Human milk contains a remarkable content and structural diversity of oligosaccharides (HMO) that act as a component of the innate immunity by preventing attachment of pathogens to the intestinal lining and by promoting colonization by a healthy microbiota. Despite their recognized importance in neonatal health, research on HMO has been hindered by insufficient quantities to conduct feeding studies. Our long range goal is to understand the mechanisms whereby HMO stimulates neonatal innate and adaptive immunity. We are ideally positioned to undertake these investigations as we have access to large quantities of enzymatically synthesized lacto-N-neotetraose (LNnT) and human milk from which to extract HMO. The objective of this application is to determine how HMO, LNnT, polydextrose and galactooligosaccharide (PDX/GOS) influence activation of dendritic cells (DC) and lymphocyte responses to vaccination against rotavirus (RV) and a subsequent RV challenge in the piglet model. Our central hypothesis is that HMO will enhance immune function by two inter-related mechanisms by directly interacting with DCs and, indirectly, by altering the intestinal microbiota. First, we postulate that HMO glycans interact with c-type lectin receptors on DC, which induce in DC activation and activation of B- and T-lymphocytes. Second, we hypothesize that HMO will promote the growth of Lactobacillus and Bifidobacterium, leading to fermentation of oligosaccharides and enhanced mucosal resistance to RV infection.
The specific aims will 1) assess the potential for HMO, LNnT and PDX/GOS to be fermented, to stimulate DC activation and to inhibit RV infectivity and binding in vitro, 2) evaluate the prebiotic actions of oligosaccharides on microbial colonization, mucosal immunity and the response RV vaccination in the piglet, and 3) establish how oligosaccharides alone or in combination with vaccination modulate the response to RV infection in the piglet. The rationale for undertaking this research is that no previous studies have systematically investigated how HMO, LNnT and synthetic prebiotics modulate the microbiota and mucosal immunity. The use of relevant preclinical animal model of RV vaccination and challenge that will further our understanding of the mechanisms underlying the disease and demonstrate the potential for HMOs to improve intestinal function, modulate host-microbe interactions and alter mucosal immunity. Reducing the morbidity and mortality from RV will decrease health care costs and improve the quality of life for infants worldwide.

Public Health Relevance

Human milk contains high concentrations of oligosaccharides that are not found in infant formulas and are proposed to contribute to the health benefits of human milk. The proposed studies will determine how oligosaccharides affect the bacteria in the intestine and immune maturation of neonates. This knowledge will allow for the development of nutritional ingredients to improve the quality of infant formulas for babies who are not breastfed.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZHD1-DSR-Z (04))
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Grave, Gilman D
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University of Illinois Urbana-Champaign
Schools of Earth Sciences/Natur
United States
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Wang, Mei; Li, Min; Wu, Shuai et al. (2015) Fecal microbiota composition of breast-fed infants is correlated with human milk oligosaccharides consumed. J Pediatr Gastroenterol Nutr 60:825-33
Li, Min; Monaco, Marcia H; Wang, Mei et al. (2014) Human milk oligosaccharides shorten rotavirus-induced diarrhea and modulate piglet mucosal immunity and colonic microbiota. ISME J 8:1609-20
Li, Min; Wang, Mei; Donovan, Sharon M (2014) Early development of the gut microbiome and immune-mediated childhood disorders. Semin Reprod Med 32:74-86
Donovan, Sharon M; Wang, Mei; Monaco, Marcia H et al. (2014) Noninvasive molecular fingerprinting of host-microbiome interactions in neonates. FEBS Lett 588:4112-9
Hester, Shelly N; Chen, Xin; Li, Min et al. (2013) Human milk oligosaccharides inhibit rotavirus infectivity in vitro and in acutely infected piglets. Br J Nutr 110:1233-42
Donovan, Sharon M; Wang, Mei; Li, Min et al. (2012) Host-microbe interactions in the neonatal intestine: role of human milk oligosaccharides. Adv Nutr 3:450S-5S
Li, Min; Bauer, Laura L; Chen, Xin et al. (2012) Microbial composition and in vitro fermentation patterns of human milk oligosaccharides and prebiotics differ between formula-fed and sow-reared piglets. J Nutr 142:681-9
Schwartz, Scott; Friedberg, Iddo; Ivanov, Ivan V et al. (2012) A metagenomic study of diet-dependent interaction between gut microbiota and host in infants reveals differences in immune response. Genome Biol 13:r32
Tao, Nannan; Ochonicky, Karen L; German, J Bruce et al. (2010) Structural determination and daily variations of porcine milk oligosaccharides. J Agric Food Chem 58:4653-9
Poroyko, Valeriy; White, James Robert; Wang, Mei et al. (2010) Gut microbial gene expression in mother-fed and formula-fed piglets. PLoS One 5:e12459