Neonatal necrotizing enterocolitis (NEC) is the single most devastating cause of gastrointestinal mortality and morbidity in premature infants. NEC affects 1.1 per 1000 live births in the general population and up to 5-7% of premature infants born with birth weights less than 1500g.  The mortality rate for NEC remains approximately 30% in those affected. Although NEC was first recognized in the mid-1900’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. However, these susceptible infants do not develop NEC at birth, but instead take weeks to develop the disease.  In fact, despite gestational age at birth, the peak incidence of NEC remains between 28 and 32 weeks corrected gestation.  This suggests that NEC is not only a disease process of the immature intestine, but that there is a specific developmental-stage dependent window of susceptibility in which infants are most likely to develop NEC.

Thus, 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 by utilizing mice. Mice provide an excellent model for studying intestinal development as the intestinal tract of both mice and humans develop in a defined, sequential pattern.  Mice, however, are born at an earlier stage of intestinal development than humans.  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 surgical 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 several complimentary mouse models that use Paneth cell disruption followed by formula feeding or induction of bacterial dysbiosis to induce intestinal pathology that is consistent with human NEC. Using these models, we are examining the role of Paneth cells, bacterial dysbiosis, and formula composition in development of NEC.

Lastly, we have begun to examine the effects of in utero inflammation on the development of the intestine and the relationship between chorioamnionitis and NEC.  To do this, we are utilizing maternal exposure in the last trimester to LPS.  LPS doesn’t cross the placenta but induces a robust inflammation in the mother.  Thus, we can model fetal exposure to inflammation and examine the long-term effects of this on growth and development of the intestinal tract. This approach has yielded important data that implicates fetal exposure to maternal inflammation in disruption of normal developmental patterns of the intestinal tract including Paneth cell development, goblet cell development, and development of important components of innate immunity.