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

 描述(由申请人提供)：我们建议的多学科研究的长期目标是识别和验证特定的微生物区系和代谢组特征，这些微生物区系和代谢组特征可以预测具有自身免疫风险的基因婴儿的耐受性丧失，以便实施早期预防干预措施，重新建立耐受性，并最终预防自身免疫。我们将集中精力研究乳糜泻(CD)，这是一种独特的自身免疫模型，其触发环境因素(摄入含面筋的谷物)、与人类白细胞抗原基因(DQ2或DQ8)的密切遗传关联以及高度特异性的体液自身免疫反应(组织转谷氨酰胺酶自身抗体)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是在将面筋引入儿童饮食时发生的；相反，它可能在生活中的任何时候发生，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耐受到免疫反应对面筋的转换。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组(未患该病的HLADQ2/DQ8阴性和阳性婴儿)的微生物组、代谢组和免疫谱，以挑战三个特定的目标。在目标1中，我们建议研究高危婴儿CD的微生物群和转录谱，以确定这些微生物区系的遗传组成与CD自身免疫的发展相关。将分析微生物组和转录组随时间的变化与分娩方式、抗生素暴露和喂养方案(包括母乳喂养和面筋引入时机)的关系。这些研究将基于有CD风险的婴儿的遗传背景和环境“压力”之间的相互作用模型。在目标2中，我们将研究婴儿代谢组学表型变异与耐受性和免疫反应之间的关系，从而导致CD典型的自身免疫性肠损伤。我们将建立婴儿代谢型(微生物来源的代谢体)的深入表征，并将这些数据与微生物组组成和基因组信息联系起来，以建立集成代谢组表型的自上而下的系统模型。这些表型模型将根据结果(耐受性与免疫反应)进行询问，以获得预测性模型和对导致CD自身免疫的易感因素的机械性洞察。在目标3中，我们将从机械上将那些发育成CD的婴儿特有的代谢产物与肠道生物学事件联系起来，包括调节肠道细胞旁细胞通透性(Subaim 3a)、粘膜调节性T细胞(Treg)功能和粘膜细胞因子表达(Subaim 3b)以及肠道干细胞生态位基因表达(Subaim 3c)。

 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).