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

影响艰难梭菌和儿童炎症性肠病的免疫、微生物和代谢因素

• 批准号: 10312145
• 负责人: Maribeth Ruth Nicholson
• 金额: $ 17.56万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10312145
• 关键词: 16S ribosomal RNA sequencing; Abdominal Pain; Acute; Antibodies; Antibody titer measurement; Award; Bile Acids; Biochemical; Biometry; Blood Transfusion; Cessation of life; Charge; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Investigator; Clinical Research; Clostridium difficile; Cohort Studies; Communicable Diseases; Data; Development; Diagnosis; Diarrhea; Disease; Enrollment; Enzyme-Linked Immunosorbent Assay; Feces; Flare; Frequencies; Functional disorder; Future; Gastroenteritis; Gastrointestinal tract structure; Germination; Goals; Guidelines; Home; Hospitalized Child; Hour; Immune; Immune response; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologics; Incidence; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Infusion procedures; Knowledge; Laboratories; Leadership; Length of Stay; Mass Spectrum Analysis; Mediator of activation protein; Mentors; Metabolic; Metabolism; Microbiology; Molecular; Outcome; Parenteral Nutrition; Pathway interactions; Patients; Pediatric Hospitals; Prevalence; Primary Infection; Proline; Pseudomembranous Colitis; Recovery; Recurrent disease; Reporting; Research; Role; Sampling; Science; Serum; Structure; Symptoms; Systems Biology; Techniques; Testing; Time; Toxin; Training; Treatment outcome; Uncertainty; United States; Work; adaptive immune response; advanced system; alpha Toxin; antibiotic-associated diarrhea; antitoxin; bacterial community; base; bile acid metabolism; career; career development; clinical care; experience; follow-up; gut microbiome; host microbiome; improved; infliximab; insight; metagenomic sequencing; microbial; microbiome alteration; microbiome analysis; multidisciplinary; pathogen; pediatric patients; prospective; stool sample; translational approach; young adult

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.

项目摘要 梭状芽胞杆菌艰难梭菌感染（CDI）是联合抗生素相关腹泻的主要原因 各州在2017年造成12,900人死亡。CDI在最近两次的发病率迅速增加 数十年来，炎症性肠病（IBD）的儿科患者的速率最为明显。 IBD是一种以胃肠道炎症为特征的慢性疾病，也证明了 全球儿童的发病率增加，被认为是全球重要的小儿疾病。共同 IBD和CDI的发生与较差的结果有关，包括较长的医院住院，更高的费用， 并更需要输血。相反，IBD儿童的艰难梭菌率也很高 定殖被定义为艰难梭菌的存在，在不存在艰难梭菌的症状。 IBD患者CDI的症状与C的IBD耀斑的症状没有区别。 艰难的殖民化。微生物扰动，与发芽和代谢相关的生物分子以及 已经对抗毒素抗体进行了单独研究，以实现其对定植和CDI的影响，但主要在 横截面方法，不适用于IBD儿童。 该提案中详细介绍的研究直接响应了更好地了解 小儿IBD患者的CDI和艰难梭菌定殖的决定因素和序列化，包括 以下特定目的：1）研究发芽和代谢介体的作用 艰难梭菌定植，有症状的CDI和IBD耀斑的发展和恢复。 2）检查 预测艰难梭菌定植，疾病和恢复的肠道微生物组的差异 IBD的孩子。 3）确定艰难梭菌抗毒素抗体的患病率和影响 IBD。 在过去的8年中，候选人与她的导师Kathryn Edwards博士紧密合作。 各种与CDI相关的项目包括预期入学360名儿科患者。 通过这个项目，候选人计划纵向跟随IBD的儿童，并连续采样 和血清可以更好地了解CDI和IBD的相互作用。这个指导的总体目标 职业发展经验是候选人成为C的独立临床研究者。 艰难和IBD，在代谢物测定和微生物组分析中建立，并充当 通过精心计划的翻译，临床研究与实验室科学之间的接口 方法。为了实现这一目标，候选人将通过高级课程来增强她的先前培训 在微生物组分析，临床研究和领导培训中。在整个奖励期间，候选人 将与一个多学科的导师团队紧密合作，包括传染病专家，IBD， 生物统计学，微生物组分析和分子技术，以实现其既定目标和职业目标。