Mechanisms by which intestinal bacteria contribute to maintenance of tolerance in food allergy

肠道细菌有助于维持食物过敏耐受性的机制

• 批准号: 10305655
• 负责人: CATHRYN R NAGLER
• 金额: $ 55.48万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-24 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305655
• 关键词: Allergens; Allergic; Allergic Disease; Antibiotics; Antigens; Atopic Dermatitis; B-Lymphocytes; Bacteria; Birth; Butyrates; Cattle; Cell Differentiation process; Cell physiology; Cesarean section; Clinical; Consumption; Data; Development; Diet; Disease; Epithelial Cells; Exhibits; Family; Family member; Feces; Food; Food Hypersensitivity; Gene Expression Profiling; Generations; Genes; Germ-Free; Gnotobiotic; Homeostasis; Human; Hypersensitivity; IgE; Immune; Incidence; Infant; Infant formula; Intervention; Intestines; Laboratories; Life; Link; Lymphoid Cell; Maintenance; Medicine; Milk; Milk Proteins; Modeling; Mucous Membrane; Mus; Nature; Pathology; Population; Predisposition; Prevalence; Public Health; Publishing; Role; Societies; Source; System; T cell differentiation; T-Lymphocyte; Therapeutic; Time; Work; allergic response; bacterial community; base; cell motility; clinically relevant; commensal bacteria; commensal microbes; dietary; differential expression; dysbiosis; effector T cell; experience; feeding; food allergen; host microbiota; host-microbe interactions; ileum; improved; intestinal epithelium; lifestyle factors; member; microbial; microbial community; microbial signature; microbiome; microbiota; microbiota profiles; mouse model; novel; novel therapeutic intervention; operational taxonomic units; pre-clinical; prevent; response; sample collection; transcriptome sequencing

The prevalence of food allergy has experienced an unprecedented increase in Western societies, rising by as much as 20% in a recent ten-year period. We have previously described a role for mucosa- associated commensal bacteria in protection from allergic sensitization in mice. To understand how the microbiota regulates allergic disease in humans, we colonized germ free mice with human bacteria from the feces of healthy or cow’s milk allergic (CMA) infants. Our data shows that colonization with bacteria derived from healthy human infant feces is sufficient to protect mice against sensitization to the cow’s milk allergen b-lactoglobulin (BLG), whereas colonization with feces from human CMA infants fails to protect. By analyzing operational taxonomic units (OTUs) differentially abundant between our human fecal donors (4 healthy, 4 CMA) we have defined a microbial signature that distinguishes the CMA and heathy populations in both the human donors and the colonized mice, emphasizing the clinical relevance of our gnotobiotic model. RNASeq analysis of ileal intestinal epithelial cells revealed differentially expressed genes (DEGs) that distinguished healthy- and CMA-colonized mice across all donors. Correlation of ileal OTUs with DEGs in the ileum of healthy-colonized mice identified a Clostridial species, Anaerostipes caccae, that protected against an allergic response to food. Our findings demonstrate a causal role for the healthy infant microbiota in protection against food allergy and suggest that interventions that modulate bacterial communities may inform the development of novel therapeutic strategies for this disease. In this proposal we will further refine our OTU signature and examine whether the CMA infant microbiome is an atopic microbiome in Aim 1. Aim 2 will explore how healthy intestinal bacteria influence the response to food allergens by examining their impact on innate lymphoid cell function, early T/B priming and effector T cell differentiation and migration. The robust, pre-clinical gnotobiotic models we describe will provide an ideal system in which to identify key host-microbial interactions that contribute to the maintenance of tolerance to dietary antigen in food allergy.

食物过敏的流行率在西方社会经历了前所未有的上升， 在最近的十年里增长了20%。我们之前已经描述了粘膜的作用- 保护小鼠免受变态反应致敏的共生菌。为了理解如何 微生物区系调节人类的过敏性疾病，我们用来自 健康或牛奶过敏(CMA)婴儿的粪便。我们的数据显示，细菌的定植 从健康的人类婴儿粪便中提取的足以保护小鼠免受奶牛粪便的过敏 牛奶过敏原b-乳球蛋白(BLG)，而人类CMA婴儿的粪便定植未能 保护好自己。通过分析人类之间不同丰富的操作分类单元(OTU) 粪便捐献者(4名健康，4名CMA)我们定义了一个微生物特征，以区分CMA和CMA 在人类捐赠者和被殖民的小鼠中的健康群体，强调临床相关性 我们的灵知生物模型。回肠上皮细胞的RNAseq分析显示差异 表达的基因(Deg)在所有捐赠者中区分健康和CMA定植的小鼠。 回肠OTUS与健康定居小鼠回肠DEGS的相关性确定了一种梭状芽孢杆菌， 咖啡厌氧菌，可防止对食物的过敏反应。我们的发现证明了 健康的婴儿微生物区系在预防食物过敏中的因果作用 调节细菌群落的干预措施可能会为开发新的治疗方法提供信息 治疗这种疾病的策略。在这项建议中，我们将进一步完善我们的OTU签名并检查是否 CMA婴儿微生物组是目标1中的特应性微生物组。目标2将探索如何健康的肠道 细菌通过检测其对天然淋巴样细胞的影响来影响对食物过敏原的反应 功能、早期T/B启动和效应性T细胞分化和迁移。强大的临床前 我们描述的灵知菌模型将提供一个理想的系统，在其中识别关键的宿主-微生物 在食物过敏中有助于维持对饮食抗原耐受性的相互作用。