Branched Chain FA and Gut Development

支链 FA 和肠道开发

基本信息

批准号：
7863228
负责人：
JAMES T. BRENNA
金额：
$ 24.3万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7863228
关键词：
Abbreviations Adverse effects Affect Age Amniotic Fluid Animal Model Anti-Bacterial Agents Antibiotic Therapy Arachidonic Acids Bacteria Bacterial Infections Biological Biological Models Birth Breast Feeding Caco-2 Cells Carbon Cell Proliferation Cell model Choline Chronic Clinic Colostrum Deglutition Development Docosahexaenoic Acids Ecology Eicosapentaenoic Acid Elderly Enterocytes Esters Ethanolamines Etiology Excretory function Exons Exposure to Extracellular Space Fatty Acids Fetus Food Future Gas Chromatography Gastrointestinal tract structure Gene Expression Genes Genome Genomics Gestational Age Health Health Status Hematoxylin and Eosin Staining Method Human Human Milk In Vitro Incidence Infant Infant formula Inflammatory Bowel Diseases Ions Length Life Life Cycle Stages Linoleic Acids Linolenic Acids Lipids Low Birth Weight Infant Low-Density Lipoproteins Mass Spectrum Analysis Meconium Membrane Membrane Lipids Metabolism Methods Microscopic Minor Modeling Molecular Monounsaturated Fatty Acids Necrotizing Enterocolitis Neonatal Neonatal Intensive Care Units Neuraxis Newborn Infant Nonesterified Fatty Acids Operative Surgical Procedures Papio Patients Pattern Phospholipids Polymerase Chain Reaction Pregnancy Premature Infant Probiotics Property Proteins Pulmonary Surfactants Rattus Reporting Research Risk Role Safety Saturated Fatty Acids Scanning Sebaceous Glands Sebum Serine Severities Skin Staining method Stains Symptoms Term Birth Therapeutic Time Tissue-Specific Gene Expression Tissues Translations Triglycerides Unsaturated Fatty Acids Vegetable Oils Vernix Caseosa Weight acyl group base branched chain fatty acid fatty acid metabolism fatty acid transport fetal high risk human tissue in vivo in vivo Model meibomian gland men microbial mortality neonate particle pathogenic bacteria pi bond postnatal public health relevance pup uptake

项目摘要

DESCRIPTION (provided by applicant): Branched chain fatty acids (BCFA) containing lipids are unusual in most human tissue, but they con- stitute 25-30% of the dry weight of vernix caseosa. The fetus swallows amniotic fluid, and in the late term it contains sloughed vernix particles. The biological significance of the GI tract's exposure to BCFA has not been investigated. We have recently demonstrated, for the first time, that meconium contains BCFA that differ in chain length and branching from the same infant's vernix. Importantly, this shows that BCFA are native to the newborn GI tract throughout its length, and that BCFA are actively and specifically metabolized by the late term fetus; thus, BCFA are metabolically ac- tive. There is virtually nothing known about this metabolism. BCFA are also known to be compo- nents of breast milk, thus exposing the breastfed infant GI tract to BCFA as bacteria colonize and microflora develops. Importantly, BCFA are not normal components of infant formulas since, for most, their lipids are derived from vegetable oils. The GI tract of premature infants born at 24-30 weeks of gestation is not exposed to BCFA because vernix concentrations in the amniotic fluid are low, and premature infant formulas contain no BCFA. These infants are at highest risk of developing necrotizing enterocolitis (NEC), a life-threatening condition affecting 10% of premature infants. Among other factors, NEC is associated with pathogenic bacterial infection rather than colonization by normal flora. BCFA are major components (>95%) of the membranes of many bacteria. We pro- pose here to explore the role of BCFA in the GI tract with consideration to the development of NEC with in vitro and in vivo models: 1) Establish how enterocytes interact with BCFA in vitro, using the Caco-2 model. BCFA uptake and excretion, incorporation into cell membrane lipids, trans- formation (elongation/chain shortening), and effects on cell proliferation and health will be studied. Exon arrays will evaluate differential gene expression to scan the entire genome. 2) Study the influ- ence of BCFA on development of NEC in the ischemic rat pup in vivo. Cecal contents will be studied by meta-genomic methods to evaluate shifts in GI tract microbial ecology due to BCFA. Relevance to human health: Normal development of the gut and its postnatal colonization with nor- mal flora are crucial to general gut health and to avoiding NEC. BCFA, a major component of the normal GI tract of human infants, may be a low risk treatment to avoid NEC, and may also have therapeutic value at other stages of the life cycle. For instance, BCFA may prove useful for those in- dividuals requiring repeated antibiotic treatments such as the elderly or those with chronic conditions, whose GI tracts are repeatedly recolonized. PUBLIC HEALTH RELEVANCE: We recently showed that the profile of branched chain fatty acids (BCFA) in vernix and meconium in term newborn differ in systematic ways, indicating that BCFA are actively metabolized by enterocytes in the late term fetus. The proposed research seeks to experimentally explore BCFA metabolism and its role in the developing GI tract using an in vitro Caco-2 cell model, and an in vivo rat pup NEC model.

