Thursday, February 19, 2009

Mucosal Immunology Laboratory

Mucosal Immunology Laboratory

A researcher in the Mucosal Immunology Laboratory

The Mucosal Immunology Laboratory, located in Building 114 in Charlestown, consists of nine principal investigators and fifteen postdoctoral/subspecialty fellows studying various aspects of microbial-intestinal interaction. Dr. Walker’s group is particularly interested in the role of initial bacterial colonization in the development of human intestinal defenses.

His laboratory had developed human fetal intestinal models (cell lines, organ cultures and xenografts) to define the immaturities in intestinal defenses of newborns (particularly premature newborn infants). A major disease affecting prematures is Necrotizing Enterocolitis (NEC).

It affects almost 10% of prematures under 1500 gm weight. This group has hypothesized that NEC is due to an immature, excessive inflammatory response to exogenous stimuli, e.g., intestinal bacteria. Using the human fetal intestinal models, they have shown that the fetal enterocyte excessively responds to the cytokine IL-1ß and gram negative bacteria lipolysaccharide (FIGURE 1). Several clinical approaches have been used to try to prevent NEC in prematures. One such approach is the introduction of probiotics with the initial enteral feeding. A clinical study in Taiwan using a combination of Lactobacillus acidophilus and Bifidobacteria infantis has shown a highly significant decrease in incidence and severity of NEC.

In this laboratory, we have used the secreted products of these same two probiotics infused into fetal human small intestinal xenografts before exposure to an inflammatory stimulus. Using IL-8 as a measure of enterocyte inflammation, we have shown that these secreted probiotic products inhibit the inflammatory response (FIGURE 2) and using DNA microarray analysis of laser-captured enterocyte RNA, we have shown that the genes that modulate the innate inflammatory response are immaturely expressed. This probably represents the basis for excessive inflammation and that the probiotic secretions cause a maturation of inflammation genes.

We believe this is the basis for prevention of NEC using these probiotic secretions. If these observations are confirmed in an animal model of NEC and in a pilot clinical trial to confirm their routine use in premature care, we plan a multicenter trial to confirm before recommending routine use in patient care.

Selected References

  1. Grave GD, Nelson SA, Walker WA, Moss RL, Dvorak B, Hamilton FA, Higgins R, Raju TNK. New therapies and preventive approaches for necrotizing enterocolitis: Report of a research planning workshop. Ped Res 2007; 62:510-514.
  2. Deshpande G, et al. Probiotics for prevention of NEC in preterm infants: A meta-analysis. Lancet 2007; 369:1614-1620
  3. Martin CR, et al. Probiotics: Role in pathophysiology and prevention of NEC. Semin Perinatol 2008; 32:127-137.
  4. Martin CR, et al. Intestinal defenses and inflammatory response in NEC. Seminar in Feta and Neonatal Med 2006; 11:369-377.


FIGURE 1: Inflammation, as measured by the IL-8 response in organ cultures, of infant and small intestine. The IL-8 response to the cytokine IL-1ß the bacterial product (LPS) was considerably higher in fetal than infant intestine.


FIGURE 2: Using secreted products of probiotics (Lactobacillus acidophilus and Bifidobacteria infantis) in xenografts of fetal human small intestine, the excessive inflammatory response (IL-8) was strikingly reduced to both inflammatory stimuli.

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