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David S. Newburg

Bio: David S. Newburg is an academic researcher from Harvard University. The author has contributed to research in topics: Oligosaccharide & Glycoconjugate. The author has an hindex of 41, co-authored 98 publications receiving 6729 citations. Previous affiliations of David S. Newburg include University of Kentucky & University of Massachusetts Amherst.


Papers
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Journal ArticleDOI
TL;DR: The argument that specific glycans, especially the oligosaccharides, are the major constituent of an innate immune system of human milk whereby the mother protects her infant from enteric and other pathogens through breastfeeding is presented.
Abstract: Breastfed infants have lower morbidity and mortality due to diarrhea than those fed artificially. This had been attributed primarily to the secretory antibodies and prebiotic factors in human milk. Oligosaccharides are the third largest component of human milk. They were initially considered to be functionless by-products of glycoprotein and glycolipid synthesis during milk production. However, in the past few decades it has become apparent that the human milk oligosaccharides are composed of thousands of components, at least some of which protect against pathogens. Oligosaccharide protection against infectious agents may result in part from their prebiotic characteristics, but is thought to be primarily due to their inhibition of pathogen binding to host cell ligands. Most human milk oligosaccharides are fucosylated, and their production depends on enzymes encoded by the genes associated with expression of the Lewis blood group system. The expression of specific fucosylated oligosaccharides in milk thus varies in relation to maternal Lewis blood group type, and is significantly associated with the risk of infectious disease in breastfed infants. Specific fucosylated moieties of oligosaccharides and related glycoconjugates (glycans) are able to inhibit binding and disease by specific pathogens. This review presents the argument that specific glycans, especially the oligosaccharides, are the major constituent of an innate immune system of human milk whereby the mother protects her infant from enteric and other pathogens through breastfeeding. The large input of energy expended by the mother in the synthesis of milk oligosaccharides is consistent with the human reproductive strategy of large parental input into rearing relatively few offspring through a prolonged period of maturation. These protective glycans may prove useful as a basis for the development of novel prophylactic and therapeutic agents that inhibit diseases caused by mucosal pathogens.

634 citations

Journal ArticleDOI
TL;DR: Interactions between human milk glycans, intestinal microflora, and intestinal mucosa surface glycans underlie ontogeny of innate mucosal immunity, pathobiology of enteric infection, and inflammatory bowel diseases.
Abstract: The neonatal adaptive immune system, relatively naive to foreign antigens, requires synergy with the innate immune system to protect the intestine. Goblet cells provide mucins, Paneth cells produce antimicrobial peptides, and dendritic cells (DCs) present luminal antigens. Intracellular signaling by Toll-like receptors (TLRs) elicits chemokines and cytokines that modulate inflammation. Enteric neurons and lymphocytes provide paracrine and endocrine signaling. However, full protection requires human milk. Breast-feeding reduces enteric infection and may reduce chronic disease in later life. Although human milk contains significant secretory immunoglobulin A (sIgA), most of its protective factors are constitutively expressed. Multifunctional milk components are nutrients whose partial digestion products inhibit pathogens. Cytokines, cytokine receptors, TLR agonists and antagonists, hormones, anti-inflammatory agents, and nucleotides in milk modulate inflammation. Human milk is rich in glycans (complex carbohydrates): As prebiotics, indigestible glycans stimulate colonization by probiotic organisms, modulating mucosal immunity and protecting against pathogens. Through structural homology to intestinal cell surface receptors, glycans inhibit pathogen binding, the essential first step of pathogenesis. Bioactive milk components comprise an innate immune system of human milk whereby the mother protects her nursing infant. Interactions between human milk glycans, intestinal microflora, and intestinal mucosa surface glycans underlie ontogeny of innate mucosal immunity, pathobiology of enteric infection, and inflammatory bowel diseases.

485 citations

Journal ArticleDOI
TL;DR: Novel evidence is provided suggesting that human milk oligosaccharides are clinically relevant to protection against infant diarrhea.

410 citations

Journal ArticleDOI
TL;DR: The alpha1,2-linked fucosylated glycan structure found in human milk is associated with protection of breastfed infants against diarrhea caused by campylobacter, caliciviruses, and stable toxin of enterotoxigenic E. coli, and moderate-to-severe diarrhea of all causes.
Abstract: Breast-feeding is a highly effective strategy for preventing morbidity and mortality in infancy. The human-milk glycans, which include oligosaccharides in their free and conjugated forms, constitute a major and an innate immunologic mechanism by which human milk protects breast-fed infants against infections. The glycans found in human milk function as soluble receptors that inhibit pathogens from adhering to their target receptors on the mucosal surface of the host gastrointestinal tract. The alpha1,2-linked fucosylated glycans, which require the secretor gene for expression in human milk, are the dominant glycan structure found in the milk of secretor mothers, who constitute the majority ( approximately 80%) of mothers worldwide. In vitro and in vivo binding studies have demonstrated that alpha1,2-linked fucosylated glycans inhibit binding by campylobacter, stable toxin of enterotoxigenic Escherichia coli, and major strains of caliciviruses to their target host cell receptors. Consistent with these findings, recently published epidemiologic data demonstrate that higher relative concentrations of alpha1,2-linked fucosylated glycans in human milk are associated with protection of breast-fed infants against diarrhea caused by campylobacter, caliciviruses, and stable toxin of enterotoxigenic E. coli, and moderate-to-severe diarrhea of all causes. These novel data open the potential for translational research to develop the human-milk glycans as a new class of antimicrobial agents that prevent infection by acting as pathogen anti-adhesion agents.

