Breastfeeding is highly protective against bacterial diarrhea, a major cause of morbidity and mortality in children. Our overallgoal is to identify secretor human milk glycans that can act as novel prophylactic/therapeutic agents against diarrhea, especially bacterial diarrhea. Weidentified human milk oligosaccharides, and especially a1,2-fucosyl (secretor) oligosaccharides, that inhibit a large family of pathogens. Secretor oligosaccharides bind to adhesins of enteropathogens, inhibiting their binding to cell surface glycans of the gastrointestinal tract. We also find that human milk high molecular weight (HMW) glycoproteins that contain secretor moieties bind strongly to pathogens, and seem to have higher affinity and more specificity in their inhibition of pathogens than oligosaccharides.This project will study binding characteristics of these HMW human milk glycans to determine their structure/function relationships, and dentify those with the highest efficacy. This will allow rational design of a new generation of synthetic human milk glycans that optimize inhibition of pathogen binding. This project will continue to produce 2'- fucosyllactose (2'-FL) the synthetic secretor human milk oligosaccharideanalog that we developed in our aboratory, and will test this product, in preclinical studies, for safety and efficacy. This project will further examine the increased burden of diarrhea! disease in secretor relative to non-secretor infants, and the reduced burden of disease obtained by consumption of secretor glycans in human milk. Thus, the specific aims are: 1) Identify, isolate and characterize HMW secretor glycoproteinsthat bind to bacterial enteric pathogens and determine the contributions of glycosylation patternsto the strength of inhibition. 2) Synthesize an a1,2-fucosylglycan in bacteria, and test its safety and efficacy in animal models. 3) Test the secretor phenotypes of infants and maternal milk in a cohort of breastfeeding children 0 - 2 years of age as determinants of infant risk of all diarrhea and bacterial diarrhea. The data obtained will extend our understanding of infant gut and human milk glycans in the innate defense of the neonate. This will ultimately translate into testing our prototype synthetic human milk glycan as a novel prophylactic or therapeutic agent, into generating a second generation synthetic glycan, as well as a novel biomarker for prediction of risk of diarrhea.

Public Health Relevance

The research proposed in this application is designed to transform our fundamental understanding of human milk glycans as agents that prevent risk of bacterial causes of diarrhea and to translate our discoveries into new medications, food substances, and diagnostic tools that promote the health and survival of infants and children worldwide

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD013021-35
Application #
8514652
Study Section
Special Emphasis Panel (ZHD1-DSR-A)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
35
Fiscal Year
2013
Total Cost
$135,365
Indirect Cost
$25,376
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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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