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Branched Chain FA and Gut Development

支链 FA 和肠道开发

基本信息

批准号：
8063525
负责人：
JAMES T. BRENNA
金额：
$ 18.41万
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 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8063525
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 Cells Choline Chronic Clinic Colostrum Deglutition Development Docosahexaenoic Acids Earwax 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 Individual Infant Infant formula Inflammatory Bowel Diseases Intestines 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 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）：含有脂质的支链脂肪酸（BCFA）在大多数人体组织中并不常见，但它们占皮脂鱼干重的25-30%。胎儿吞下羊水，在晚期，羊水中含有脱落的羊脂颗粒。胃肠道暴露于BCFA的生物学意义尚未被研究。我们最近首次证明，胎粪中含有链长度和分支不同的BCFA，来自同一个婴儿的皮脂。重要的是，这表明BCFA在整个新生儿胃肠道中都是原生的，并且BCFA被晚期胎儿积极和特异性地代谢；因此，BCFA具有代谢活性。我们对这种新陈代谢几乎一无所知。BCFA也被认为是母乳的组成部分，因此当细菌定植和微生物群发育时，母乳喂养的婴儿胃肠道暴露于BCFA。重要的是，BCFA不是婴儿配方奶粉的正常成分，因为大多数BCFA的脂质来自植物油。在妊娠24-30周出生的早产儿消化道不暴露于BCFA，因为羊水中的vernix浓度很低，而且早产儿配方奶粉不含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与致病性细菌感染有关，而不是正常菌群的定植。BCFA是许多细菌膜的主要成分（约占95%）。我们建议通过体外和体内模型来探讨BCFA在胃肠道中的作用，并考虑NEC的发展：1)利用Caco-2模型建立肠细胞如何与BCFA在体外相互作用。将研究BCFA的摄取和排泄、与细胞膜脂质的结合、转化（伸长/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扫描整个基因组。2)研究BCFA对缺血幼鼠体内NEC发育的影响。盲肠内容物将通过元基因组方法来评估BCFA引起的胃肠道微生物生态的变化。与人类健康的相关性：肠道的正常发育及其出生后与正常菌群的定植对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组成部分，可能是避免NEC的低风险治疗方法，在生命周期的其他阶段也可能具有治疗价值。例如，BCFA可能被证明对那些需要反复抗生素治疗的个体有用，比如老年人或那些患有慢性疾病的人，他们的胃肠道反复重新定植。