Abstract
ABSTRACTPrematurity and enteral feedings are major risk factors for intestinal injury leading to necrotizing enterocolitis (NEC). An immature digestive system can lead to maldigestion of macronutrients and increased vulnerability to intestinal injury. The aim of this study was to test in neonatal mice the effect of maltodextrin, a complex carbohydrate, on the risk of intestinal injury. The goal was to develop a robust and highly reproducible murine model of intestinal injury that allows insight into the pathogenesis and therapeutic interventions of nutrient-driven intestinal injury. Five- to 6-day-old C57BL/6 mice were assigned to the following groups: dam fed (D); D+hypoxia+Klebsiella pneumoniae; maltodextrin-dominant human infant formula (M) only; M+hypoxia; and M+hypoxia+K. pneumoniae. The mice in all M groups were gavage fed five times a day for 4 days. Mice were exposed to hypoxia twice a day for 10 min prior to the first and last feedings, and K. pneumoniae was added to feedings as per group assignment. Mice in all M groups demonstrated reduced body weight, increased small intestinal dilatation and increased intestinal injury scores. Maltodextrin-dominant infant formula with hypoxia led to intestinal injury in neonatal mice accompanied by loss of villi, increased MUC2 production, altered expression of tight junction proteins, enhanced intestinal permeability, increased cell death and higher levels of intestinal inflammatory mediators. This robust and highly reproducible model allows for further interrogation of the effects of nutrients on pathogenic factors leading to intestinal injury and NEC in preterm infants.This article has an associated First Person interview with the first author of the paper.
Highlights
No spontaneous mortality was observed in the dam-fed alone (D) and D+hypoxia+K. pneumoniae (DHK) groups
Necrotizing enterocolitis (NEC) is defined by the culmination of several pathogenic features with unpredictable penetrance in preterm infants, owing to variable degrees of host vulnerability
The current murine models of NEC do not focus on specific nutrient-processing vulnerabilities and do not have a high penetrance of the NEC phenotype
Summary
NEC is a complex and multifactorial disease, and three major risk factors are thought to contribute to the pathogenesis of this disease: prematurity, altered bacterial colonization and enteral feeding, with the risk of NEC greater in formula-fed versus breastmilk-fed infants (Neu and Walker, 2011; Niño et al, 2016). These multifactorial processes culminate in an unbalanced and unmitigated inflammatory response in the immature intestine, leading to intestinal injury (Nanthakumar et al, 2000)
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