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.

摘要 我们提出的多学科研究的长期目标是识别和验证特定的 微生物群和代谢组学特征，可以预测婴儿遗传耐受性的丧失， 自身免疫，以便实施早期预防性干预，以重建耐受性，并最终预防 自身免疫我们将研究重点放在乳糜泻（CD）上，这是一种独特的自身免疫模型， 触发环境因素（摄入含谷蛋白的谷物），与 HLA基因（DQ 2或DQ 8）和高度特异性体液自身免疫反应（组织自身抗体） 转氨酶）是已知的。我们最近的研究颠覆了以前的观念，即面筋耐受性的丧失 发生在它引入儿童的饮食时;相反，它可以发生在生活中的任何时候， 其他环境刺激。我们的初步数据还表明，肠道微生物组的组成和随之而来的 特定代谢途径的变化先于疾病的发作，并可能有助于从 对麸质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 有CD风险的婴儿的前瞻性队列，以比较儿童的微生物组、代谢组和免疫特征 与年龄和性别匹配的对照组（HLA DQ 2/DQ 8阴性和阳性婴儿， 没有发展疾病），以解决三个具体目标。就目标1而言，我们建议维持 基础设施，并最大限度地监测现有的CD风险婴儿前瞻性队列， 研究高危婴儿CD的基因组、宏基因组、代谢组和免疫特征，以确定多基因组的 与CD自身免疫发展相关的组学组成。在目标2中，我们将研究 在我们的初步研究中发现，特定肠道微生物和代谢物的分子和功能效应发生了改变， 通过使用肠道类器官和巨噬细胞的共培养物对谷蛋白诱导的粘膜先天免疫应答的影响 患CD的儿童。在目标3中，我们将使用多组学统计分析和机器学习 确定CD的微生物组生物标志物，并构建一个整合组学和 来自宿主和微生物群的Meta组学数据以及临床元数据，以预测CD的机会 风险儿童的发展。总的来说，我们的研究结果可能不仅对 CD，但也对其他自身免疫性疾病，其中饮食-基因组-微生物组的相互作用， 该疾病的发病机制已被假设。在美国，近300万人受到 CD和大约1700万人患有其他自身免疫性疾病，目前没有 有效的战略，以防止这些条件，该项目可能会产生巨大的影响，公众 健康