visiting professor of biology
Ph.D., Boston University Biochemistry (Neuroscience, Nutrition)
Graduate School of Arts and Sciences
Office Location: Higgins 477
Lab Location: Higgins 480
Narrative Description of Research
The overall focus of this research program is to study bioactive glycans of human milk, glycans of the immature intestinal mucosa, and how these glycans interact to provide a coordinated innate immune system that promotes normal gut colonization while inhibiting enteric diseases. The glycobiology program specializes in developing new methods by using state-of-the-art technology for the analysis of glycans, for measuring their metabolism, and for determining genetic control mechanisms of their expression. Biologically active dietary glycans from exogenous sources (prebiotics), are studied in the context of gut colonization by microbiota (both mutualists and pathogens), ontogeny of glycans in the intestinal mucosa, and inflammation and disease, including necrotizing enterocolitis.
Human milk glycans inhibit pathogens:
Human milk is extremely rich in glycans, many of which are bioactive. Some inhibit the ability of pathogens to bind to their cell surface targets in the intestine, thereby sparing breastfed infants from infection. This glycobiology program studies the genetics of glycoconjugate expression, the metabolism of glycoconjugates that inhibit pathogens, mechanisms whereby human milk glycoconjugates interfere with pathogenesis, the structure/function relationship of glycan epitopes of the binding sites, and the role of endogenous and exogenous glycans in gut colonization and inflammatory processes. The efficacy of various human milk glycan epitopes in inhibiting pathogen binding and in protecting against infection by pathogens in vivo is a major emphasis of this work. The pathogens studied include: stable toxin of enterotoxigenic E. coli; enterohemorrhagic E. coli; enteropathogenic E. coli; rotavirus; HIV; campylobacter; cholera; noroviruses; group B streptococcus, influenza; respiratory syncytial virus, and others. This research includes studies on the mechanisms whereby inhibition of pathogen binding protects the human mucosal host cell, including modulation of cell signaling.
|A scanning electron micrograph of a Chinese hamster ovary cell FUT1 transfect, whose expression of H(O) antigens on the cell surface allows attachment by Campylobacter jejuni. The sugars that comprise H-2-antigen (Fuc1,2Gal1,4GlcNAc) tether campylobacter to cell surface glycoconjugate (left). Campylobacter binding to these glycoconjugates is inhibited by fucosyloligosaccharide H-2 homologues present in human milk (right). From Ruiz-Palacios et al, JBC, 2003.|
Human milk glycans as therapeutics:
The glycans found in human milk may represent a unique class of antimicrobials that provide a major line of defense of breastfeeding infants against enteric and other pathogens. These glycans promise to be novel, powerful anti-microbial agents that act mainly at the mucosal level. Novel methods for synthesizing these glycans are being developed, and the anti-infective glycans are tested in animal models and human populations.
Cell surface glycans:
A related research emphasis is the role of cell surface glycans as targets for common pathogens of infants and children. Most enteric pathogens use specific cell surface glycans as receptors, and this binding is the first step in their pathogenesis. The specific glycan epitope to which they bind defines the species and organ specificity of the pathogen. We study how individual heterogeneity in the expression of cell surface glycans causes some humans to be more susceptible to specific pathogens than others.
The innate immune system of the intestinal mucosa seems to be modulated by glycans. For example, expression of intestinal mucosa glycans seems to have a major role in establishing the symbiotic relationship between humans and their intestinal microbes, and the lack of a healthy microbiota may underlie many human diseases, including inflammatory bowel diseases, such as necrotizing enterocolitis.
Instrumental analysis of glycans:
A major activity in this laboratory is devising and applying methods of glycan separation and analysis toward understanding the role of exogenous dietary glycans and endogenous glycans of the intestinal mucosa on innate immune functions of the developing human.
Newburg DS, Frankel DL, Fillios LC. An asparagine requirement in young rats fed the dietary combinations of aspartic acid, glutamine, and glutamic acid. J Nutr 1975;105:356-63.
Concon JM, Newburg DS, Swerczek TW. Black pepper (Piper nigrum): Evidence of carcinogenicity. Nutr & Cancer 1979;1:22-6.
Newburg DS, Fillios LC. A requirement for dietary asparagine in pregnant rats. J Nutr 1979;109: 2190-7.
Newburg DS, Concon JM. Malonaldehyde concentrations in food are affected by cooking conditions. J Food Sci 1980;45:1681-7.
Newburg DS, Fillios LC. Brain development in neonatal rats nursing asparagine-deprived dams.
Dev Neurosci 1982;5:332-44.
