Gut Viral and Bacterial Associations with Celiac Disease in the TEDDY Cohort

TEDDY 队列中肠道病毒和细菌与乳糜泻的关联

• 批准号: 10240455
• 负责人: Daniel Agardh
• 金额: $ 67.66万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240455
• 关键词: 15 year old; 4 year old; Age; Age-Months; Alleles; Antibody Formation; Antibody Response; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial Genome; Birth; Breast Feeding; Celiac Disease; Child; Collection; Complex; Conflict (Psychology); Consumption; Country; Data; Deposition; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Diet; Disease; Disease Outcome; Etiology; Exposure to; Feces; Finland; Future; Gender; Genetic; Genetic Databases; Genetic Predisposition to Disease; Genetic Risk; Genomics; Genotype; Germany; Gluten; Goals; HLA-DR3 Antigen; Human; Incidence; Individual; Infant; Infectious Agent; Insulin-Dependent Diabetes Mellitus; Intake; International; Knowledge; Lead; Life; Link; Literature; Logistic Regressions; Minority; Modeling; Nested Case-Control Study; Outcome; Plasma; Play; Prevention strategy; Probiotics; Process; Prospective Studies; Prospective cohort; Prospective cohort study; Quantitative Reverse Transcriptase PCR; Regression Analysis; Reporting; Research Design; Research Project Grants; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Rotavirus; Sampling; Series; Serology; Serum; Shapes; Site; Structure; Sweden; Therapeutic; Time; United States; Vaccination; Vaccines; Variant; Viral; Virus; Virus Diseases; Work; base; case control; clinical center; cohort; deep sequencing; design; dietary; disorder risk; early childhood; fecal microbiome; gastrointestinal infection; genetic analysis; genetic variant; gut microbiome; gut microbiota; high risk; indexing; innovation; insight; metagenomic sequencing; microbial; microbiome; microbiome analysis; microbiome components; microbiome signature; microbiota; next generation sequencing; preventive intervention; prospective; response; screening; stool sample; synergism; treatment strategy; trend; virome

The goal of this project is to examine stool and sera of 900 children previously collected from the prospective cohort TEDDY study, to determine if changes in microbiome or virus infections or both are linked to development of autoimmunity that leads to celiac disease. Previous studies and emerging evidence have implicated several viruses and microbiome signatures with celiac disease but have not proven strong linkage and have resulted inconclusive findings for the celiac disease field. The current application is an ancillary research project of the large international 15 year prospective TEDDY Study that is designed to find environmental triggers of Type 1 Diabetes and has had 297 children develop celiac disease but not T1D autoimmunity. The project will utilize the large scale and international scope of TEDDY and its rich genetic and dietary data on these children, to study this new celiac case-control cohort. We will use proven next generation sequencing, qRT-PCR and serologic approaches recently carried out for microbiome and virome analysis for T1D outcomes with TEDDY. Aim 1 will discover and analyze the complete stool virome in these children over time, before conversion to tTGA autoimmunity and celiac disease, to identify viruses associated with celiac autoimmunity and disease. Aim 2 will examine the microbiome structure over time to determine bacterial taxa or functions associated with celiac disease development and will derive complete genomic sequences of key variant bacteria found associated with disease outcomes. Both of these aims will identify agents that contribute independently to the risk of celiac outcomes, controlling for confounders or other components of the disease with regression approaches. Aim 3 will probe further to determine if there is synergy or interactions of viruses or bacteria with other known risk factors such as the child's gluten intake and genetic risk (HLA and known associated SNPs). This will identify the set(s) of components that may contribute synergistically to cause CD outcomes. The proposed work is significant since it will apply the power of the larger and international TEDDY cohort and its rich database of genetic analyses of children to study progressively collected stools and sera to determine viruses and/or microbiome signatures that are linked to tTGA autoimmunity and celiac disease. The proposed work is innovative because it will provide the first comprehensive analysis of virome and microbiome components sufficient to cause celiac disease outcomes that may work synergistically. These findings will lead to a better understanding of what triggers celiac disease that will be more relevant for developing hypotheses of causal mechanisms and will open conceptual avenues for key diagnostic or preventative interventions.

该项目的目的是检查先前从预期的900名儿童的粪便和血清 队列泰迪研究，以确定微生物组或病毒感染或两者的变化是否与 自身免疫的发展导致腹腔疾病。以前的研究和新兴证据有 与腹腔疾病有关的几种病毒和微生物组特征，但尚未证明有牢固的联系 并导致腹腔疾病领域的发现不确定。当前申请是辅助 大型国际大型预期泰迪研究的研究项目旨在找到 1型糖尿病的环境触发因素，并有297名儿童患腹腔疾病，但没有T1D 自身免疫性。该项目将利用泰迪的大规模和国际范围及其丰富的遗传和 这些儿童的饮食数据，研究这种新的乳糜泻病例对照队列。下一步我们将使用经过证明的 最近针对微生物组和病毒素进行的生成测序，QRT-PCR和血清学方法 用Teddy分析T1D结果。 AIM 1将发现并分析这些完整的粪便病毒蛋白 随着时间的流逝，儿童在转换为TTGA自身免疫和腹腔疾病之前，以识别与病毒相关的病毒 腹腔自身免疫和疾病。 AIM 2会随着时间的推移检查微生物组的结构以确定 细菌分类单元或与乳糜泻发展有关的功能，并将得出完整的基因组 关键变异细菌的序列发现与疾病结局有关。这两个目标都将确定 独立促进腹腔结局风险的代理人，控制混杂因素或其他 疾病的组成部分具有回归方法。 AIM 3将进一步探测以确定是否存在 病毒或细菌与其他已知危险因素（例如儿童的面筋摄入量和）的协同作用或相互作用 遗传风险（HLA和已知相关的SNP）。这将确定可能贡献的组件集 协同作用引起CD结果。拟议的工作很重要，因为它将运用 更大的国际泰迪队列及其对儿童遗传分析的丰富数据库 逐渐收集的凳子和血清，以确定与之相关的病毒和/或微生物组特征 TTGA自身免疫和腹腔疾病。拟议的工作是创新的，因为它将提供第一个 对足以引起腹腔疾病结果的病毒蛋白和微生物组成分的全面分析 这可能会协同起作用。这些发现将使人们更好地了解什么触发腹腔疾病 这将与开发因果机制的假设相关，并将开放概念途径 用于关键诊断或预防性干预措施。