Impact of fatty acid imbalance in intestinal health and disease in prematurity

 描述（由申请人提供）：一般而言，极早产儿通常在肠外营养一段时间后肠内喂养会延迟和缓慢进行。不幸的是，新生儿ICU中的这种常见营养策略无法维持长链多不饱和脂肪酸（LCPUFA）的临界血液水平，如果早产儿没有早产，他们将在子宫内暴露于该水平。选择性LCPUFA过量和不足的重要性通过其在早产动物模型中慢性肺病、败血症、早产儿视网膜病和坏死性小肠结肠炎（NEC）的临床相关性和因果关系得到强调。我们的总体假设是，肠外营养驱动的早期启动和随后的异常LCPUFA谱导致早产儿的适应不良的全身和肠道宿主反应，增加了他们的疾病风险。我们的研究小组已经证明，目前给予的胃肠外脂肪乳剂（Intraperoid）导致出生后第一周内二十二碳六烯酸（DHA）和花生四烯酸（AA）的血液水平降低2-3倍，同时亚油酸（LA）增加2.5倍。这些血液LCPUFA谱的深刻变化与慢性肺病和医院感染的风险增加有关。NEC是一种危及生命的疾病，其特征为炎症和坏死，主要局限于回肠，几乎仅发生在早产儿中，是研究LCPUFA水平改变对早期启动的影响的理想模型，因为它几乎仅发生在开始肠内喂养后的短时间内，通常在暴露于肠外营养后，脂肪酸改变已经建立。本申请将建立在我们以前的研究和测试我们的中心假设，即早期暴露于改变配置文件的LCPUFAs引发早产儿的主机的反应和随后的肠道适应性反应，引入肠内喂养增加NEC的风险。我们的方法利用了世界知名的合作团队，该团队汇集了Baylor USDA早产仔猪组学策略、脂肪酸代谢、新生儿结局和营养影响研究的领导者，将利用正在进行的NEC免费动物模型来评价肠外提供脂肪乳剂诱导的脂肪酸改变的启动效应（早产仔猪模型，目的1）和直接评价不同肠内脂肪酸的发育肠适应（鼠幼仔模型，目的2）。总之，将使用转录组学和代谢组学策略，辅以蛋白质印迹、Luminex和组织学分析，确定通过关键脂肪酸（肠外和肠内）营养供应调节的早产宿主反应途径。综上所述，这些动物模型将使我们能够严格检验我们的假设，并定义关键PUFA的营养改变诱导的早产模型中宿主适应性反应的分子特征。

 DESCRIPTION (provided by applicant): Universally, extremely preterm infants experience a delayed and slowly progressive advancement in enteral feedings often after a period of parenteral nutrition Unfortunately, this common nutritional strategy in the neonatal ICU fails to maintain critical blood levels of long chain polyunsaturated fatty acids (LCPUFAs) that the premature infant would have been exposed to in utero had they not been born early. The importance of selective LCPUFA excesses and deficiencies is highlighted by their clinical associations and causation in preterm animal models for chronic lung disease, sepsis, retinopathy of prematurity, and necrotizing enterocolitis (NEC). Our overall hypothesis is that early priming driven by parenteral nutrition and subsequent abnormal LCPUFA profiles lead to maladaptive systemic and intestinal host responses in the preterm infant increasing their risk of disease. Our group has shown that the currently administered parenteral lipid emulsion (Intralipid) results in a 2-3 fold reduction in blood levels of Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) concomitant with a 2.5 fold increase in Linoleic Acid (LA) within the first postnatal week. These profound changes in blood LCPUFA profiles were associated with a later increased risk of chronic lung disease and nosocomial sepsis. NEC, a life-threatening disease characterized by inflammation and necrosis largely confined to the ileum and occurring almost exclusively in preterm infants, is an ideal model to study the effect of early priming by altered LCPUFA levels since it almost exclusively occurs within a short time frame after initiation of enteral feedings often following exposure to parenteral nutrition when fatty acid alterations have already been established. This application will build upon our prior studies and test our central hypothesis that early exposure to altered profiles of LCPUFAs primes the premature infant's host responses and subsequent intestinal adaptive responses to the introduction of enteral feedings increasing the risk of NEC. Our approach utilizing a world renown collaborative team that brings together leaders in omics strategies, fatty acid metabolism, neonatal outcomes, and nutritional impact studies in preterm piglets at Baylor USDA, will take advantage of ongoing complimentary animal models of NEC to evaluate the priming effect of altered fatty acids induced by parenteral provision of lipid emulsions (preterm piglet model, Aim 1) and to directly evaluate the developmental intestinal adaptations of varying enteral fatty acids (murine pup model, Aim 2). Together, preterm host response pathways that are modulated by nutritional provision of critical fatty acids (parenteral and enteral) will be identified using a transcriptomis and metabolomics strategy complimented by western blot, Luminex and histologic analyses. Taken together, these animal models will allow us to rigorously test our hypothesis and define the molecular signatures of the host's adaptive responses in models of prematurity induced by nutritional alterations of critical PUFAs.