nfants consuming human milk exhibit fewer symptomsof infection than those who do not. We have demonstrated that human milk glycans prevent infection by inhibiting the ability of enteric pathogens to bind to host ligands. These glycans include the unbound human milk oligosaccharides (HMOS) and larger glycoconjugates containing carbohydrate moieties with blood group antigens on the non-reducing terminus. In the current project, we will focus on other potentially major functions of human milk glycans in the ntestinal mucosa during infant development. We recently discovered that HMOS strongly quench inflammation of the gut, and that the microbiota in the lumen of the gut affects glycan expression on the mucosal cell surface. Our grand hypothesis is that HMOS provide several integrated layers of protection: 1) promote mucosal barriers that inhibit pathogen penetration to the mucosalcell surface, 2) inhibit binding by pathogens that do reach host mucosal cell surface receptors, 3) directly attenuate the host inflammatory response to pathogens,and 4) indirectly stimulate maturation of the mucosal innate immune system. This project investigates major protective mechanisms of human milk glycansthat may work in synergywith nhibition of pathogen adhesion, specifically, inhibition of inflammation in infant intestinal mucosa, promotion of colonization by symbiotic microbiota, and maturation of the infant mucosa and its innate immune system. This project will: Characterize the HMOS that directly suppress mucosal inflammation, and determine their mechanism of action. Investigate HMOS as prebiotics that modify the intestinal microbiota andthereby indirectly affect glycosylation and gut mucosal proinflammatory signaling. Determine the independent and interdependent effects of maternal milk fucosylglycansand infant gut fucosylglycanson the composition of the gut microbiota and risk of NEC and other enteric disease in infants. Test the ability of a synthetic human milk secretorfucosylglycanto suppress mucosalinflammation and to function as a prebiotic in preclinical studies. Understanding the multiple interactions of HMOS with the nascent infant mucosal immune system and with mutualist symbiotic bacteria will provide the basis for optimizing the design of therapeutic glycans to protect all infants, irrespective of their age of weaning.
The research proposedin this application is designed to transform our fundamental understanding of human milk glycans as factors that promote beneficial bacteria and reduce inflammation in the gastrointestinal tract of breastfeeding infants and to translate our discoveries into new medications, food substances, and diagnostic toolsthat promote the health and survival of infants and children worldwide.
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