During the last three decades this laboratory has studied the development of intestinal host defenses that protect neonates from infections and allergic diseases in the contaminated extrauterine environment. We have systematically defined host defense immaturities in animal and human models of small intestinal development. During the last ten years as part of a MERIT award, we have begun to determine the effect of breast milk on the maturation of these defined host defense immaturities using established human intestinal models of development (cell lines, organ cultures and xenograft transplants). As part of this approach we have begun to examine DNA microarrays of laser capture microdisection epithelial RNA from immature vs mature enterocytes, confirmed by qRT-PCR. The preliminary studies suggest that the immune response of immature enterocytes after exposure to exogenous (LPS) and endogenous (IL-12) inflammatory stimuli is excessive, e.g., a 20 fold increase in IL-8 in immature vs mature enterocytes. Using these techniques we have shown that enterocyte surface TLRs and their signaling molecules are upregulated which can account for the enhanced innate inflammatory response. In addition, the cellular inhibitors of TLR-induced inflammation (SIGIRR, IRAK-M, Tollip, A-20 etc) are underexpressed, another possible cause of excessive inflammation. Accordingly, our working hypothesis for this renewal reapplication is that human milk provides a protective link from mother to newborn in the extrauterine environment by actively stimulating the maturation of innate immune defense in immature enterocytes and thereby prevents the expression of age-related infectious and immune-mediated diseases during that period. Accordingly, to address this hypothesis, we will use human intestinal models and DNA microarrays to determine in experimental detail three representative anti-inflammatory factors in breast milk, e.g. 1) the regulatory cytokine, TGF-22;2) the direct effect of a representative breast milk oligosaccharide, galacto-oligosaccharide and 3) the effect of Bifidobacteria and Lactobacillus, the predominantly colonizing bacteria in breast fed infants, media secretory products on the development of intestinal innate immunity in nursing newborns. These studies should help define the mechanism(s) of breast milk protection in newborns and support the importance of breast feeding and may help provide legislation to support working mothers breast feeding longer.

Public Health Relevance

Human breast milk factors control excessive inflammation occurring in response to microorganisms and inflammatory cytokines in newborn intestine. We will determine how breastfeeding prevents age-related neonatal inflammatory diseases

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD012437-31
Application #
8242638
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Grave, Gilman D
Project Start
1979-05-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
31
Fiscal Year
2012
Total Cost
$333,423
Indirect Cost
$135,740
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Cahill, Catherine M; Zhu, Weishu; Oziolor, Elias et al. (2016) Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte. PLoS One 11:e0145184
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
Wijendran, Vasuki; Brenna, J T; Wang, Dong Hao et al. (2015) Long-chain polyunsaturated fatty acids attenuate the IL-1β-induced proinflammatory response in human fetal intestinal epithelial cells. Pediatr Res 78:626-33
Houghteling, Pearl D; Walker, W Allan (2015) From Birth to ""Immunohealth,"" Allergies and Enterocolitis. J Clin Gastroenterol 49 Suppl 1:S7-S12
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
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
Guo, Shuangshuang; Guo, Yuming; Ergun, Ayla et al. (2015) Secreted Metabolites of Bifidobacterium infantis and Lactobacillus acidophilus Protect Immature Human Enterocytes from IL-1β-Induced Inflammation: A Transcription Profiling Analysis. PLoS One 10:e0124549
Floch, Martin H; Walker, W Allan; Sanders, Mary Ellen et al. (2015) Recommendations for Probiotic Use--2015 Update: Proceedings and Consensus Opinion. J Clin Gastroenterol 49 Suppl 1:S69-73
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

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