David Newburg

David S Newburg , PhD

Adjunct Professor

Kettering Lab Complex

COM Environmental and Public Health Scie - 0056

Professional Summary

My initial studies on nutrition in brain development led to a pioneering research program in 1984 on bioactive components of human milk. Human milk oligosaccharides (HMOS) are the third largest component of milk, representing 10% of the maternal caloric input, but are essentially indigestible by the infant, suggesting other essential functions. First, specific HMOS contain moieties that mimic intestinal glycans that are used by enteric pathogens as receptors; competitive inhibition of binding by specific HMOS protects breastfeeding infants from infection. Second, although (and because) HMOS are essentially indigestible by the mammalian intestinal mucosa, they promote growth in distal gut of specific mutualist symbionts of the microbiota. We found a unique transcellular signaling pathway by which healthy microbiota communicate with intestinal mucosal epithelial cells through fut2 expression, promoting mucosal homeostasis, and resilience to damage by pathogen infection, physical, or immunologic insult. This prebiotic effect indirectly reduces gut inflammation. Third, we find that individual HMOS directly inhibit specific pro-inflammatory signaling pathways. These data strongly support our original hypothesis that the glycans of human milk constitute an innate immune system whereby the mother confers potent clinically significant protection to her nursing infant. 


BS: University of Massachusetts (Amherst) Amherst, MA, 1970 (Chemistry)

PhD: Boston University Boston, MA, 1976 (Biochemistry (Nutrition and Neuroscience))

Research and Practice Interests

My research focuses on glycobiology of human milk, with emphasis on functional interactions with intestinal mucosa, including control of glycan ontogeny in gut development and function. Developing and validating instrumental methods of analysis and biological models of mucosal signaling have allowed the following five significant research contributions:
Human milk glycans inhibit pathogens.  An essential step for most enteropathogens is to bind to their target receptor in the gut mucosa, through adhesin (bacteria) or capsid (virus) ligation. The uniquely rich array of glycans in human milk include moieties that enteric pathogens use for docking to intestinal glycans, allowing competitive inhibition of pathogen binding, thereby protecting breastfeeding infants from infection. We pioneered identification and characterization of these human milk glycans. For example, a human milk fucosylated oligosaccharide inhibits stable toxin of enterotoxigenic E. coli in vivo. Campylobacter binds to fucosylated H-2 host cell receptors , and the binding is inhibited by 2¢-fucosyllactose (2’-FL) in milk. Norovirus binding is inhibited by lacto-N-difucohexaose-I. Pathogens that use non-fucosylated glycan moieties for binding to their mucosal target are inhibited by milk glycans that contain these other relevant epitopes: Enterohemorrhagic E. coli binding is inhibited by a mannosylated glycopeptide. Rotavirus infection is inhibited by the glycoprotein lactadherin. Binding of gp120 of HIV to CD4 of its target T-4 lymphocytes is inhibited by glycosaminoglycans and sulfatides. Sulfatides also inhibit recruitment of polymorphonucleocytes by salmonella. Strains of noroviruses bind to distinct carbohydrate epitopes and are inhibited by the corresponding milk glycans. Thus, this type of protection is through inhibition of pathogen binding. 
Interkingdom signaling in the gut underlies strong mutualism. Signaling between gut microbes and the mucosa heretofore has always involved inflammatory pathways, but we found that pioneering microbes can induce adaptive gene expression without activating inflammation. Post-weaning murine gut is heavily fucosylated, whereas suckling gut has sparse fucosylation. The possible proximate signal for this transition includes 1) change in diet; 2) innate timing by developmentally sensitive genes; 3) modified hormonal milieu; or 4) a shift in microbiota. In germ-free mice the shift in fucosylation did not occur at weaning, eliminating all candidates except 4) microbiota. Furthermore, colonization of adult germ-free mice induces fucosylation of their mucosa. Moreover, when standard mice are treated with antibiotics, the gut microbes are depleted and dysbiotic, and the mucosa reverts to the immature, minimally fucosylated state. This can be reversed by recolonization by fecal slurry or just a single fucose-utilizing isolate of normal microbiota, such as Bacteriodes fragilis. Such recolonization rapidly induces fut2 (secretor) gene expression through up-regulation of the ERK and JNK signaling pathways, their nuclear transcription factors ATF-2 and jun, which activate AP-1 control elements found in the fut2 gene. The NF-kB pro-inflammatory signaling usually associated with bacterial recognition is not activated. The induced fut2 gene product, FucT 2, adds a1,2 linked L-fucose to glycans targeted to the extracellular glycocalyx of the intestinal mucosa, providing a fucosylated niche favored by mutualists of the microbiota. This ostensible mutualism implies a host benefit. Mice whose bacteria have been disrupted by antibiotics with limited intestinal fucosylation more fragile to mucosal injury. Restoration of the microbiota or recolonization with only B. fragilis (9343) fully reinstates fucosylation a

Positions and Work Experience

1976 -1984 Assistant to Associate Professor (tenured), Teaching and research Nutrition, Biochemistry, Advanced Normal and Therapeutic Nutrition, Graduate Courses in research and seminars., University of Kentucky, Lexington, KY

1984 -2004 Associate to Senior Scientist (Biochemist), NIH funded Research, Eunice Kennedy Shriver Center for Mental Retardation, Waltham, MA

1988 -2000 Research Fellow to Instructor, Neurology, Faculty of Medicine, Harvard University, Boston, MA

1988 -2000 Assistant to Associate Biochemist, Neurology, Massachusetts General Hospital, Boston, MA

1998 -2004 Director, Program in Glycobiology, NIH funded Research, Eunice Kennedy Shriver Center for Mental Retardation, Waltham,MA

1998 -2010 Investigator, Clinical Nutrition Research Center, Harvard Medical School, Boston, MA

2000 -2004 Professor, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA

2001 -2004 Professor, Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA

2004 -2010 Glycobiologist, Pediatric Gastroenterology and Nutrition , Massachusetts General Hospital, Boston, MA

2004 -2010 Director, Program in Glycobiology, Developmental Immunology Laboratory, Massachusetts General Hospital, Boston, MA

2006 -2010 Associate Professor (tenured), Department of Pediatrics, Harvard Medical School, Boston, MA

2010 -2016 Professor, Department of Biology, Boston College, Chestnut Hill, MA

2010 -2016 Director, Program in Glycobiology, Boston College, Chestnut Hill, MA

2016 - Director, DSN Medical Consulting, NK Labs, Cambridge, MA

2020 - Adjunct Professor, Department of Environmental and Public Health, University of Cincinnati College of Medicine, Cincinnati, OH

Contact Information

Research - Kettering Laboratories
160 Panzeca Way
Cincinatti  Ohio, 45267
Phone: (617)835-3236

Home - 15 Harrington Street
Newtonville  Massachusetts, 02460
Phone: (617)835-3236