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

项目总结 艰难梭状芽胞杆菌感染(CDI)是美国抗生素相关性腹泻的主要原因 2017年造成12 900人死亡。在过去的两年中，CDI的发病率迅速上升 几十年来，发病率增加在患有炎症性肠病(IBD)的儿科患者中最为明显。 IBD，一种以胃肠道炎症为特征的慢性疾病，也证明了 全球儿童发病率不断上升，被认为是一种全球重要的儿科疾病。联席- IBD和CDI的发生与更糟糕的结果相关，包括住院时间更长，费用更高， 以及对输血的更大需求。相反，患有IBD的儿童也有很高的艰难梭菌感染率。 定植，定义为在没有艰难梭菌症状的情况下存在艰难梭菌。 IBD患者的CDI症状与C.IBD患者的IBD症状难以区分。 艰难菌的定植。微生物扰动，与萌发和代谢有关的生物分子，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。 本提案中详述的研究直接回应了更好地理解 儿童IBD患者CDI和艰难梭菌定植的决定因素和后遗症 以下是具体目标：1)研究种子萌发和代谢调节因子在植物生长发育过程中的作用。 艰难梭菌定植、有症状的CDI和IBD发作后的发展和恢复。2)审查 肠道微生物群中预测艰难梭菌定植、疾病和恢复的差异 患有IBD的儿童。3)确定艰难梭菌抗毒素抗体在儿童中的流行率和影响 IBD。 在过去的8年里，这位候选人一直与她的导师凯瑟琳·爱德华兹博士密切合作 各种CDI相关项目，包括360多名儿科患者的预期登记。 通过这个项目，候选人计划对患有IBD的儿童进行纵向追踪，对他们的粪便进行连续采样 和血清，以更好地了解CDI和IBD的相互作用。这位导师的首要目标是 职业发展经验是应聘者成为C。 艰难梭菌和IBD在代谢物测定和微生物组分析中得到确立，并作为一种 通过精心计划的翻译实现临床研究和实验室科学之间的接口 接近了。为了实现这一目标，应聘者将通过高级课程来补充她之前的培训。 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 将与多学科导师团队密切合作，其中包括传染病、IBD、 生物统计学、微生物组分析和分子技术，以实现她所宣布的目标和职业目标。

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.