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.

在西方社会，食物过敏的患病率出现了前所未有的增长， 近十年来增长了 20%。我们之前已经描述过粘膜的作用- 相关共生细菌可防止小鼠过敏。要了解如何 微生物群调节人类过敏性疾病，我们用来自以下来源的人类细菌在无菌小鼠中定殖 健康婴儿或牛奶过敏 (CMA) 婴儿的粪便。我们的数据表明，细菌定植 来自健康人类婴儿粪便的成分足以保护小鼠免受对牛粪便的过敏 牛奶过敏原 b-乳球蛋白 (BLG)，而人类 CMA 婴儿的粪便却无法定植 保护。通过分析人类之间差异丰富的操作分类单元（OTU） 粪便捐献者（4 名健康者，4 名 CMA）我们定义了一个微生物特征来区分 CMA 和 人类供体和定植小鼠的健康群体，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) 可以区分所有供体中的健康小鼠和 CMA 定植小鼠。 回肠 OTU 与健康定植小鼠回肠中 DEG 的相关性鉴定出梭菌属物种， Anaerostipes caccae，可以防止对食物的过敏反应。我们的研究结果表明 健康婴儿微生物群在预防食物过敏方面的因果作用，并表明 调节细菌群落的干预措施可能会为新型治疗方法的开发提供信息 针对这种疾病的策略。在本提案中，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 将探索健康的肠道如何 细菌通过检查食物过敏原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 启动以及效应 T 细胞分化和迁移。稳健的临床前 我们描述的无菌模型将提供一个理想的系统来识别关键的宿主微生物 有助于维持食物过敏中饮食抗原耐受性的相互作用。