The Neonatal Microbiome and Necrotizing Enterocolitis

新生儿微生物组和坏死性小肠结肠炎

• 批准号: 7650793
• 负责人: PHILLIP I TARR
• 金额: $ 102.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-11 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650793
• 关键词: Abdomen; Affect; Age; Alleles; Biological; Biomass; Birth; Caring; Case Fatality Rates; Child; Clinical; Clinical Data; Cohort Studies; Collaborations; Colon; Complication; Consensus; Databases; Development; Digestive System Disorders; Disease; Distal; Elderly; Enrollment; Enteral; Epidemiology; Feces; Functional disorder; Genes; Genome; Human; Incidence; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Informatics; Injury; Institutes; Institution; Intestines; Left; Life; Low Birth Weight Infant; Lung diseases; Microbe; Microbiology; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Newborn Infant; Patients; Play; Population; Populations at Risk; Premature Infant; Prevention; Probiotics; Process; Relative (related person); Research; Research Personnel; Resources; Risk; Risk Factors; Role; Severities; Small Intestines; Specimen; Staging; Stimulus; Survivors; Testing; Time; Translational Research; Universities; Very Low Birth Weight Infant; Virus; Washington; body system; cohort; density; high risk; improved; insight; member; microbial; microbiome; mortality; premature; prevent; public health relevance; response

DESCRIPTION: Necrotizing enterocolitis (NEC) is a devastating disorder that affects approximately 10% of premature infants. Its mortality remains high (15-30%), and its cause remains unknown. About 80% of cases occur within 35 days of birth among hospitalized newborns of low birth weight. Probiotics diminish the incidence and severity of NEC, and NEC does not occur antepartum. NEC affects a readily identifiable at-risk group, has a tightly defined interval before its onset, occurs in an organ system that is intimately associated with a microbial population in flux, has a plausible association with the intestinal microbiota, and cohorts at risk have rarely been studied in large numbers, or prospectively. This disorder, therefore, provides a unique opportunity to explore the role of the human enteric microbiome in a devastating disease. Moreover, NEC epidemiology and age-incidence present an ability to enroll and study cohorts that are highly likely to provide valuable pathophysiologic and microbiologic insights. In this project, we will identify and quantify the microbial components of stool and its products before and at the onset of NEC. In doing so, we will test the overarching hypothesis that NEC is a direct or indirect consequence of the enteric biomass, its products, or both. We will use multicenter cohorts of premature infants at high risk of developing NEC, extend our research on this disease currently sponsored by the Washington University Institute of Clinical and Translational Sciences, and continue our longstanding collaborations with the Genome Center at Washington University and the Washington University Digestive Diseases Research Core Center (Informatics Core). The Aims of this proposal are to (1) conduct a case cohort study in which we compare clinical data and biological specimens from cases and well-matched controls; (2) determine if the kind and density of intestinal biomass, its gene content, and transcriptional activity are associated with, and potential determinants of, NEC; and (3) determine if host risk alleles for intestinal inflammation play a role in the development of NEC. These efforts will be accomplished using subjects from three collaborating neonatal intensive care units (NICUs), focusing on the critical, instructive, and understudied pre-NEC stage of illness, and formulating a data repository that will be a resource for investigators worldwide who wish to focus their efforts on NEC, its precipitants, and its prevention and cure. PUBLIC HEALTH RELEVANCE: Necrotizing enterocolitis (NEC) is a devastating complication of prematurity. It occurs suddenly, usually during the first month of life, and we don't know how to prevent it. It is probably more dangerous to premature infants than lung disease today. About one-third of children die and many of the survivors are left with very little intestines. NEC is a disorder that we think might relate to the microbes in the gut. We propose to study this disease intensively, compare cases to controls especially in the days leading up to NEC, and try to determine what differentiates the patients who get this disorder from those who don't. We might then be able to alter these factors, and prevent this abdominal catastrophe from occurring.

描述：坏死性小肠结肠炎 (NEC) 是一种破坏性疾病，影响约 10% 的早产儿。其死亡率仍然很高（15-30%），且原因尚不清楚。约80%的病例发生在出生后35天内住院的低出生体重新生儿中。益生菌可降低 NEC 的发生率和严重程度，并且 NEC 不会发生在产前。 NEC 影响易于识别的高危人群，发病前有严格定义的间隔，发生在与微生物种群变化密切相关的器官系统中，与肠道微生物群有合理的关联，并且高危人群很少发生已被大量研究或前瞻性研究。因此，这种疾病为探索人类肠道微生物组在毁灭性疾病中的作用提供了独特的机会。此外，NEC 流行病学和年龄发病率提供了招募和研究队列的能力，这些队列很可能提供有价值的病理生理学和微生物学见解。 在这个项目中，我们将在 NEC 发生之前和发生时识别和量化粪便及其产物的微生物成分。在此过程中，我们将检验一个总体假设，即 NEC 是肠道生物量、其产物或两者的直接或间接结果。我们将使用患有 NEC 高风险早产儿的多中心队列，扩展目前由华盛顿大学临床和转化科学研究所资助的对该疾病的研究，并继续与华盛顿大学基因组中心和华盛顿大学的长期合作消化疾病研究核心中心（信息学核心）。该提案的目的是（1）进行病例队列研究，比较病例和匹配对照的临床数据和生物样本； (2)确定肠道生物量的种类和密度、其基因含量和转录活性是否与NEC相关以及NEC的潜在决定因素； (3) 确定肠道炎症的宿主风险等位基因是否在 NEC 的发展中发挥作用。这些工作将利用来自三个合作的新生儿重症监护病房 (NICU) 的受试者来完成，重点关注疾病的关键、指导性和未充分研究的 NEC 前阶段，并制定一个数据存储库，为世界各地希望研究的研究人员提供资源。他们的重点是 NEC、其诱发因素及其预防和治疗。 公共卫生相关性：坏死性小肠结肠炎 (NEC) 是一种毁灭性的早产儿并发症。它突然发生，通常在出生后的第一个月，我们不知道如何预防。对于早产儿来说，它可能比当今的肺部疾病更危险。大约三分之一的儿童死亡，许多幸存者只剩下很少的肠子。我们认为 NEC 是一种可能与肠道微生物有关的疾病。我们建议深入研究这种疾病，将病例与对照进行比较，特别是在 NEC 之前的几天，并尝试确定患有这种疾病的患者与未患这种疾病的患者之间的区别。然后我们也许能够改变这些因素，并防止这种腹部灾难的发生。

项目成果

Hypothesis testing and power calculations for taxonomic-based human microbiome data.

• DOI: 10.1371/journal.pone.0052078
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: La Rosa PS;Brooks JP;Deych E;Boone EL;Edwards DJ;Wang Q;Sodergren E;Weinstock G;Shannon WD
• 通讯作者: Shannon WD

Bacterial DNA content in the intestinal wall from infants with necrotizing enterocolitis.

• DOI: 10.1016/j.jpedsurg.2011.03.026
• 发表时间: 2011-06
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Bucher BT;McDuffie LA;Shaikh N;Tarr PI;Warner BB;Hamvas A;White FV;Erwin CR;Warner BW
• 通讯作者: Warner BW

Statistical object data analysis of taxonomic trees from human microbiome data.

• DOI: 10.1371/journal.pone.0048996
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: La Rosa PS;Shands B;Deych E;Zhou Y;Sodergren E;Weinstock G;Shannon WD
• 通讯作者: Shannon WD