Abstract
Human milk lactoferrin (hmLF) is the most abundant glycoprotein present in human milk and displays a broad range of protective functions in the gut of newborn infants. hmLF is N-glycosylated, but little is known about the lactation stage-related development of the glycosylation phenotype. hmLF glycosylation from milk samples from five donors during the first 10 weeks of lactation was assessed and observed to be more diverse than previously reported. During this period dynamic changes in glycosylation were observed corresponding to a decrease in glycosylation in the second week followed by an increase in total glycosylation as well as higher order fucosylation thereafter. Gene expression analysis was performed in milk somatic cells from a sixth subject. It was found that fucosyltransferase expression increased during entire period, whereas expression of genes for the oligosaccharyl transferase complex decreased in the second week. The effect of hmLF glycosylation was examined for the protein's ability to affect bacterial binding to epithelial cells. hmLF significantly inhibited pathogen adhesion and purified hmLF glycans significantly reduced Salmonella invasion of colonic epithelial cells to levels associated with non-invasive deletion mutants. This study indicates that hmLF glycosylation is tightly regulated by gene expression and that glyco-variation is involved in modulating pathogen association.
Highlights
Human milk constitutes the first source of nutrients for the newborn infant, but it has evolved to endow several key
Glycans attached to human milk glycoproteins may act to block or modulate pathogen association to the epithelial surface, which in turn may be a key role in the protection of breast-fed infants against gastrointestinal tract infections
Given the central role of lactoferrin in infant development and health and its status as the most abundant glycoprotein in milk, we examined the changes in glycosylation during the first months of lactation with the hypothesis that glycan variation is common over the course of lactation as a mechanism to block pathogen association during breastfeeding. human milk LF (hmLF) binds several pathogenic Gram-positive [21, 22] and Gramnegative [23, 24] bacteria to exert antimicrobial activity because of either iron-depletion and/or bacterial membrane disruption; the latter being triggered by a short sequence of amino acids found in the N-terminal domain of the protein, known as lactoferricin [25, 26]
Summary
Human milk constitutes the first source of nutrients for the newborn infant, but it has evolved to endow several key. Glycosylation is a common but complex type of post-translational modification of proteins, directly affecting glycoprotein structure, trafficking, recognition, and biological functions [7,8,9,10]. Carbohydrate structures attached to proteins play key roles in mediating cell signaling and cell-cell recognition events [11, 12]. Glycosylation and glycan diversity are directly related to modulating. Dynamic Changes in Glycosylation of Human Milk Lactoferrin microbial adhesion and invasion during infection [9]. Glycans attached to human milk glycoproteins may act to block or modulate pathogen association to the epithelial surface, which in turn may be a key role in the protection of breast-fed infants against gastrointestinal tract infections
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