Concon JM, Newburg DS, Eades SN. Lectins in wheat gluten proteins. J Agric Food Chem 1983;31:939-41.
Newburg DS, Concon JM. Lectins in rice and corn endosperm. J Agric Food Chem 1985;33:685-7.
Newburg DS, Yatziv S, McCluer RH, Raghavan S. β-Glucosidase inhibition in murine peritoneal macrophages by conduritol-B-epoxide: an in vitro model of the Gaucher cell. Biochim Biophys Acta 1986;877:121-6.
Yatziv S, Barfi G, Newburg DS. Lysosomal hydrolases in blood-derived macrophages of patients with I-cell disease. J Lab Clin Med 1986;108:365-8.
Newburg DS, Shea TB, Yatziv S, Raghavan SS, McCluer RH. Macrophages exposed in vitro to conduritol B epoxide resemble Gaucher cells. Exp Mol Pathol 1988;48:317-23.
Yatziv S, Newburg DS, Livni N, Barfi G, Kolodny EH. Gaucher-like changes in human blood-derived macrophages induced by β-glucocerebrosidase inhibition. J Lab Clin Med 1988;111:416-20.
Daniel PF, Newburg DS, O'Neil NE, Smith PW, Fleet GW. Effects of the α-mannosidase inhibitors, 1,4-dideoxy-1,4-imino-D-mannitol and swainsonine, on glycoprotein catabolism in cultured macrophages. Glycoconj J 1989;6:229-40.
Newburg DS, Pickering LK, McCluer RH, Cleary TG. Fucosylated oligosaccharides of human milk protect suckling mice from heat-stabile enterotoxin of Escherichia coli. J Infect Dis 1990;162:1075-80.
Johnson JR, Berggren T, Newburg DS, McCluer RH, Manivel JC. Detailed histopathological examination contributes to the assessment of Escherichia coli urovirulence. J Urol 1992;147:1160-6.
Newburg DS, Ashkenazi S, Cleary TG. Human milk contains the Shiga toxin and Shiga-like toxin receptor glycolipid Gb3. J Infect Dis 1992;166:832-6.
Newburg DS, Chaturvedi P. Neutral glycolipids of human and bovine milk. Lipids 1992;27:923-7.
Newburg DS, Viscidi RP, Ruff A, Yolken RH. A human milk factor inhibits binding of human immunodeficiency virus to the CD4 receptor. Pediatr Res 1992;31:22-8.
Yolken RH, Peterson JA, Vonderfecht SL, Fouts ET, Midthun K, Newburg DS. Human milk mucin inhibits rotavirus replication and prevents experimental gastroenteritis. J Clin Invest 1992;90:1984-91.
Newburg DS, Chaturvedi P, Lopez EL, Devoto S, Fayad A, Cleary TG. Susceptibility to hemolytic-uremic syndrome relates to erythrocyte glycosphingolipid patterns. J Infect Dis 1993;168:476-9.
Crane JK, Azar SS, Stam A, Newburg DS. Oligosaccharides from human milk block binding and activity of the Escherichia coli heat-stable enterotoxin (STa) in the T84 cell line. J Nutr 1994;124:2358-64.
Newburg DS, Linhardt RJ, Ampofo SA, Yolken RH. Human milk glycosaminoglycans inhibit HIV glycoprotein gp120 binding to its host cell CD4 receptor. J Nutr 1995;125:419-24.
Wiederschain GY, Newburg DS. Human milk fucosyltransferase and α-L-fucosidase activities change during the course of lactation. J Nutr Biochem 1995;6:582-7.
Natowicz MR, Prence EM, Chaturvedi P, Newburg DS. Urine sulfatides and the diagnosis of metachromatic leukodystrophy. Clin Chem 1996;42:232-8.
Prence EM, Chaturvedi P, Newburg DS. In vitro accumulation of glucocerebroside in neuroblastoma cells: a model for study of Gaucher disease pathobiology. J Neurosci Res 1996;43:365-71.
Wiederschain GY, Newburg DS. Compartmentalization of fucosyltransferase and α-L-fucosidase in human milk. Biochem Mol Med 1996;58:211-20.
Chaturvedi P, Warren CD, Ruiz-Palacios GM, Pickering LK, Newburg DS. Milk oligosaccharide profiles by reversed-phase HPLC of their perbenzoylated derivatives. Anal Biochem 1997;251:89-97.
Newburg DS, Peterson JA, Ruiz-Palacios GM, Matson DO, Morrow AL, Shults J, Guerrero ML, Chaturvedi P, Newburg SO, Scallan CD, Taylor MR, Ceriani RL, Pickering LK. Role of human-milk lactadherin in protection against symptomatic rotavirus infection. Lancet 1998;351:1160-4.
