Neonatal necrotizing enterocolitis (NEC) is the single most devastating cause of gastrointestinal mortality and morbidity in premature infants. NEC affects over 4000 infants every year in the United States and carries a mortality of 30% in those affected. Although NEC was first recognized in the1960’s, the medical treatments and mortality are essentially unchanged since that time. The incidence of NEC is greatest in the most premature babies, suggesting that susceptibility is a consequence of incomplete gut development. The leading hypothesis for the pathophysiology of NEC is that bacteria normally confined to the intestinal lumen penetrate the immature intestinal epithelial barrier defenses. This leads to invasion of the epithelium and underlying lamina propria, resulting in an exaggerated inflammatory response and tissue destruction. Bacterial invasion is normally prevented by intestinal innate immune components, but this defense system is immature in preterm infants, and may be further diminished during episodes of inflammation.
The long-term goal of our lab is to better understand how different gastrointestinal developmental stages differ in their response to inflammation, and specifically the mechanism by which immaturity of the small intestine predisposes development of NEC. To accomplish this, we are actively examining the effects of inflammation on intestinal homeostasis and repair mechanisms at different stages of intestinal development in mice. Mice provide an excellent model for studying intestinal development. Mice and human intestine develop in a defined, sequential pattern. Newborn mice have small intestine that is developmentally similar to human infants at approximately 16 weeks, and mice at four weeks of age are developmentally similar to term human infants. Thus examining mice at various points during their first four weeks of life are allowing us to better understand how inflammation affects the intestines of premature infants.
We have also discovered that infants with NEC have significantly decreased numbers of Paneth cells. Paneth cells are located at the base of intestinal crypts and are a key cellular component of the innate immune system. Paneth cells are important in mucosal development, host defense, and regulation of the intestinal microbiota, and maintenance of intestinal stem cell populations. However, their role in NEC is unknown. We have developed a novel model of NEC that uses Paneth cell ablation to induce intestinal pathology that is consistent with human NEC. Using this model, we are examining the role of Paneth cells in development of NEC.
McElroy, SJ, Weitkamp, JH.
The importance of innate immunity in the small intestine of premature infant.
Zhang C, Sherman MP, Prince LS, Bader D, Weitkamp JH, Slaughter JC, McElroy SJ.
“Paneth cell ablation in the presence of Klebsiella pneumonia induces NEC-like injury in immature murine small intestine.”
Disease Models and Mechanisms. 2012