Microbiome-derived Metabolites Linked to Celiac Disease Onset in Infants at Risk

 描述（由申请人提供）：我们提出的多学科研究的长期目标是鉴定和验证特定的微生物群和代谢组学特征，这些特征可以预测遗传上有自身免疫风险的婴儿的耐受性丧失，以便实施早期预防性干预措施，以重建耐受性并最终预防自身免疫。我们将把研究重点放在乳糜泻（CD）上，这是一种独特的自身免疫模型，其触发环境因素（摄入含麸质的谷物），与HLA基因（DQ 2或DQ 8）的密切遗传关联以及高度特异性的体液自身免疫反应（组织转氨酶自身抗体）是已知的。我们最近的研究颠覆了以前的概念，即麸质耐受性的丧失发生在其引入儿童饮食的时候;相反，它可以发生在生活中的任何时候，作为其他环境刺激的结果。我们的初步数据还表明，肠道微生物组组成和随后特定代谢途径的变化可能有助于从对麸质的耐受性转变为免疫反应。为了实现我们的目标，我们将对500名有CD风险的婴儿进行前瞻性观察研究。我们将比较患有CD的婴儿与年龄和性别匹配的对照（HLA DQ 2/DQ 8阴性和阳性婴儿，未患该疾病）的微生物组，代谢组和免疫特征，以挑战三个特定目标。目的1：我们建议研究高危婴儿CD的微生物群和元转录谱，以确定这些微生物群与CD自身免疫发展相关的遗传组成。随着时间的推移，微生物组学和元转录组学特征的变化将与分娩方式、抗生素暴露和喂养方案（包括母乳喂养和麸质引入时间）相关进行分析。这些研究将基于有CD风险的婴儿中遗传背景和环境“压力”之间相互作用的模型。目标2：我们将研究婴儿的代谢组学表型变化与耐受性和免疫应答的关系，导致CD典型的自身免疫性肠道损伤。我们将建立婴儿代谢型（微生物衍生的代谢组）的深入表征，并将这些数据与微生物组学组成和基因组信息联系起来，以建立自上而下的综合代谢组学表型系统模型。将对这些表型模型的结局（耐受性vs.免疫应答）进行研究，以获得预测模型和对导致CD自身免疫的诱发因素的机制见解。通过目标3，我们将从机制上将CD婴儿特有的代谢产物与肠道生物学事件联系起来，包括肠道细胞旁通透性（Subaim 3a）、粘膜调节性T细胞（Treg）功能和粘膜细胞因子表达（Subaim 3b）以及肠道干细胞小生境基因表达（Subaim 3c）的调节。

 DESCRIPTION (provided by applicant): Our proposed multidisciplinary investigations have the long-term objective of identifying and validating 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 will focus 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 into 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 metabolomic pathways may contribute to the switch from tolerance to immune response to gluten. To achieve our objective, we will perform a prospective observational study on 500 infants at risk of CD. We will compare the microbiome, metabolome, and immune profiles of infants who develop CD with age- and sex-matched controls (both HLA DQ2/DQ8 negative and positive infants who do not develop the disease) in order to challenge three specific aims. With Aim 1 we propose to study the microbiomic and metatranscriptomic profiles of CD in at-risk infants to define the genetic makeup of these microbiota in association with the development of CD autoimmunity. Changes in microbiomic and metatranscriptomic profiles over time will be analyzed in relation to mode of delivery, exposure to antibiotics, and feeding regimens, including breast feeding and timing of gluten introduction. These studies will be based on the model of interaction between genetic background and environmental "pressure" in infants at risk of CD. With Aim 2 we will study the infants' metabolomics phenotype variation in relation to tolerance vs. immune response leading to the autoimmune intestinal insult typical of CD. We will establish an in-depth characterization of the infants' metabotypes (microbe-derived metabolomes) and link those data with microbiomic composition and genomic information to build top-down system models of integrated metabolomic phenotypes. These phenotypic models will be interrogated with respect to outcome (tolerance vs. immune response) to obtain predictive models and mechanistic insight into predisposing factors leading to CD autoimmunity. With Aim 3 we will mechanistically link the identified metabolomic products unique to those infants developing CD to intestinal biological events including modulation of intestinal paracellular permeability (Subaim 3a), mucosal regulatory T cell (Treg) functions and mucosal cytokines expression (Subaim 3b), and intestinal stem cell niche gene expression (Subaim 3c).