Immunology Faculty Member - W. Allan Walker, MD

W. Allan Walker, MD

Member, Mucosal Immunology and Biology Research Center
Massachusetts General Hospital
114 16th Street (114-3503)
Charlestown, MA 02129-4404
Tel: 617-726-7988
Fax: 617-726-1731
Email: wwalker@mgh.harvard.edu

The overall mission of this laboratory is to determine the mechanism of “crosstalk” between colonizing bacteria and the developing human intestine immune function. We know from a decade of investigation that for the mucosal immune system in the human intestine at birth to be operational, it must have the stimulus of colonizing bacteria interacting with both epithelial cells and appendages of sub-mucosal dendritic cells extending into the lumen. Using established models for human intestinal development (a fetal cell line, primary fetal enterocytes, intestinal organoids), we have determined that the immature gut produces an excessive inflammatory response to both pathogens and commensal bacteria because of an increased expression of surface toll receptors and an underexpression of negative regulators (e.g., IRAK-M, A-20, etc.). We believe this immaturity of interaction by colonizing bacteria in the human gut accounts for the severe necrotizing enterocolitis (NEC) which is common in human prematures. Our current studies attempt to define other immaturities in “crosstalk” between colonizing bacteria and the immature human intestine.

Another major project in this laboratory is to determine the effect of human breast milk on the maturation of intestinal host defenses in the immature human intestine. We have published several observations on the effect of hydrocortisone and transforming growth factor beta on inflammation and immune barrier function. These studies use the same human models to determine the mechanism of anti-inflammation by protective nutrients in breast milk. Our studies have shown that a combination of probiotics and breastmilk produces postbiotic substances which are anti-inflammatory to the fetal intestine and may be a therapeutic approach to preventing NEC.

Last Update: 6/18/2020

Publications

For a complete listing of publications click here.

Jiang F*, Meng D*, Weng M, Kasper DL, Walker WA. The symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis inhibits IL-1β-induced inflammation in human fetal enterocytes via toll receptors 2 and 4. PLoS One. 2017;12(3):e0172738. Published 2017 Mar 9. PMID: 28278201 (*shared authorship).

Senger S, Ingano L, Freire R, Anselmo A, Zhu W, Sadreyev R, Walker WA*, Fasano A*. Human Fetal-Derived Enterospheres Provide Insights on Intestinal Development and a Novel Model to Study Necrotizing Enterocolitis (NEC). Cell Mol Gastroenterol Hepatol. 2018;5(4):549-568. Published 2018 Jan 31. PMID: 29930978 (*shared senior authorship).

Gorreja F, Rush ST, Kasper DL, Meng D, Walker WA. The developmentally regulated fetal enterocyte gene, ZP4, mediates anti-inflammation by the symbiotic bacterial surface factor polysaccharide A on Bacteroides fragilis. Am J Physiol Gastrointest Liver Physiol. 2019;317(4):G398-G407. PMID: 31314571

Meng D, Sommella E, Salviati E, et al. Indole-3-lactic acid, a metabolite of tryptophan, secreted by Bifidobacterium longum subspecies infantis is anti-inflammatory in the immature intestine [published online ahead of print, 2020 Jan 16]. Pediatr Res. 2020;10.1038/s41390-019-0740-x. PMID: 31945773

Zheng N, Gao Y, Zhu W, Meng D, Walker WA. Short chain fatty acids produced by colonizing intestinal commensal bacterial interaction with expressed breast milk are anti-inflammatory in human immature enterocytes. PLoS One. 2020;15(2):e0229283. Published 2020 Feb 21. PMID: 32084202