Deletion of the heparin-binding epidermal growth factor-like growth factor gene increases susceptibility to necrotizing enterocolitis

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Background Necrotizing enterocolitis (NEC) is the leading surgical cause of death in premature infants. We have accumulated evidence supporting a role for heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) in protection of the intestines from NEC. The aim of the current study was to evaluate the effect of loss-of-function of endogenous HB-EGF on susceptibility to NEC. Methods Neonatal HB-EGF (−/−) knockout (KO) mice and their HB-EGF (+/+) wild-type (WT) counterparts were exposed to experimental NEC. An additional group of HB-EGF KO pups were also exposed to NEC but had HB-EGF added to their formula. To examine gut barrier function, HB-EGF KO and WT pups received intragastric fluorescein isothiocyanate-labeled dextran (FITC dextran) under basal and stressed conditions, and serum FITC dextran levels were measured. Results The WT mice had an incidence of NEC of 53%, whereas HB-EGF KO mice had a significantly increased incidence of NEC of 80% ( P = .04). Importantly, administration of exogenous HB-EGF to HB-EGF KO pups significantly reduced the incidence of NEC to 45% ( P = .04). Heparin-binding EGF KO mice had significantly increased intestinal permeability compared to WT mice under basal and stressed conditions. Conclusions Our results provide evidence that loss of the HB-EGF gene increases susceptibility to NEC and that administration of exogenous HB-EGF reverses this susceptibility.