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 我们提出的多学科调查的长期目标是确定和验证具体的 微生物群和代谢组学特征可以预测有遗传风险的婴儿的耐受性丧失 自身免疫，以便实施早期预防干预措施，重新建立耐受性并最终预防 我们的研究重点是乳糜泻（CD），这是一种独特的自身免疫模型。 其中触发环境因素（摄入含麸质谷物），与遗传密切相关 HLA 基因（DQ2 或 DQ8）和高度特异性的体液自身免疫反应（针对组织的自身抗体） 转谷氨酰胺酶）是众所周知的。 它发生在将其引入儿童饮食时；相反，它可以由于以下原因发生在生命中的任何时候； 我们的初步数据还表明肠道微生物组的组成及其后果。 特定代谢途径的变化先于疾病发作，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。 对有 CD 风险的婴儿进行前瞻性队列比较，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（HLA DQ2/DQ8 阴性和阳性婴儿 没有患上这种疾病），为了实现目标 1，我们建议维持 基础设施并最大限度地监测现有的潜在 CD 风险婴儿群体，以实现以下目标 研究高危婴儿 CD 的基因组、宏基因组、代谢组学和免疫谱，以定义多因素 在目标 2 中，我们将研究与 CD 自身免疫发展相关的组学构成。 我们的初步研究中发现的特定肠道微生物和代谢物的分子和功能影响 通过使用肠道类器官和巨噬细胞的共培养物来研究麸质诱导的粘膜先天免疫反应 在 Aim 3 中，我们将使用多组学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整合组学和 来自宿主和微生物群的元组学数据以及临床元数据，以预测 CD 的机会 总体而言，我们的研究结果可能不仅对高危儿童的发展产生深远的影响。 CD，而且还涉及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利用，因为在美国有近 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，目前还没有 预防这些情况的有效策略，该项目可能会对公众产生巨大影响 健康。