Metabolic mechanisms induced by enteral DHA and ARA supplementation in preterm infants

早产意味着胎儿丰富的多不饱和脂肪酸供应的结束，如二十二碳六烯酸(DHA)和花生四烯酸(ARA)，它们是大脑和眼睛发育的关键构件，也是重要的炎症调节剂。然而，近40年来，肠内补充DHA和ARA以取代丢失的胎儿附着未能转化为长期的临床益处。未能了解出生后脂肪酸补充剂的新陈代谢和诱导的分子变化，导致了错误的假设和替代策略，在最好的情况下，对临床没有好处，在最坏的情况下，是有害的。本研究的总体目标是探讨极早产儿从出生到出生后36周肠内补充DHA和ARA的诱导代谢及其下游分子机制。我们组建了一支在新生儿-围产期医学和生物统计学/生物信息学方面具有专业知识的多学科团队。新生儿专家团队是营养、生长和脂肪酸方面的临床和研究领导者，代表着五个具有不同人口统计人口的III/IV级新生儿重症监护病房。我们假设，DHA和ARA肠内补充剂的代谢受发育调节，脂类代谢产物对生物学的影响取决于婴儿的健康状况(上下文特异性)。为了验证我们的假设，我们提出了一项多中心、随机的临床试验，评估从出生到绝经后36周期间联合服用DHA和ARA对280名出生在25.0/7周到29.6/7周之间的极低胎龄新生儿的血脂作用。将对以下目标进行评估：目标1-确定联合补充DHA和ARA对脂肪酸代谢的影响，包括产生专门的促分解介质(SPM)和产生氧脂；以及目标2-确定作为肠道补充DHA/ARA的结果，炎症和器官发育和完整性的循环标志物的多系统变化。这些目标的成功完成将确定未成熟宿主中发育调节的脂肪酸代谢以及补充脂肪酸对关键生物学功能的影响。需要机械性数据来弥合科学鸿沟到有效和安全的适当临床翻译。这些数据将为早产儿脂肪酸输送提供一种生物学上合理的方法，并确定在未来的临床疗效试验中可能作为生物标记物的分子读数。

Preterm birth indicates an end to the rich fetal supply of polyunsaturated fatty acids such as docosahexaenoic acid (DHA) and Arachidonic Acid (ARA) which are a critical building blocks for brain and eye development and an important inflammatory modulator. Yet, for almost 40 years, enteral supplementation of DHA and ARA to replace lost fetal accretion has failed to translate into long-standing clinical benefit. The failure to understand the metabolism and induced molecular changes of fatty acid supplementation during the postnatal period has led to erroneous assumptions and replacement strategies that are, at best, not clinical beneficial and, at worst, harmful. The overall study objective of this proposal is to investigate the induced metabolism and downstream molecular mechanisms of enteral DHA and ARA supplementation from birth to 36 weeks' postnatal age in the extremely preterm infant. We have assembled a multidisciplinary team with expertise in neonatal-perinatal medicine and biostatistics/bioinformatics. The team of neonatologists are clinical and research leaders in nutrition, growth, and fatty acids and represents five level III/IV neonatal intensive care units with diverse demographic populations. We hypothesize that metabolism of DHA and ARA enteral supplementation is developmentally regulated and the impact of lipid derived metabolites on biology is dependent on the health state of the infant (context specificity). To interrogate our hypothesis, we propose a multi-center, randomized clinical trial to evaluate lipidomic actions of combined DHA and ARA supplementation from birth to 36 weeks postmenstrual age in 280 extremely low gestational age newborns born between 25 0/7 and 29 6/7 weeks of gestation. The following aims will be evaluated: Aim 1 – Identify the impact of combined enteral DHA and ARA supplementation on fatty acid metabolism including derivation of specialized pro-resolving mediators (SPMs) and oxylipin production and, Aim 2 – Determine the multisystemic change in circulating markers of inflammation and organ development and integrity as a function of enteral DHA/ARA supplementation. Successful completion of these aims will define developmentally regulated fatty acid metabolism in the immature host and impact of fatty acid supplementation on critical biological functions. Mechanistic data is required to bridge the scientific gap to appropriate clinical translation that is effective and safe. These data will inform a biologically rational approach to fatty acid delivery in preterm infants and identify molecular read-outs that may serve as biomarkers in future trials of clinical efficacy.