In this revised application, we seek competitive renewal of our program project, """"""""The Role of Human Milk in Infant Nutrition and Health,"""""""" which is now entering its 31st year. This is a unique research program on human milk bioactive factors that addresses a long-standing priority of NICHD. Our program project involves a highly interactive, interdisciplinary team of senior and junior investigators with cores and projects at Cincinnati, Mexico, and Boston. Breastfeeding conveys potent bioactive factors that protect child health. During the current grant cycle we have shown that the human milk glycans, particularly, the a1,2 fucosyl (""""""""secretor"""""""") oligosaccharides and their high molecular weight glycoconjugates, are a major new class of antimicrobial agents. We have achieved initial synthesis of human milk secretor oligosaccharide analogs (H- 2 on LNneoT) in bioengineered bacteria. In this competitive renewal, we focus on the human milk glycans as novel antimicrobials with three major functions - pathogen-binding inhibition, prebiotic activity, and antiinflammatory activity - that protect breastfeeding children against enteric infectious and inflammatory diseases, three projects are proposed pertaining to the human milk glycans: 1) Inhibition of bacterial gastroenteritis;2) Inhibition of viral gastroenteritis;and 3) Modulation of inflammation, colonization, and mucosal development. In each project, we propose basic, clinical and translational research. Two complementary lines of translational research will be pursued: 1) Developing and testing human milk glycan analogs as novel antimicrobials and 2) testing the secretor phenotype as a novel clinical biomarker for enteric infectious and inflammatory diseases. The projects will be supported by cores in Biometry (Epidemiology, Biostatistics, and Informatics);Glycobiology;and Molecular Biology. Our focus and approach addresses NIH Road Map 2008 priorities pertaining to inflammation, the microbiome, and phenotyping.
The research proposed in this application is designed to transform our fundamental understanding of human milk glycans and infant glycans in relation to disease risk and translate our discoveries into novel therapeutics, dietary interventions, and diagnostic tools that improve infant and child health.
|Young, Bridget E; Patinkin, Zachary W; Pyle, Laura et al. (2017) Markers of Oxidative Stress in Human Milk do not Differ by Maternal BMI But are Related to Infant Growth Trajectories. Matern Child Health J 21:1367-1376|
|He, YingYing; Lawlor, Nathan T; Newburg, David S (2016) Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv Nutr 7:102-11|
|Vanchiere, John A; Carillo, Berenice; Morrow, Ardythe L et al. (2016) Fecal Polyomavirus Excretion in Infancy. J Pediatric Infect Dis Soc 5:210-3|
|Ward, Doyle V; Scholz, Matthias; Zolfo, Moreno et al. (2016) Metagenomic Sequencing with Strain-Level Resolution Implicates Uropathogenic E. coli in Necrotizing Enterocolitis and Mortality in Preterm Infants. Cell Rep 14:2912-24|
|Newburg, David S; Ko, Jae Sung; Leone, Serena et al. (2016) Human Milk Oligosaccharides and Synthetic Galactosyloligosaccharides Contain 3'-, 4-, and 6'-Galactosyllactose and Attenuate Inflammation in Human T84, NCM-460, and H4 Cells and Intestinal Tissue Ex Vivo. J Nutr 146:358-67|
|He, YingYing; Liu, ShuBai; Kling, David E et al. (2016) The human milk oligosaccharide 2'-fucosyllactose modulates CD14 expression in human enterocytes, thereby attenuating LPS-induced inflammation. Gut 65:33-46|
|Newburg, David S; Morelli, Lorenzo (2015) Human milk and infant intestinal mucosal glycans guide succession of the neonatal intestinal microbiota. Pediatr Res 77:115-20|
|Currier, Rebecca L; Payne, Daniel C; Staat, Mary A et al. (2015) Innate Susceptibility to Norovirus Infections Influenced by FUT2 Genotype in a United States Pediatric Population. Clin Infect Dis 60:1631-8|
|Payne, Daniel C; Currier, Rebecca L; Staat, Mary A et al. (2015) Epidemiologic Association Between FUT2 Secretor Status and Severe Rotavirus Gastroenteritis in Children in the United States. JAMA Pediatr 169:1040-5|
|Hill, David R; Newburg, David S (2015) Clinical applications of bioactive milk components. Nutr Rev 73:463-76|
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