Ogborn MR, Hamiwka L, Orrbine E, Newburg DS, Sharma A, McLaine PN, Orr P, Rowe P. Renal function in Inuit survivors of epidemic hemolytic uremic syndrome. Pediatr Nephrol 1998;12:485-8.
Shen Z, Warren CD, Newburg DS. High-performance capillary electrophoresis of sialylated oligosaccharides of human milk. Anal Biochem 2000;279:37-45.
Bulik DA, van Ophem P, Manning JM, Shen Z, Newburg DS, Jarroll EL. UDP-N-acetylglucosamine pyrophosphorylase, a key enzyme in encysting Giardia, is allosterically regulated. J Biol Chem 2000;275:14722-8.
Eisenhauer PB, Chaturvedi P, Fine RE, Ritchie AJ, Pober JS, Cleary TG, Newburg DS. TNF-α increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin. Infect Immun 2001;69:1889-94.
Chaturvedi P, Warren CD, Altaye M, Morrow AL, Ruiz-Palacios GM, Pickering LK, Newburg DS. Fucosylated human milk oligosaccharides vary among individuals over the course of lactation. Glycobiology 2001;11:365-72.
Shen Z, Warren CD, Newburg DS. Resolution of structural isomers of sialylated oligosaccharides by capillary electrophoresis. J Chromatogr A 2001;921(2):315-21.
Wiederschain GY, Newburg DS. Glycoconjugate stability in human milk: glycosidase activities and sugar release. J Nutr Biochem 2001;12:559-64.
Dai D, Nanthakumar NN, Savidge TC, Newburg DS, Walker WA. Region-specific ontogeny of α2,6 sialyltransferase during normal and cortisone-induced maturation in the mouse intestine. Am J Physiol Gastrointest Liver Physiol 2002;282:G480-90.
Nanthakumar NN, Dai D, Newburg DS, Walker WA. The role of indigenous microflora in the development of murine intestinal fucosyl- and sialyltransferases. FASEB J (November 15, 2002) 10.1096/fj.02-0031fje (summary: FASEB J 2003;17:44-6).
Ruiz-Palacios GM, Cervantes LE, Ramos P, Chavez-Munguia B, Newburg DS. Campylobacter jejuni binds intestinal H(O) antigen (Fucα1,2Galβ1,4GlcNAc), and fucosyloligosaccharides of human milk inhibit its binding and infection. J Biol Chem. 2003;278:14112-20.
Huang P, Farkas T, Marionneau S, Zhong W, Ruvoën-Clouet N, Morrow AL, Altaye M, Pickering LK, Newburg DS, LePendu J, Jiang X. Noroviruses bind to human ABO, Lewis and secretor histo-blood group antigens: Identification of four distinct strain-specific patterns. J Infect Dis 2003;188:19-31.
Newburg DS, Ruiz-Palacios GM, Altaye M, Chaturvedi P, Meinzen-Derr J, Guerrero ML, Morrow AL. Innate protection conferred by fucosylated oligosaccharides of human milk against diarrhea in breastfed infants. Glycobiology 2004;14(3):253-63. Published erratum Glycobiology 14(5):13G.
Sener K, Shen Z, Newburg DS, Jarroll EL. Levels of amino sugar phosphate intermediates in Giardia change during encystment. Microbiology 2004;150:1225-30.
Eisenhauer PB, Jacewicz MS, Conn KJ, Koul O, Wells JM, Fine RE, Newburg DS. Escherichia coli Shiga toxin 1 and TNF-α induce cytokine release by human cerebral microvascular endothelial cells. Microb Pathog 2004;36:189-96.
Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang X, Guerrero ML, Meinzen-Derr JK, Farkas T, Chaturvedi P, Pickering LK, Newburg DS. Human milk oligosaccharides are associated with protection against diarrhea in breastfed infants. J Pediatr 2004;145:297-303.
Jiang X, Huang P, Zhong W, Tan M, Farkas T, Morrow AL, Newburg DS, Ruiz-Palacios GM, Pickering LK. Human milk contains elements that block binding of Noroviruses to human histo-blood group antigens in saliva. J Infect Dis 2004;190:1850-9.
Nanthakumar NN, Dai D, Meng D, Chaudry N, Newburg DS, Walker WA. Regulation of intestinal ontogeny: Effect of glucocorticoids and luminal microbes on galactosyltransferase and trehalase induction in mice. Glycobiology 2005;15(3):221-232.
