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

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。我们的初步数据还表明，肠道微生物群的组成和结果 在疾病发生之前，特定代谢途径的变化可能有助于从 对面筋蛋白免疫反应的耐受性。为了实现我们的目标，我们将利用我们独特的出生 CD高危婴儿的前瞻性队列比较儿童的微生物组、代谢组和免疫谱 世卫组织将与年龄和性别匹配的对照组(HLADQ2/DQ8阴性和阳性婴儿 没有患上这种疾病)，以解决三个具体目标。就目标1而言，我们建议维持 基础设施和最大限度地监测现有的CD高危婴儿预期队列，目标是 研究高危婴儿CD的基因组、元基因组、代谢和免疫图谱，以确定多个 组学构成与CD自身免疫的发展相关。对于目标2，我们将调查 我们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效应 利用肠道类器官和巨噬细胞共培养研究面筋蛋白诱导的粘膜天然免疫反应 来自发展成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 识别CD的微生物组生物标志物，构建整合组学和蛋白质组学的包容性模型 来自宿主和微生物区系以及临床元数据的元组学数据，以预测CD的发生几率 高危儿童的发展。总的来说，我们的研究结果可能不仅对以下方面产生深远的影响 CD，还涉及其他自身免疫性疾病，其中饮食-基因组-微生物组相互作用在 对该病的发病机制进行了推测。因为在美国有近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 预防这些情况的有效策略，这个项目可能会对公众产生巨大的影响 健康。

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.