Role of Creatine Metabolism in Necrotizing Enterocolitis

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PROJECT SUMMARY Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease of the neonatal period with an unclear, and likely multifactorial, pathogenesis. NEC most often affects preterm, very low birthweight (VLBW, < 1500 g) infants, and risk factors including dysbiosis, formula feeding, and prematurity have been implicated in NEC etiology. Our long-term goal is to identify nutritional strategies promoting postnatal intestinal resilience to environmental, developmental, and microbiological influences increasing susceptibility to NEC. Creatine (Cr) is an amino acid derivative with demonstrated antioxidant, anti-inflammatory, and bioenergetic benefits in a number of diverse diseases. During inflammatory bowel disease (IBD), reduced Cr production or uptake promotes intestinal epithelial cell (IEC) dysfunction, while Cr supplementation stabilizes intestinal barrier function, improves bioenergetics, and accelerates wound healing. While fetal Cr is provided through maternal transfer, infants must endogenously synthesize Cr postnatally, as both human milk and infant formula contain negligible levels. In preterm infants, a lack of third trimester accretion of the nutrient due to premature birth, immature functionality of enzyme systems responsible for endogenous synthesis, and increased requirements due to rapid growth and development in the neonatal period likely render Cr a conditionally essential nutrient, and one in which these infants are likely deficient at homeostasis. Periods of intermittent hypoxia, a common maturational consequence of prematurity, and the development of acute intestinal inflammation could further extend the requirement for Cr in this population. Our preliminary data suggest Cr accelerates intestinal epithelial restitution following wounding and inhibits caspase 3/7-induced apoptosis in a preterm human intestinal enteroid model of NEC-like inflammatory injury. This project will test the hypotheses that (Aim 1) Cr deficiency detrimentally affects preterm infant intestinal epithelial injury, while Cr supplementation prevents NEC-like injury, and that (Aim 2) Cr metabolism is bidirectionally related to NEC development in preterm infants, with low urine Cr levels in preterm infants a proxy for systemically low Cr stores and/or high tissue Cr utilization, and intestinal Cr depletion associating with development of NEC. Successful completion of this project will introduce a novel treatment target for NEC, a condition for which there are currently no effective prophylactic alternatives to human milk, and no effective therapeutics beyond surgical intervention and supportive care, using a supplement already noted to be well-tolerated in the preterm population.