The Celiac Disease Genomic, Environmental, Microbiome, and Metabolomic (CD-GEMM) Prospective Cohort Study

乳糜泻基因组、环境、微生物组和代谢组 (CD-GEMM) 前瞻性队列研究

• 批准号: 10905694
• 负责人: Alessio Fasano
• 金额: $ 82.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10905694
• 关键词: Address; Affect; Age; Antibiotics; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Barley; Biological; Biological Markers; Biology; Birth; Celiac Disease; Cells; Child; Childhood; Clinical; Coculture Techniques; Collection; Computational Biology; Data; Derivation procedure; Development; Diet; Disease; Early Intervention; Environment; Environmental Risk Factor; Epidemiology; Epithelium; Event; Exposure to; Functional disorder; Funding; Gastroenterology; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Gluten; Goals; Grain; HLA-DQ2; Human Genetics; Immune; Immune response; Immune system; Immunologics; Immunology; Individual; Infant; Inflammation; Infrastructure; Ingestion; Innate Immune Response; Intervention; Intestinal Mucosa; Intestinal permeability; Intestines; Investigation; Life; Link; Machine Learning; Macrophage; Metabolic; Metabolic Pathway; Metadata; Metagenomics; Microbiology; Modeling; Modification; Molecular; Mucous Membrane; Onset of illness; Organoids; Outcome; Pathogenesis; Pediatric Hospitals; Persons; Play; Predisposition; Prevention strategy; Prospective cohort; Prospective, cohort study; Public Health; Regimen; Regulatory T-Lymphocyte; Research; Resources; Risk; Role; Rye cereal; Statistical Data Interpretation; Stimulus; Time; Tissue Transglutaminase Antibodies; Wheat; biobank; chronic inflammatory disease; cohort; design; dysbiosis; feeding; genetic association; genome sequencing; gut microbes; gut microbiome; gut microbiota; immune function; insight; longitudinal dataset; metabolome; metabolomics; microbiome; microbiome composition; microbiome research; microbiota; multidisciplinary; multiple omics; novel; predictive modeling; prevent; preventive intervention; prospective; response; sex; treatment strategy; whole genome

ABSTRACT Our proposed multidisciplinary investigations have the long-term objective to identify and validate specific microbiota and metabolomic profiles that can predict loss of tolerance in infants genetically at risk of autoimmunity in order to implement early preventive interventions to re-establish tolerance and ultimately prevent autoimmunity. We have focused our research effort on celiac disease (CD), a unique model of autoimmunity for which the triggering environmental factor (ingestion of gluten containing grains), a close genetic association with HLA genes (DQ2 or DQ8) and a highly specific humoral autoimmune response (autoantibodies to tissue transglutaminase) are known. Our recent studies have subverted the previous notion that loss of gluten tolerance occurs at the time of its introduction in the child's diet; rather it can occur at any time in life as a consequence of other environmental stimuli. Our preliminary data also suggest that gut microbiome composition and consequent changes in specific metabolic pathways precede the onset of the disease and may contribute to switching from tolerance to immune response to gluten. To achieve our objective, we will capitalize on our unique birth prospective cohort of infants at-risk of CD to compare microbiome, metabolome, and immune profiles of children who will develop CD with age- and sex-matched controls (both HLA DQ2/DQ8 negative and positive infants who did not develop the disease) in order to address three specific aims. With Aim 1, we propose to maintain the infrastructure and maximize surveillance of the existing prospective cohort of infants at-risk for CD with the goal of studying genome, metagenomic, metabolomic, and immune profiles of CD in at-risk infants to define the multi- omics makeup associated with the development of CD autoimmunity. With Aim 2, we will investigate the molecular and functional effects of specific gut microbes and metabolites found altered in our preliminary studies on gluten-induced mucosal innate immune response by using co-cultures of gut organoids and macrophages from children who developed CD. With Aim 3, we will use multi-omics statistical analysis and machine learning to identify microbiome biomarkers of CD and to construct an inclusive model that integrates omics and meta’omics data from the host and microbiota as well as clinical metadata in order to predict the chance of CD development in at-risk children. Overall, the outcome of our studies may have far-reaching impact not only on CD, but also on other autoimmune diseases in which the diet-genome-microbiome interaction in the pathogenesis of the disease has been hypothesized. Since in the U.S. almost 3 million people are affected by CD and approximately 17 million people suffers of other autoimmune diseases and that currently there are no effective strategies to prevent these conditions, this project can potentially have a tremendous impact on public health.

抽象的 我们拟议的多学科调查具有长期目标，以识别和验证特定 微生物群和代谢组谱可以预测婴儿的耐受性丧失 自身免疫性是为了实施早期的预防干预措施以重新建立耐受性并最终阻止 自身免疫性。我们将研究工作集中在乳糜泻（CD）上，这是一种独特的自身免疫模型 它引发环境因素（摄入含有谷物的麸质），这是与 HLA基因（DQ2或DQ8）和高度特异的体液自身免疫反应（自身抗体对组织 转谷氨酰胺酶）是已知的。我们最近的研究颠覆了先前的通知，即衰老耐受性 发生在孩子饮食中的引入时；而是由于 其他环境刺激。我们的初步数据还表明肠道微生物组组成及其结果 特定代谢途径的变化先于疾病发作，并可能有助于从 对面筋的免疫反应的耐受性。为了实现我们的目标，我们将利用我们独特的出生 预期的婴儿在CD风险中比较儿童的微生物组，代谢组和免疫特征 谁将使用年龄和性别匹配的对照组开发CD（HLA DQ2/DQ8负面和阳性婴儿 没有发展这种疾病）是为了解决三个特定目标。在AIM 1中，我们建议维护 现有的基础设施和最大监视cd的婴儿在现有婴儿队中的最大监视 研究基因组，宏基因组，代谢组和CD的免疫特征，以定义多种 与CD自身免疫的发展相关的OMICS化妆。使用AIM 2，我们将调查 特定肠道微生物和代谢产物的分子和功能效应在我们的初步研究中发生了改变 通过使用肠道和巨噬细胞的共培养麸质诱导的粘膜先天免疫反应 来自开发CD的孩子。使用AIM 3，我们将使用多摩斯统计分析和机器学习 识别CD的微生物组生物标志物，并构建一个包含OMICS和 来自宿主和微生物群以及临床元数据的元数据数据，以预测CD的机会 处于危险儿童的发展。总体而言，我们研究的结果可能不仅对 CD，但也是其他自身免疫性疾病，其中饮食基因组 - 微生物组相互作用 该疾病的发病机理已被假设。由于在美国，近300万人受到影响 CD和大约1700万人患有其他自身免疫性疾病，目前没有 预防这些条件的有效策略，该项目可能会对公众产生巨大影响 健康。