W. Allan Walker
Member, Mucosal Immunology and Biology Research Center
Massachusetts General Hospital
114 16th Street (114-3503)
Charlestown, MA 02129-4404
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, organ culture and fetal intestinal xenograft transplants), 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 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.
Rautava S, Nanthakumar NN, Dubert-Ferrandon, Lu L, Rautava J, Walker WA. Breast milk transforming growth factor-β2 specifically attenuates IL-1β-induced inflammatory responses in the immature human intestine via a SMAD6 and ERK-dependent mechanism. Neonatology 2010; 99:192-201. PMID: 20881435
Lu L, Li T, William G, Petit E, Walker WA. Hydrocortisone induces changes in gene expression and differentiation in immature human enterocyres. Am J Phys- Gastrointestinal and Liver Physiol 2011; 300:G425-G432.
Nanthakumar N, Meng D, Goldstein AM, Zhu W, Lu K, Uauy R, Llano A, Claud EC, Walker WA. The mechanism of excessive intestinal inflammation in necrotizing enterocolitis: An immature innate immune response. Plos One 6:(3):E17776.doi:10.1371/journal.one.001766.
Cahill CM, Rogers JT, Walker WA. The role of phosphoinositide 3-kinase signaling in intestinal inflammation. J Signal Transduction, 2012; 2012:358476, doi:10.1155/2012/358476.
Ganguli K, Meng D, Rautava S, Lu L, Walker WA*, Nanthakumar N*. Probiotics prevent necrotizing enterocolitis by modulating enterocyte genes that regulate innate immune- mediated inflammation. Am J Phys: Gastrointestinal and Liver Physiology 2013; 304:G132-G141. (* shared senior authorship) PMID: 23139215; PMCID: PMC3543644
Last Update: 1/6/2014