal in human models should provide the mechanistic basis for excessive inflammation in prematures and in vitro evidence for prevention leading eventually to an acceptable regime for preventing NEC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK033506-28
Application #
8545572
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
28
Fiscal Year
2013
Total Cost
$279,362
Indirect Cost
$118,810
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
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
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
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
Houghteling, Pearl D; Walker, W Allan (2015) From Birth to "Immunohealth," Allergies and Enterocolitis. J Clin Gastroenterol 49 Suppl 1:S7-S12
O'Keeffe, Michael S; Song, Joo-Hye; Liao, Gongxian et al. (2015) SLAMF4 Is a Negative Regulator of Expansion of Cytotoxic Intraepithelial CD8+ T Cells That Maintains Homeostasis in the Small Intestine. Gastroenterology 148:991-1001.e4
Zhou, Yanjiao; Shan, Gururaj; Sodergren, Erica et al. (2015) Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS One 10:e0118632
Walker, W Allan; Iyengar, Rajashri Shuba (2015) Breast milk, microbiota, and intestinal immune homeostasis. Pediatr Res 77:220-8
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
Meng, Di; Zhu, Weishu; Shi, Hai Ning et al. (2015) Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis. Pediatr Res 77:416-24

Showing the most recent 10 out of 265 publications