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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-8)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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