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: 10654800
• 负责人: Daniel Agardh
• 金额: $ 64.97万
• 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/10654800
• 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; 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; Life; Link; Literature; Logistic Regressions; Minority; Modeling; Nested Case-Control Study; Outcome; Plasma; Prevention strategy; 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; 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; probiotic therapy; 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.

该项目的目标是检查之前从预期收集的 900 名儿童的粪便和血清。 队列 TEDDY 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乳糜泻。先前的研究和新出现的证据表明 多种病毒和微生物组特征与乳糜泻有关，但尚未证明有很强的联系 并对乳糜泻领域产生了不确定的发现。目前的应用程序是一个辅助 大型国际 15 年前瞻性 TEDDY 研究的研究项目旨在发现 1 型糖尿病的环境诱因，已导致 297 名儿童患上乳糜泻，但未患上 T1D 自身免疫。该项目将利用TEDDY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，以研究这个新的乳糜泻病例对照队列。接下来我们将使用经过验证的 最近针对微生物组和病毒组进行了世代测序、qRT-PCR 和血清学方法 使用 TEDDY 分析 T1D 结局。目标 1 将发现并分析这些中的完整粪便病毒组 在转为 tTGA 自身免疫和乳糜泻之前，随着时间的推移，对儿童进行检测，以识别相关病毒 患有乳糜泻自身免疫和疾病。目标 2 将随着时间的推移检查微生物组结构，以确定 与乳糜泻发展相关的细菌分类群或功能，并将获得完整的基因组 发现与疾病结果相关的关键变异细菌序列。这两个目标都将确定 独立影响乳糜泻结果风险的药物，控制混杂因素或其他因素 用回归方法分析疾病的组成部分。目标 3 将进一步探测以确定是否存在 病毒或细菌与其他已知风险因素的协同作用或相互作用，例如儿童的麸质摄入量和 遗传风险（HLA 和已知的相关 SNP）。这将识别可能有助于的组件集 协同作用导致 CD 结果。拟议的工作意义重大，因为它将运用委员会的权力 更大的国际 TEDDY 队列及其丰富的儿童遗传分析数据库可供研究 逐步收集粪便和血清以确定与相关的病毒和/或微生物组特征 tTGA 自身免疫和乳糜泻。拟议的工作具有创新性，因为它将提供第一个 对足以导致乳糜泻结果的病毒组和微生物组成分的综合分析 这可能会产生协同作用。这些发现将有助于更好地了解引发乳糜泻的原因 这对于发展因果机制的假设更加相关，并将开辟概念途径 用于关键的诊断或预防性干预措施。