The Celiac Disease Genome, Environment, Microbiome, and Metabolome (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: 10474123
• 负责人: Alessio Fasano
• 金额: $ 41.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474123
• 关键词: Celiac; Disease; Genome; Environment; Microbiome

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 generated during the previous funding period 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 我们建议的多学科调查具有长期目标，以确定和验证特定的 微生物群和代谢组学特征可预测遗传风险婴儿的耐受性丧失 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 自身免疫力。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 触发环境因素(摄入含面筋的谷物)与基因密切相关 人类白细胞抗原基因(DQ2或DQ8)和高度特异的体液自身免疫反应(组织自身抗体 转谷氨酰胺酶)是已知的。我们最近的研究颠覆了之前的观念，即面筋耐受性丧失 在儿童饮食中引入时发生；相反，它可能发生在生活中的任何时候，作为以下结果 其他环境刺激。我们在前一个资金期产生的初步数据也表明 肠道微生物组组成和特定代谢途径的相应变化在发病前 并可能有助于从耐受性转换为对面筋的免疫反应。为了实现我们的目标， 我们将利用我们独特的有CD风险的婴儿出生预期队列来比较微生物群， 与年龄和性别匹配的对照组(两者)将发展为CD的儿童的代谢组和免疫学特征 未患此病的人类白细胞抗原DQ2/DQ8阴性和阳性婴儿)，以解决三个具体的 目标。对于目标1，我们建议维护基础设施，并最大限度地监视现有的潜在客户 以研究基因组、后基因组、代谢组学和免疫为目标的CD高危婴儿队列 高危婴儿的CD谱以确定与CD的发展相关的多组学组成 自身免疫力。在目标2中，我们将研究特定肠道微生物和 在我们对面筋蛋白诱导的粘膜先天免疫反应的初步研究中发现的代谢物发生了变化 使用来自患有CD的儿童的肠道类器官和巨噬细胞的共培养。对于目标3，我们将使用 多组学统计分析和机器学习识别CD微生物组标志物并构建 整合了来自宿主和微生物区系以及临床的组学和偏位组学数据的包容性模型 元数据，以预测高危儿童发展成CD的机会。总体而言，我们的研究结果 不仅对CD有深远的影响，而且对其他自身免疫性疾病也有深远的影响，在这些疾病中，饮食-基因组- 微生物组相互作用在该病发病机制中的作用已被假说。因为在美国几乎有300万人 100万人受到CD的影响，大约1700万人患有其他自身免疫性疾病 而且目前还没有有效的策略来预防这些情况，这个项目可能会 对公众健康的巨大影响。

项目成果

Microbiota and Metabolomic Patterns in the Breast Milk of Subjects with Celiac Disease on a Gluten-Free Diet.

• DOI: 10.3390/nu13072243
• 发表时间: 2021-06-29
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Olshan KL;Zomorrodi AR;Pujolassos M;Troisi J;Khan N;Fanelli B;Kenyon V;Fasano A;Leonard MM
• 通讯作者: Leonard MM