描述（由申请人提供）：含有支链脂肪酸（BCFA）的脂质在大多数人体组织中并不常见，但它们占干酪皮脂干重的 25-30%。胎儿吞咽羊水，在晚期羊水中含有脱落的胎脂颗粒。胃肠道接触 BCFA 的生物学意义尚未得到研究。我们最近首次证明，胎便中含有的 BCFA 与同一婴儿胎脂的链长和分支不同。重要的是，这表明 BCFA 在整个新生儿胃肠道中都是天然存在的，并且 BCFA 会被晚期胎儿积极且特异性地代谢；因此，BCFA 具有代谢活性。对于这种新陈代谢几乎一无所知。 BCFA 也是母乳的成分，因此，随着细菌定植和微生物区系的发展，母乳喂养的婴儿胃肠道会暴露于 BCFA。重要的是，BCFA 不是婴儿配方奶粉的正常成分，因为对于大多数婴儿来说，它们的脂质来自植物油。妊娠 24-30 周出生的早产儿的胃肠道不会接触 BCFA，因为羊水中的胎脂浓度较低，而且早产儿配方奶粉中不含 BCFA。这些婴儿患坏死性小肠结肠炎 (NEC) 的风险最高，这是一种危及生命的疾病，影响 10% 的早产儿。除其他因素外，NEC 与病原菌感染有关，而不是与正常菌群定植有关。 BCFA 是许多细菌细胞膜的主要成分 (>95%)。我们在此建议探索 BCFA 在胃肠道中的作用，同时考虑到 NEC 的体外和体内模型的发展：1）使用 Caco-2 模型建立肠细胞如何在体外与 BCFA 相互作用。将研究 BCFA 的摄取和排泄、掺入细胞膜脂质、转化（延长/链缩短）以及对细胞增殖和健康的影响。外显子阵列将评估差异基因表达以扫描整个基因组。 2）研究BCFA对缺血幼鼠体内NEC发育的影响。将通过宏基因组方法研究盲肠内容物，以评估 BCFA 引起的胃肠道微生物生态变化。与人类健康的相关性：肠道的正常发育及其产后正常菌群的定植对于一般肠道健康和避免 NEC 至关重要。 BCFA 是人类婴儿正常胃肠道的主要成分，可能是避免 NEC 的低风险治疗方法，并且在生命周期的其他阶段也可能具有治疗价值。例如，BCFA可能对那些需要重复抗生素治疗的人有用，例如老年人或患有慢性病的人，他们的胃肠道反复重新定植。公共健康相关性：我们最近表明，足月新生儿胎脂和胎便中支链脂肪酸 (BCFA) 的分布存在系统性差异，表明 BCFA 在晚期足月胎儿中被肠上皮细胞积极代谢。该研究旨在利用体外 Caco-2 细胞模型和体内大鼠幼仔 NEC 模型，通过实验探索 BCFA 代谢及其在胃肠道发育中的作用。