Stepans MBF, Wilhelm SL, Hertzog M, CRdehorst TKC, Blaney S, Clemens B, Polak JJ III, Newburg DS. Early consumption of human milk oligosaccharides is inversely rlated to subsequent risk of respiratory and enteric disease in infants. Breastfeeding Medicine 2006;1(4):207-215.
Proceedings of Meetings
Newburg DS, Daniel PF, O'Neil NE, McCluer RH. High performance liquid chromatography of oligosaccharides from human milk and colostrum. In: Hamosh M, Goldman AS, editors. Human Lactation 2: Maternal and Environmental Factors. New York: Plenum Press; 1986. p 581-8.
Newburg DS, Hundreiser KE, McCluer RH. Novel glycolipids of human and bovine milk. In: Atkinson SA, Hanson LA, Chandra RK, editors. Human Lactation 4: Breastfeeding, Nutrition, Infection and Infant Growth in Developed and Emerging Countries. St. John’s, Newfoundland, Canada: ARTS Biomedical Publishers; 1990. p 541.
Ashkenazi S, Newburg DS, Cleary TG. The effect of human milk on the adherence of enterohemorrhagic E. coli to rabbit intestinal cells. Adv Exp Med Biol 1991;310:173-7.
Newburg DS, Yolken RH. Characterization of a human milk factor that inhibits binding of HIV gp120 to its CD4 receptor. Adv Exp Med Biol 1991;310:281-91.
Newburg DS, Yolken RH. Anti-HIV components of human milk. In: Picciano MF, Lonnerdal B, editors. Mechanisms Regulating Lactation and Infant Nutrient Utilization. New York: John Wiley & Sons; 1992. p 189-210.
Newburg DS, Chaturvedi P, Crane JK, Cleary TG, Pickering LK. Fucosylated oligosaccharide(s) of human milk inhibits stable toxin of Escherichia coli. In: Agrawal VP, Sharma CB, Abidi SAH, Zingde MD, editors. Complex Carbohydrates and Advances in Biosciences. Muzaffarnagar, India: Society of Biosciences; 1995. p 199-226.
Newburg DS. Do the binding properties of oligosaccharides in milk protect the infant from gastrointestinal bacteria? J Nutr 1997;127(Suppl):980-4.
Newburg DS. Oligosaccharides in human milk and bacterial colonization. First Annual Sino-American Symposium on Pediatric Gastroenterology and Nutrition; 1999 March 23-25; Shanghai, China. J Pediatr Gastroenterol Nutr 2000;30:S8-17.
Dai D, Nanthakumar NN, Newburg DS, Walker WA. Role of oligosaccharides and glycoconjugates in intestinal host defense. J Pediatr Gastroenterol Nutr 2000; 30:S23-33.
Newburg D, Shen Z, Warren C. Quantitative analysis of human milk oligosaccharides by capillary electrophoresis. Adv Exp Med Biol 2000;478:381-2.
Newburg DS. Bioactive components of human milk: Evolution, efficiency, and protection. Adv Exp Med Biol 2001;501:3-10.
Chaturvedi P, Warren CD, Buescher CR, Pickering LK, Newburg DS. Survival of human milk oligosaccharides in the intestine of infants. Adv Exp Med Biol 2001;501:315-23.
Warren CD, Chaturvedi P, Newburg AR, Oftedal OT, Tilden CD, Newburg DS. Comparison of oligosaccharides in milk specimens from humans and twelve other species. Adv Exp Med Biol 2001;501:325-32.
Herrera-Insua I, Gomez HF, Diaz-Gonzalez VA, Chaturvedi P, Newburg DS, Cleary TG. Human milk lipids bind Shiga toxin. Adv Exp Med Biol 2001;501:333-9.
Gomez HF, Herrera-Insua I, Siddiqui MM, Diaz-Gonzalez VA, Carceres E, Newburg DS, Cleary TG. Protective role of human lactoferrin against invasion of Shigella Flexneri M90T. Adv Exp Med Biol 2001;501:457-67.
Wiederschain GY, Newburg DS. Glycosidase activities and sugar release in human milk. Adv Exp Med Biol 2001;501:573-7.
Newburg DS, Chaturvedi P, Warren CD, Altaye M, Morrow AL, Ruiz-Palacios GM, Pickering LK. Milk oligosaccharides vary within individuals and during lactation. Adv Exp Med Biol 2002;503:
Davidson B, Meinzen-Derr J, Wagner CL, Newburg DS, Morrow AL. Fucosylated oligosaccharides in human milk in relation of infant gestational age. Adv Exp Med Biol 2004;554:427-30.
