SUMMARY Necrotizing enterocolitis (NEC) is an inflammatory intestinal disorder that affects 2–5% of all premature infants. Enterobacter sakazakii (ES), a common contaminant in milk-based powdered infant formula, is implicated as a causative agent of sepsis, meningitis, and NEC in newborn infants with high mortality rates. However, the role of ES in the pathogenesis of NEC is not known to date. Here, we demonstrate for the first time that ES is able to induce clinical and histological NEC in newborn rats. ES was found to bind to enterocytes in rat pups at the tips of villi and to intestinal epithelial cells, IEC-6, in culture with no significant invasion. Exposure to ES induced apoptosis and increased the production of interleukin-6 in IEC-6 cells and in the animal model. These data suggest that ES could be a potential pathogen that induces NEC, and triggers intestinal disease by modulating enterocyte intracellular signaling pathways.

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Necrotizing Enterocolitis (NEC) is the most common life-threatening gastrointestinal disease encountered in the premature infant. Although the inciting events leading to NEC remain elusive, various risk factors including prematurity, hypoxemia, formula feeding and intestinal ischemia have been implicated in the pathogenesis of NEC. Data from our lab and others suggest that NEC evolves from disruption of the intestinal epithelial barrier, as a result of a combination of local and systemic insults. We postulate that nitric oxide (NO), an important second messenger and inflammatory mediator, plays a key role in intestinal barrier failure seen in NEC. Nitric oxide and its reactive nitrogen derivative, peroxynitrite, may affect gut barrier permeability by inducing enterocyte apoptosis (programmed cell death) and necrosis, or by disrupting tight junctions or gap junctions that normally play a key role in maintaining epithelial monolayer integrity. Intrinsic mechanisms that serve to restore monolayer integrity following epithelial injury include enterocyte proliferation, epithelial restitution via enterocyte migration, and re-establishment of cell contacts. This review focuses on the biology of NO and the mechanisms by which it promotes epithelial injury while concurrently disrupting the intrinsic repair mechanisms. INDEX WORDSNecrotizing Enterocolitis; Nitric Oxide; Intestinal inflammation; Intestinal restitution Necrotizing Enterocolitis (NEC) is the most common life-threatening gastrointestinal disease encountered in the premature infant. The incidence of NEC approaches 1 per 1000 live-births, with approximately 1 out of 7 affected neonates succumbing to the disease 1 . The mortality rate

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