W. Allan Walker
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.
Massachusetts General Hospital
114 16th Street (114-3503)
Charlestown, MA 02129-4404