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

脂肪酸失衡对肠道健康和早产儿疾病的影响

• 批准号: 8825238
• 负责人: CAMILIA R MARTIN
• 金额: $ 49.97万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-18 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8825238
• 关键词: Affect; Animal Model; Arachidonic Acids; Blood; Chronic lung disease; Clinical; Data; Development; Disease; Docosahexaenoic Acids; Emulsions; Enteral; Enteral Feeding; Etiology; Exposure to; Fat emulsion; Fatty Acids; Fetus; Growth; Health; Histologic; Immune response; Inflammation; Inflammation Mediators; Inflammatory Bowel Diseases; Injury; Interruption; Intestines; Intravenous; Lead; Life; Linoleic Acids; Lipids; Mediator of activation protein; Metabolic; Modeling; Molecular Profiling; Mothers; Mus; Necrosis; Necrotizing Enterocolitis; Neonatal; Nutritional; Oral; Organ; Organogenesis; Outcome; Parenteral Nutrition; Pathway interactions; Polyunsaturated Fatty Acids; Premature Birth; Premature Infant; Retinopathy of Prematurity; Risk; Sepsis; Series; Signal Transduction; Soybean Oil; Testing; Time; Western Blotting; attenuation; disorder risk; experience; fatty acid metabolism; feeding; ileum; in utero; metabolomics; multidisciplinary; nutrition; nutritional genomics; postnatal; premature; prevent; public health relevance; pup; response; transcriptomics

 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.

 描述(申请人提供)：普遍而言，极早产儿在肠内喂养中进展缓慢，通常在一段时间的肠外营养后。不幸的是，新生儿ICU中的这种常见营养策略未能维持血液中长链多不饱和脂肪酸(LCPUFAs)的临界水平，如果早产儿不是在宫内出生，他们可能会接触到这些脂肪酸。在慢性肺部疾病、败血症、早产儿视网膜病变和坏死性小肠结肠炎(NEC)的早产动物模型中，选择性LCPUFA过量和不足的重要性被它们的临床相关性和原因所强调。我们的总体假设是，由肠外营养驱动的早期启动以及随后异常的LCPUFA特征会导致早产儿的全身和肠道宿主反应不良，增加他们患病的风险。我们小组已经证明，目前使用的肠外脂肪乳剂(Intralipid)导致血液中二十二碳六烯酸(DHA)和花生四烯酸(AA)水平降低2-3倍，同时亚油酸(LA)水平在出生后第一周增加2.5倍。血中LCPUFA的这些深刻变化与后来慢性肺部疾病和医院内败血症的风险增加有关。NEC是一种危及生命的疾病，其特征是炎症和坏死主要局限于回肠，几乎只发生在早产儿中，是研究通过改变LCPUFA水平来早期启动的效果的理想模型，因为它几乎只发生在开始肠内喂养后的短时间内，通常是在脂肪酸变化已经确定的情况下暴露于肠外营养之后。这项应用将建立在我们先前研究的基础上，并检验我们的中心假设，即早期暴露于改变的LCPUFAs谱启动早产儿的宿主反应和随后的肠道适应性反应，因为引入肠道喂养增加了NEC的风险。我们的方法利用世界知名的协作团队，汇集了美国农业部贝勒早产仔猪组学策略、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免费动物模型来评估通过肠外提供脂肪乳剂诱导的脂肪酸变化的启动效果(早产仔猪模型，目标1)，并直接评估各种肠道脂肪酸对发育的肠道适应性(小鼠幼猪模型，目标2)。总之，由关键脂肪酸(肠外和肠内)的营养供应调节的早产宿主反应途径将使用转录和代谢组学策略，并辅之以蛋白质印迹、Luminex和组织学分析。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，并在关键多不饱和脂肪酸营养变化诱导的早产模型中定义宿主适应性反应的分子特征。