Formula feeding and immature gut microcirculation promote intestinal hypoxia, leading to necrotizing enterocolitis

Major risk factors for necrotizing enterocolitis (NEC) are formula feeding and prematurity; however, their pathogenic mechanisms are unknown. Here, we found that insufficient arginine/nitric oxide synthesis limits blood flow in the intestinal microvasculature, leading to hypoxia, mucosal damage and NEC in the premature intestine after formula feeding. Formula feeding led to increased intestinal hypoxia in pups at postnatal day (P)1 and P5, but not inmore mature pups at P9. Accordingly, blood flow in the intestinal microvasculature increased after formula feeding in P9 pups only. mRNAprofiling revealed that regulators of arginine/nitric oxide synthesis are at higher levels in endothelial cells of the intestine in P9 than in P1 pups. Importantly, arginine supplementation increased intestinal microvasculature blood flow and prevented NEC, whereas an arginine antagonist exacerbated NEC. Our results suggest that balancing intestinal oxygen demand and supply in the premature intestine by modulating arginine/nitric oxide could be used to prevent NEC.