A multi-center study of the microbiome in biliary atresia

项目总结/摘要： 尽管发生率为1：8，000 -1：18，000，但胆道闭锁（BA）是儿科肝脏的主要适应症 移植BA是一种病因不明的肝外胆管树进行性纤维狭窄疾病。 加塞门肠吻合术（KP）是一种允许胆汁流动的外科手术，目前是BA的唯一治疗方法 除了肝移植KP后成功的胆汁流动可改善发病率并预测早期无肝移植 结果。2，3然而，50%接受及时KP的婴儿需要肝移植或在前两个月死亡 7，8因此，迫切需要了解导致死亡的病理生理因素。 KP后无或有胆汁流。最近的调查表明，有双向的相互作用， 肠道微生物组和胆汁酸稳态之间的关系。虽然胆汁可以改变微生物组，但由于 根据我们令人兴奋的初步数据，我们认为微生物因素可能是BA结果的关键。因此， 假设是微生物组通过影响胆汁流量来影响BA结果。的前瞻性研究 在患有胆汁淤积和BA的婴儿中的微生物组将允许在3个目标中测试该假设。在aim 1中，一个多- 将开发来自胆汁淤积婴儿的中心前瞻性粪便生物库。在目标2中，胆汁流量对 将使用全基因组测序来比较患有胆汁淤积的婴儿的早期微生物特征。在aim中 将确定与BA阳性结果相关的3种微生物特征。预期的结果是， 我们将阐明胆汁淤积婴儿中微生物组和胆汁流动的复杂关系， 特别是BA。 Tessier博士是一名委员会认证的儿科胃肠病学家和终身助理教授， 贝勒医学院。她的长期目标是成为一名独立的NIH资助的医生科学家 研究小儿胆汁淤积症中微生物组的相互作用。研究目的支持PI的 通过建立她在儿科胃肠病学的背景，提供硕士水平的职业发展 临床试验设计和实施、微生物组和全基因组测序分析方面的培训， 生物统计学解释这将通过1）一个指导和咨询团队来实现，其中包括 国际公认的，独立资助的研究人员，具有儿科胆汁淤积的专业知识， 特别是BA，婴儿微生物组和临床试验设计; 2）生物信息学高级课程， 先进的测序技术和生物统计学;和3）学术活动，导致独立。 最后，候选人的研究环境是一个卓越的学术研究机构， 世界上最大的医疗中心与全国最大的儿童医院结盟。该环境将提供 富有成效和协作的氛围，以及时完成她的研究和培训目标。在 总之，这个培训计划将使Tessier博士成为一名独立资助的医生科学家， 以患者为导向的研究，儿科胆汁淤积和微生物组。

PROJECT SUMMARY/ABSTRACT: Despite an incidence of 1:8,000-1:18,000, biliary atresia (BA) is the leading indication for pediatric liver transplantation. BA is a progressive fibrostenotic disease of the extrahepatic biliary tree of unknown etiology. The Kasai portoenterostomy (KP), a surgical procedure to allow bile flow, is currently the only treatment for BA besides liver transplant. Successful bile flow after KP improves morbidity and predicts early liver-transplant free outcomes.2,3 However 50% of infants who receive a timely KP require liver transplant or die in the first two years of life.7,8 Thus, there is desperate need to understand the pathophysiological factors responsible for the absence or presence of bile flow after KP. Recent investigations suggest that there is bidirectional interplay between the intestinal microbiome and bile acid homeostasis. While bile can change the microbiome, due to our exciting preliminary data, we believe that microbial factors may be key to BA outcomes. Thus, the grant’s hypothesis is that the microbiome influences BA outcomes by affecting bile flow. A prospective study of microbiome in infants with cholestasis and BA will allow testing of this hypothesis in 3 aims. In aim 1, a multi- center prospective stool biobank from cholestatic infants will be developed. In aim 2, the effects of bile flow on early microbial signatures will be compared using whole genome sequencing in infants with cholestasis. In aim 3 microbial signatures associated with positive outcomes in BA will be identified. The expected outcome is that we will elucidate the complex relationship of the microbiome and bile flow in infants with cholestasis, specifically BA. Dr. Tessier is a board-certified pediatric gastroenterologist and tenure-track Assistant Professor at Baylor College of Medicine. Her long-term goal is to become an independent NIH-funded physician-scientist investigating the interactions of the microbiome in pediatric cholestasis. The research aims support the PI’s career development by building on her background in pediatric gastroenterology to provide master’s level training in clinical trial design and implementation, microbiome and whole genome sequencing analysis and biostatical interpretation. This will be fulfilled via 1) A mentorship and advisory team which includes internationally-recognized, independently funded investigators with an expertise in pediatric cholestasis, particularly BA, the infant microbiome, and clinical trial design; 2) advanced course work in bioinformatics, advanced sequencing technologies and biostatistics; and 3) scholarly activities to lead to independence. Finally, the candidate’s research environment is a preeminent academic research institution in the world’s largest medical center allied with the nation’s largest children’s hospital. This environment will provide a productive and collaborative atmosphere to accomplish her research and training goals in a timely manner. In summary, this training plan will allow Dr. Tessier to become an independently funded physician scientist in patient-oriented research, pediatric cholestasis and microbiome.