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: 10411606
• 负责人: CATHRYN R NAGLER
• 金额: $ 5.23万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-12 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411606
• 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.

食物过敏的患病率在西方社会经历了前所未有的增长， 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- 在小鼠过敏性致敏中的保护作用。理解如何 微生物群调节人类过敏性疾病，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 来自健康人类婴儿粪便的抗生素足以保护小鼠免受牛的致敏作用。 牛奶过敏原b-乳球蛋白（BLG），而人类CMA婴儿粪便的定殖， 保护。通过分析我们的人类之间差异丰富的操作分类单位（OTU）， 粪便供体（4名健康，4名CMA），我们已经定义了区分CMA和 在人类供体和定殖小鼠中的健康群体，强调临床相关性 我们的知生模型。回肠肠上皮细胞的RNASeq分析显示差异 表达基因（DEG），在所有供体中区分健康和CMA定殖小鼠。 回肠OTU与健康定殖小鼠回肠中DEG的相关性鉴定了梭菌属物种， 一种防止对食物过敏的厌氧杆菌。我们的研究结果表明， 健康婴儿微生物群在防止食物过敏中的因果作用，并建议， 调节细菌群落的干预措施可能会为开发新的治疗药物提供信息。 应对这种疾病的策略。在本建议中，我们将进一步完善OTU签名，并研究是否 CMA婴儿微生物组是Aim 1中的特应性微生物组。目标2将探索如何健康肠道 细菌通过检查它们对先天淋巴细胞的影响来影响对食物过敏原的反应 功能、早期T/B引发和效应T细胞分化和迁移。稳健的临床前 我们所描述的知菌模型将提供一个理想的系统，以确定关键的宿主微生物 这些相互作用有助于维持食物过敏中对膳食抗原的耐受性。