Role of Creatine Metabolism in Necrotizing Enterocolitis

项目摘要 坏死性小肠结肠炎（NEC）是一种新生儿期的炎症性胃肠道疾病， 和可能的多因素发病机制。NEC最常影响早产、极低出生体重（VLBW，< 1500 g） 婴儿和危险因素，包括生态失调，配方奶粉喂养和早产已牵连在NEC 病因学我们的长期目标是确定营养策略，促进出生后肠道的恢复能力， 环境、发育和微生物影响增加了对NEC的易感性。肌酸（Cr） 一种氨基酸衍生物，在许多方面具有抗氧化、抗炎和生物能量益处， 各种疾病。在炎症性肠病（IBD）期间，Cr产生或摄取减少促进了 肠上皮细胞（IEC）功能障碍，而铬补充稳定肠屏障功能，改善 生物能量学，并加速伤口愈合。虽然胎儿铬是通过母体转移，婴儿必须 由于人乳和婴儿配方奶粉中铬的含量可忽略不计，因此新生儿在出生后内源性合成铬。在 早产儿，由于早产，功能不成熟， 负责内源性合成的酶系统，以及由于快速生长和 新生儿期的发育可能使Cr成为一种条件性必需营养素， 婴儿可能缺乏体内平衡。间歇性缺氧，一种常见的成熟后果 早产儿和急性肠道炎症的发展可进一步延长对Cr的需求 在这个人群中。我们的初步数据表明，铬加速肠上皮细胞修复后，创伤 并抑制caspase 3/7诱导的早产人NEC样肠样模型中的细胞凋亡 炎性损伤本项目将检验以下假设：（目的1）铬缺乏对早产儿的影响 婴儿肠上皮损伤，而补充铬可预防NEC样损伤，且（目标2）铬 代谢与早产儿NEC的发展是双向相关的，早产儿尿Cr水平低， 婴儿是全身性低铬储存和/或高组织铬利用和肠道铬耗竭的代表 结合NEC的发展。该项目的成功完成将引入一种新的治疗方法， 以NEC为目标，NEC是一种目前没有有效的母乳预防替代品的疾病， 除了手术干预和支持性护理外，没有有效的治疗方法，使用已经注意到的补充剂， 在早产儿人群中耐受性良好。

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.