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

微生物组衍生的代谢物与高危婴儿乳糜泻的发病有关

• 批准号: 9766265
• 负责人: Alessio Fasano
• 金额: $ 68.09万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766265
• 关键词: Address; Affect; Age; Antibiotics; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Bacteria; Barley; Biological; Biological Models; Biology; Biometry; Breast Feeding; Butyrates; Celiac Disease; Cell Compartmentation; Child; Childhood; Data; Development; Diagnostic; Diet; Disease; Early Intervention; Environment; Environmental Risk Factor; Epidemiology; Event; Exposure to; Functional disorder; Gastroenterology; Gene Expression; Genes; Genetic; Genome; Genomics; Gliadin; Gluten; Goals; Grain; Gut Mucosa; Hand; Human Genetics; Immune; Immune response; Immunologics; Immunology; Individual; Infant; Inflammation; Ingestion; Intestinal Mucosa; Intestinal permeability; Intestines; Investigation; Lactobacillus; Life; Link; Metabolic; Metabolic Pathway; Microbe; Microbiology; Modeling; Modification; Molecular; Mucous Membrane; Observational Study; Onset of illness; Outcome; Pathogenesis; Pathway interactions; Pediatric Hospitals; Permeability; Phenotype; Play; Predisposing Factor; Preventive Intervention; Primary Prevention; Public Health; Regimen; Regulatory T-Lymphocyte; Research; Resources; Risk; Role; Rye cereal; Stem cells; Stimulus; Susceptibility Gene; Therapeutic Intervention; Time; Tissues; Transglutaminases; Variant; Wheat; base; cytokine; feeding; genetic association; genetic makeup; gut bacteria; gut microbiome; immune function; implementation strategy; insight; metabolic phenotype; metabolic profile; metabolome; metabolomics; metatranscriptomics; microbiome; microbiome composition; microbiome research; microbiota; multidisciplinary; novel; predictive modeling; pressure; prevent; prospective; public health relevance; sex; stem cell niche; tool

 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).

 描述（由适用提供）：我们拟议的多学科研究的长期目标是识别和验证特定的微生物群和代谢组学特征，可以预测一般有自身免疫风险的婴儿的容忍度丧失，以实施早期预防干预措施以重新建立耐受性并最终预防自身免疫性。我们将研究研究工作将腹腔疾病（CD）重点放在自身免疫性的独特模型上，触发环境因素（摄入含麸质谷物），与HLA基因（DQ2或DQ8）的紧密遗传关联，以及高度特定的体液自身免疫性反应（自动抗体反应（自动抗体抗体）。我们最近的研究颠覆了先前的通知，即麸质耐受性的丧失发生在引入儿童饮食时。相反，由于其他环境刺激，它可以在生活中的任何时候发生。我们的初步数据还表明，肠道微生物组的组成以及随之而来的特定代谢组途径的变化可能有助于从耐受性转变为免疫响应到面筋。为了实现我们的目标，我们将对有500名CD风险的婴儿进行前瞻性观察性研究。我们将比较具有年龄和性别匹配对照的CD（HLA DQ2/DQ8阴性和未发展疾病的阳性婴儿）的CD的微生物组，代谢组和免疫学特征，以挑战三个特定目标。使用AIM 1，我们建议研究高危婴儿中CD的微生物组和元文字谱图，以定义这些微生物群的遗传组成，并与CD自身免疫的发展有关。随着时间的推移，将分析微生物组和元文字组合谱的变化，这些变化将与输送方式，暴露于抗生素和喂养方案有关，包括母乳喂养和麸质引入时间。这些研究将基于遗传背景和环境“压力”之间的相互作用模型，处于CD风险。使用AIM 2，我们将研究婴儿与耐受性与免疫反应有关的代谢组学表型变异，从而导致自身免疫性肠道损害CD的典型。我们将建立对婴儿的代谢型（微生物代谢组）的深入表征，并将这些数据与微生物组成和基因组信息联系起来，以构建综合代谢组型表型的自上而下的系统模型。这些表型模型将在结果（公差与免疫反应）方面进行审问，以获得预测模型和对导致CD自身免疫性的诱发因子的机理洞察力。使用AIM 3，我们将从机械上将开发CD开发CD的代谢产物与肠生物学事件相关，包括调节肠道副细胞通透性（SUBAIM 3A），粘膜调节T细胞（TREG）功能和粘膜溶质细胞因子表达（Subaim 3B）和肠道干细胞Niche Gene Gene Gene Gene Gene（SupiaM 3C）（Supemaim 3C）。