The Neonatal Microbiome and Necrotizing Enterocolitis

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。它的死亡率仍然很高（15-30%），其原因仍然未知。大约80%的病例发生在出生后35天内的住院低出生体重新生儿中。益生菌降低NEC的发生率和严重程度，并且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时间间隔，发生在与流动的微生物群密切相关的器官系统中，与肠道微生物群有合理的关联，并且风险队列很少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，我们将确定和量化粪便及其产品的微生物成分之前和NEC的发病。在此过程中，我们将测试总体假设，即NEC是肠道生物量，其产品或两者的直接或间接后果。我们将使用NEC高危早产儿的多中心队列，扩展我们目前由华盛顿大学临床和转化科学研究所赞助的对这种疾病的研究，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。本提案的目的是（1）进行病例队列研究，比较病例和匹配良好的对照组的临床数据和生物标本;（2）确定肠道生物量的种类和密度、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;和（3）确定肠道炎症的宿主风险等位基因是否在NEC的发展中起作用。这些工作将使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，并制定一个数据库，该数据库将成为世界各地希望专注于NEC，其促发剂及其预防和治疗的研究人员的资源。 公共卫生相关性：坏死性小肠结肠炎（NEC）是早产儿的一种毁灭性并发症。它通常在出生后的第一个月突然发生，我们不知道如何预防它，它对早产儿的危险性可能比现在的肺病更大。大约三分之一的儿童死亡，许多幸存者只剩下很少的肠子。NEC是一种我们认为可能与肠道微生物有关的疾病。我们建议对这种疾病进行深入研究，特别是在NEC之前的日子里，将病例与对照进行比较，并试图确定患有这种疾病的患者与未患这种疾病的患者的区别。我们也许能够改变这些因素，防止这种腹部灾难的发生。

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.