The Neonatal Microbiome and Necrotizing Enterocolitis

描述：坏死性小肠结肠炎(NEC)是一种破坏性的疾病，影响大约10%的早产儿。它的死亡率仍然很高(15%-30%)，其原因尚不清楚。大约80%的病例发生在低出生体重住院新生儿出生后35天内。益生菌可以降低NEC的发生率和严重程度，而且NEC不会在产前发生。NEC影响一个容易识别的高危人群，在发病前有一个严格定义的间隔，发生在与流动中的微生物种群密切相关的器官系统中，与肠道微生物区系有看似合理的联系，而且很少有大量或前瞻性的研究高危队列。因此，这种疾病提供了一个独特的机会来探索人类肠道微生物群在一种毁灭性疾病中的作用。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，这些队列极有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，我们将鉴定和量化NEC发病前和发病时粪便及其产物的微生物成分。在这样做的过程中，我们将检验最重要的假设，即NEC是肠道生物量、其产品或两者的直接或间接结果。我们将使用高风险患NEC的多中心早产儿队列，扩大我们目前由华盛顿大学临床和翻译科学研究所赞助的关于这种疾病的研究，并继续我们与华盛顿大学基因组中心和华盛顿大学消化疾病研究核心中心(信息学核心)的长期合作。这项建议的目的是：(1)进行病例队列研究，比较病例和配对对照的临床数据和生物标本；(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，以及是否与NEC的潜在决定因素相关；(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。这些工作将利用三个合作的新生儿重症监护病房(NICU)的受试者来完成，重点放在NEC疾病前的关键、有启发性和未被充分研究的阶段，并建立一个数据库，该数据库将成为世界各地希望将他们的努力集中在NEC、其沉淀物和其预防和治疗上的研究人员的资源。

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.