389 citations

Journal ArticleDOI
TL;DR: The patterns of milk oligosaccharides among individuals suggest the existence of many genotype subpopulations and that the protective activities of human milk could also vary among individuals and during lactation.
Abstract: Specific human milk oligosaccharides, especially fucosylated neutral oligosaccharides, protect infants against specific microbial pathogens. To study the concentrations of individual neutral oligosaccharides during lactation, a total of 84 milk samples were obtained from 12 women at 7 time periods during weeks 1-49 postpartum. The neutral oligosaccharides from each sample were isolated, perbenzoylated, resolved, and quantified by reversed-phase high-performance liquid chromatography. The resultant oligosaccharide peaks, identified by co-elution with authentic standards and mass spectrometry, ranged in size from tri- to octasaccharides. The total concentration of oligosaccharides declined over the course of lactation; the mean concentration at 1 year was less than half that in the first few weeks postpartum. One of the 12 donors produced milk fucosyloligosaccharides that were essentially devoid of alpha1,2 linkages (but contained alpha1,3- and alpha1,4-linked fucose) until late in lactation, consistent with the nonsecretor phenotype. In milk samples from the remaining 11 donors, fucosyloligosaccharides containing alpha1,2-linked fucose were prevalent, and their profiles were distinct from those of fucosyloligosaccharides devoid of alpha1,2-linked fucose. The ratio of alpha1,2-linked oligosaccharide concentrations to oligosaccharides devoid of alpha1,2-linked fucose changed during the first year of lactation from 5:1 to 1:1. Furthermore, the absolute and the relative concentrations of individual oligosaccharides varied substantially, both between individual donors and over the course of lactation for each individual. The patterns of milk oligosaccharides among individuals suggest the existence of many genotype subpopulations. This variation in individual oligosaccharide concentrations suggests that the protective activities of human milk could also vary among individuals and during lactation.

361 citations


Cited by
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Journal ArticleDOI
23 Sep 1983-Science
TL;DR: Dietary intake of natural antioxidants could be an important aspect of the body's defense mechanism against these agents of cancer and other age-related diseases.
Abstract: The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body’s defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.

2,924 citations

Journal ArticleDOI
TL;DR: The goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category.
Abstract: With the continued interest in the role of the gut microbiota in health, attention has now turned to how to harness the microbiota for the benefit of the host. This Consensus Statement outlines the definition and scope of the term 'prebiotic' as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in December 2016. In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation.

2,863 citations

Journal ArticleDOI
TL;DR: The composition of human milk is the biological norm for infant nutrition and contains many hundreds to thousands of distinct bioactive molecules that protect against infection and inflammation and contribute to immune maturation, organ development, and healthy microbial colonization.

1,859 citations

Journal ArticleDOI
TL;DR: This review focuses on aspects of heparin structure and conformation, which are important for its interactions with proteins, and describes the interaction ofheparin and heparan sulfate with selected families of heParin-binding proteins.
Abstract: Heparin, a sulfated polysaccharide belonging to the family of glycosaminoglycans, has numerous important biological activities, associated with its interaction with diverse proteins. Heparin is widely used as an anticoagulant drug based on its ability to accelerate the rate at which antithrombin inhibits serine proteases in the blood coagulation cascade. Heparin and the structurally related heparan sulfate are complex linear polymers comprised of a mixture of chains of different length, having variable sequences. Heparan sulfate is ubiquitously distributed on the surfaces of animal cells and in the extracellular matrix. It also mediates various physiologic and pathophysiologic processes. Difficulties in evaluating the role of heparin and heparan sulfate in vivo may be partly ascribed to ignorance of the detailed structure and sequence of these polysaccharides. In addition, the understanding of carbohydrate-protein interactions has lagged behind that of the more thoroughly studied protein-protein and protein-nucleic acid interactions. The recent extensive studies on the structural, kinetic, and thermodynamic aspects of the protein binding of heparin and heparan sulfate have led to an improved understanding of heparin-protein interactions. A high degree of specificity could be identified in many of these interactions. An understanding of these interactions at the molecular level is of fundamental importance in the design of new highly specific therapeutic agents. This review focuses on aspects of heparin structure and conformation, which are important for its interactions with proteins. It also describes the interaction of heparin and heparan sulfate with selected families of heparin-binding proteins.

1,722 citations

Journal ArticleDOI
TL;DR: This review summarises the current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health, underlying the need for mechanistic studies focusing on host–microbe interactions.
Abstract: The human gastrointestinal (GI) tract harbours a complex and dynamic population of microorganisms, the gut microbiota, which exert a marked influence on the host during homeostasis and disease Multiple factors contribute to the establishment of the human gut microbiota during infancy Diet is considered as one of the main drivers in shaping the gut microbiota across the life time Intestinal bacteria play a crucial role in maintaining immune and metabolic homeostasis and protecting against pathogens Altered gut bacterial composition (dysbiosis) has been associated with the pathogenesis of many inflammatory diseases and infections The interpretation of these studies relies on a better understanding of inter-individual variations, heterogeneity of bacterial communities along and across the GI tract, functional redundancy and the need to distinguish cause from effect in states of dysbiosis This review summarises our current understanding of the development and composition of the human GI microbiota, and its impact on gut integrity and host health, underlying the need for mechanistic studies focusing on host–microbe interactions

1,708 citations