The Celiac Disease Genome, Environment, Microbiome, and Metabolome (CD-GEMM) prospective cohort study

摘要 我们提出的多学科研究的长期目标是确定和验证特定的 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。我们在上一个融资期生成的初步数据也表明， 肠道微生物组组成和随后的变化，在特定的代谢途径之前的发病， 疾病，并可能有助于从耐受性转换到对麸质的免疫反应。为了实现我们的目标， 我们将利用我们独特的有CD风险的婴儿出生前瞻性队列来比较微生物组， 将发展为CD的儿童与年龄和性别匹配的对照组（两者均 HLA DQ 2/DQ 8阴性和阳性婴儿谁没有发展的疾病），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控现有前景 有CD风险的婴儿队列，目的是研究基因组、宏基因组、代谢组和免疫 高危婴儿的CD特征，以确定与CD发展相关的多组学组成 自身免疫在目标2中，我们将研究特定肠道微生物的分子和功能效应， 在我们对谷蛋白诱导的粘膜先天免疫应答的初步研究中发现， 使用CD儿童的肠道类器官和巨噬细胞的共培养物。对于目标3，我们将使用 多组学统计分析和机器学习，以鉴定CD的微生物组生物标志物并构建 一个包容性的模型，整合了来自宿主和微生物群以及临床的组学和Meta组学数据， 元数据，以预测风险儿童CD发展的机会。总的来说，我们的研究结果 可能不仅对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， 在疾病的发病机制中的微生物组相互作用已经被假设。在美国，近3 约有100万人受CD影响，约有1700万人患有其他自身免疫性疾病 目前还没有有效的策略来防止这些情况，这个项目可能会有 对公众健康的巨大影响。

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.