INTRODUCTION: The primary risk factors for necrotizing enterocolitis (NEC) are preterm birth, enteral feeding and gut colonization. It is unclear if feeding and colonization induce excessive expression of immune genes that lead to NEC. Using a pig model, we hypothesized that reduced gestational age would up-regulate immune-related genes and cause bacterial imbalance after birth.

METHODS: Preterm (85-92% gestation, n = 53) and near-term (95-99% gestation, n = 69) pigs were delivered by cesarean section and euthanized at birth or after two days of infant formula or bovine colostrum feeding.

RESULTS: At birth, preterm delivery reduced 5 of 30 intestinal genes related to nutrient absorption and innate immunity, relative to near-term pigs, whereas two genes were up-regulated. Preterm birth also reduced ex vivo intestinal glucose and leucine uptake (40-50%), but failed to increase cytokine secretions from intestinal explants relative to near-term birth. After two days of formula-feeding, NEC incidence was increased in preterm vs. near-term pigs (47 versus 0-13%). Six of 30 genes related to immunity (TLR2, IL1B, IL8), permeability (CLDN3, OCLN) and absorption (SGLT) decreased in preterm pigs without affecting gram-negative bacteria related responses (TLR4, IKBA, NFkB1, TNFAIP3, PAFA). Bacterial abundance tended to be higher in preterm vs. near-term pigs (P = 0.09), whereas the composition was unaffected.

CONCLUSION: Preterm birth predisposes to NEC and reduces nutrient absorption, but does not induce up-regulation of immune-related genes or cause bacterial dyscolonization in the neonatal period. Excessive inflammation and bacterial overgrowth may occur relatively late in NEC progression in preterm neonates.