Morrow AL, Ruiz-Palacios GM, Altaye M, Jiang X, Guerrero ML, Meinzen-Derr JK, Farkas T, Chaturvedi P, Pickering LK, Newburg DS. Human milk oligosaccharide blood group epitopes and innate immune protection against diarrhea in breast-fed infants. Adv Exp Med Biol 2004;554:443-6.
Newburg DS, Ruiz-Palacios, GM, Altaye M, Chaturvedi P, Guerrero ML, Meinzen-Derr JK, Morrow AL. Human milk α1,2-linked fucosyloligosaccharides decrease risk of ST-Escherichia coli diarrhea in breastfed infants. Adv Exp Med Biol 2004;554:457-61.
Viveros-Rogel M, Soto-Ramirez L, Newburg D, Ruiz-Palacios GM. Inhibition of HIV-1 infection in vitro by human milk sulfated glycolipids and glycosaminoglycans. Adv Exp Med Biol 2004;554:481-7.
Newburg D, Morrow A, Jiang X, Ruiz-Palacios G. Beyond FOS and GOS for infant formulas. Pediatric Gastroenterology 2004: Reports from the 2nd World Congress of Pediatric Gastroenterology, Hepatology and Nutrition, Paris (France), July 3–7, 2004. Bologna, Italy: Medimonde International Proceedings, 2004.
Newburg DS. Innate immunity and human milk. J Nutr (Suppl) 2005;135:1310-4.
Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human milk glycans that inhibit pathogen binding protect infants against infectious diarrhea. J Nutr (Suppl) 2005;135:1306-10.
Reviews, Chapters, Editorials
Concon JM, Swerczek TW, Newburg DS. Potential carcinogenicity of black pepper (Piper nigrum). In: Ory RL, editor. Antinutrients and natural toxicants in foods. Westport CN: Food and Nutrition Press; 1981. pp 359-74.
Ruiz-Palacios GM, Cervantes LE, Newburg DS, Lopez-Vidal Y, Calva JJ. In vitro models for studying Campylobacter infections. In: Nachamkin I, Blaser MJ, Tomkins LS, editors. Campylobacter jejuni. Current Status and Future Trends. Washington, DC: American Society for Microbiology; 1992. pp 176-83.
Jensen RG, Newburg DS. Bovine milk lipids. In: Jensen RG, editor. Handbook of Milk Composition. Orlando: Academic Press; 1995. pp 543-75.
Jensen RG, Bitman J, Carlson SE, Couch SC, Hamosh M, Newburg DS. Human milk lipids. In: Jensen RG, editor. Handbook of Milk Composition. Orlando: Academic Press; 1995. pp 495-542.
Newburg DS, Neubauer, SH. Carbohydrates in milk: analysis, quantities, and significance. In: Jensen RG, editor. Handbook of Milk Composition. Orlando: Academic Press; 1995. pp 273-349.
Newburg DS. Oligosaccharides and glycoconjugates in human milk: Their role in host defense. Mammary Gland Biol Neoplasia 1996;1996:271-83.
Newburg DS, Street JM. Bioactive materials in human milk: Milk sugars sweeten the argument for breast-eeding. Nutr Today 1997;32:191-201.
Jungalwala FB, Natowicz M, Chaturvedi P, Newburg DS. Analyses of sulfatide and enzymes of sulfatide metabolism. Meth Enzymol 1999;311:94-105.
Newburg DS. Human milk glycoconjugates that inhibit pathogens. Curr Med Chem 1999;6:117-27.
Newburg DS. [editorial] Are all human milks created equal? Variation in human milk oligosaccharides. J Pediatr Gastroenterol Nutr 2000;30:131-3.
Wiederschain GY, Newburg DS. α-Fucosidases. In: Creighton TE, editor. Wiley Encyclopedia of Molecular Medicine. New York: John Wiley & Sons, 2002. pp 133-6.
Wiederschain GY, Newburg DS. Fucosyltransferases. In: Creighton TE, editor. Wiley Encyclopedia of Molecular Medicine. New York: John Wiley & Sons, 2002. pp 1335-8.
Newburg DS. [editorial comment] Do breastfeeding mothers provide innate immunity to their infants through milk oligosaccharides? Riv Ital Pediatr 2003;29:6-8.
Newburg DS, Morrow AL, Ruiz-Palacios GM. Human milk glycans protect infants against enteric pathogen. Annu Rev Nutr 2005;25:2537-58.
Newburg DS, Walker, WA. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res 2007;61:1-8.
Newburg DS, editor. Bioactive components of human milk. Advances in Experimental Medicine and Biology Series, Vol. 501. New York: Kluwer Academic/Plenum Publishers, 2001, 592 pp.
two issued, six pending