Immune, Microbial, and Metabolic Factors that Impact Clostridioides difficile and Inflammatory Bowel Disease in Children

项目摘要 艰难梭菌感染（CDI）是美国腹泻的主要原因。 2017年造成12，900人死亡。CDI在过去两年中的发病率迅速增加 几十年来，在患有炎症性肠病（IBD）的儿科患者中，发病率增加最明显。 IBD是一种以胃肠道炎症为特征的慢性疾病， 在全球儿童中的发病率不断增加，被认为是全球重要的儿科疾病。该公司- IBD和CDI的发生与更差的结局相关，包括住院时间更长，费用更高， 更需要输血。相反，患有IBD的儿童也有很高的C。艰难 定殖，定义为C.艰难梭菌在没有症状的情况下归因于C。很难 IBD患者的CDI症状与C. 艰难的殖民微生物扰动，与发芽和代谢相关的生物分子，以及 抗毒素抗体已经单独研究了它们对定植和CDI的影响，但主要是在 横断面方法，不适用于IBD儿童。 本提案中详细介绍的研究直接回应了更好地了解 CDI和C. IBD儿科患者中的艰难定植，包括 以下具体目标：1）研究发芽和代谢介质的作用，因为它们与植物的生长发育有关。 发展和恢复，C。艰难定植、症状性CDI和IBD发作。2)审查 预测C.艰难的殖民化，疾病和恢复， IBD患儿3)确定C.儿童艰难梭菌抗毒素抗体 IBD。 在过去的8年里，候选人与她的导师凯瑟琳·爱德华兹博士密切合作， 各种CDI相关项目，包括前瞻性入组超过360例儿科患者。 通过这个项目，候选人计划纵向跟踪IBD儿童的粪便连续采样 和血清，以更好地了解CDI和IBD的相互作用。指导的总体目标是 职业发展经验是候选人成为一个独立的临床研究者的C。 艰难梭菌和IBD，在代谢物测定和微生物组分析中确立，并作为一种 临床研究和实验室科学之间的接口，通过精心策划的翻译 接近。为了实现这一目标，候选人将增加她的先进的课程，她以前的培训 微生物组分析临床研究和领导力培训在整个颁奖期间，候选人 将与包括传染病，IBD， 生物统计学，微生物组分析和分子技术，以实现她的既定目标和职业目标。

PROJECT SUMMARY Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea in the United States, causing 12,900 deaths in 2017. CDI has demonstrated a rapid increase in incidence in the last two decades, with rate increases most pronounced in pediatric patients with inflammatory bowel disease (IBD). IBD, a chronic disease characterized by inflammation of the gastrointestinal tract, has also demonstrated increasing incidence in children worldwide and is considered a globally important pediatric disease. The co- occurrence of IBD and CDI is associated with worse outcomes including longer hospital stays, higher charges, and greater need for blood transfusions. Conversely, children with IBD also have high rates of C. difficile colonization, defined as the presence of C. difficile in the absence of symptoms attributable to C. difficile. Symptoms of CDI in IBD patients are indistinguishable from symptoms of an IBD flare in patients with C. difficile colonization. Microbial perturbations, biomolecules associated with germination and metabolism, and antitoxin antibodies have been studied individually for their influence on colonization and CDI but primarily in cross-sectional approaches and not applied to children with IBD. The research detailed in this proposal responds directly to the need to better understand the determinants and sequalae of CDI and C. difficile colonization in pediatric patients with IBD and includes the following specific aims: 1) To investigate the role of germination and metabolic mediators as they relate to the development of, and recovery from, C. difficile colonization, symptomatic CDI, and IBD flares. 2) To examine differences in the intestinal microbiome that are predictive of C. difficile colonization, disease, and recovery in children with IBD. 3) To determine the prevalence and impact of C. difficile antitoxin antibodies in children with IBD. For the past 8 years the candidate has worked closely with her mentor, Dr. Kathryn Edwards on a variety of CDI-related projects which have included the prospective enrollment of over 360 pediatric patients. Through this project, the candidate plans to longitudinally follow children with IBD with serial sampling of stool and serum to better understand the interaction of CDI and IBD. The overarching objective of this mentored career development experience is for the candidate to emerge as an independent clinical investigator of C. difficile and IBD, become established in metabolite determination and microbiome analysis, and serve as an interface between clinical research and laboratory sciences through carefully planned translational approaches. To accomplish this goal, the candidate will augment her prior training with advanced coursework in microbiome analysis, clinical research, and leadership training. Throughout the award period, the candidate will work closely with a multidisciplinary team of mentors including experts in infectious diseases, IBD, biostatistics, microbiome analysis, and molecular techniques to carry out her stated aims and career goals.