Inflammation in the developing human intestine: A possible pathophysiologic contribution to necrotizing enterocolitis

Necrotizing enterocolitis (NEC), a major cause of morbidity and mortality i n premature infants, occurs after the introduction of oral feedings in conj unction with initial bacterial colonization of the gut and is hypothesized to be due to an immature (inappropriate) enterocyte response to bacterial s timuli. To test this hypothesis, we compared the enterocyte IL-8 response t o inflammatory stimuli [lipopolysaccharide (LPS) and IL-1 beta] in immature vs. mature human small intestine. Initial in vitro studies comparing confl uent Caco-2 cells, a model for mature human enterocytes, with a primary hum an fetal intestinal cell line (H4 cells) demonstrated that after inflammato ry stimulation fetal cells secreted more IL-8 (LPS, 8-fold; IL-1 beta, 20-f old) than Caco-2 cells. IL-8 mRNA activity in fetal compared to Caco-2 cell s was proportionately increased by the same magnitude with both stimuli. To validate the in vitro observations, small intestinal organ cultures from f etuses vs. older children were exposed to LPS and IL-1 beta. Again in human organ cultures from fetuses compared to older children, IL-8 secretion was greater (LPS, 2.5-fold; IL-1 beta, 200-fold) and mRNA activity after stimu lation was comparably higher, suggesting that increased transcription of th e IL-8 gene may account for the excessive response. Using immunohistochemic al staining to identify the cellular source of IL-8, activity was noted pre dominantly in villous and crypt epithelium but also in a few immunoresponsi ve lymphoid cells, The observation that immature human enterocytes react wi th excessive pro-inflammatory cytokine production after inflammatory stimul ation may help in part explain why prematures exposed to initial colonizing bacteria develop necrotizing enterocolitis.