Protective role of intestinal microbiota in food allergy

肠道微生物群在食物过敏中的保护作用

基本信息

批准号：
8787710
负责人：
CATHRYN R NAGLER
金额：
$ 38.94万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8787710
关键词：
AHR gene Accounting Allergic Disease Allergic Reaction Anaphylaxis Antibiotics Aryl Hydrocarbon Receptor Attention B-Lymphocytes Bacteria Clostridium Colon Cre-LoxP Data Dendritic Cells Development Disease Environment Epithelial Epithelial Cells Epithelium Exhibits Food Food Hypersensitivity Genes Genetic Gnotobiotic Health Hypersensitivity ITGAX gene Immune system Immunity Immunoglobulin A Incidence Intestines Laboratories Lead Ligands Link Lipopolysaccharides Mediating Microarray Analysis Modeling Molecular Mus Mutant Strains Mice Mutation Neonatal Pathway interactions Peptides Population Predisposition Prevalence Public Health Regulation Role Schools Signal Transduction Source Stimulus Surface TLR4 gene Technology Tight Junctions United States Variant Work allergic response antimicrobial base commensal microbes disorder risk food allergen gene environment interaction gut microbiota interleukin-22 interleukin-23 novel novel strategies prevent protein expression protein function receptor-mediated signaling research study response toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): The prevalence of food allergy is rising at an alarming rate in the United States and in other parts of the developed world. Environmental stimuli that alter populations of beneficial commensal bacteria have been implicated in this increase. Earlier work from our laboratory showed that mice unable to signal via TLR4 exhibit enhanced allergic responses to food. We hypothesized that commensal bacteria were the source of the TLR4 ligand and demonstrated that neonatal administration of a cocktail of broad-spectrum antibiotics (Abx) induced an allergic response in TLR4 sufficient mice equivalent to that seen in TLR4 mutant mice. In the preliminary data presented in this revised application we have established a novel gnotobiotic model of food allergy and show that a defined bacterial consortium, derived directly from the intestinal microbiota of healthy mice, protects against systemic hyperreactivity to a food allergen. We demonstrate that bacteria in the Clostridia class selectively induce a barrier protective response that includes activation of the IL-23/IL-22 axis, induction of the expression of the anti-microbial peptides Reg3b and Reg3g and the expansion of intestinal Tregs and IgA secreting B cells; part of this response is TLR4-dependent. We hypothesize that a Clostridia-containing microbiota is sufficient to elicit a barrier protective response that protets against allergic responses to food. In the experiments proposed we will examine how allergy-protective bacterial populations deliver signals to their hosts at both the cellular and molecular level. Seven new figures of preliminary data are provided in support of the two Aims outlined in this revised application. Aim 1 will determine which cellular interactions with commensal bacteria are necessary and sufficient to induce a barrier protective response. We have used Cre- Lox technology to generate mice with targeted mutations in MyD88 signaling in CD11c+ dendritic cells (DC) and in intestinal epithelial cells (IEC). We will also examine whether TLR4 signaling is required by the Tregs themselves. Microarray analysis of intestinal epithelial cells highlighted two novel genes/pathways selectively upregulated in the epithelium of Clostridia colonized mice; the anti-microbial peptide Reg3b and a target gene for the aryl hydrocarbon receptor (Ahr). Both pathways have been intimately linked to the regulation of intestinal immunity. Aim 2a will examine how Ahr-mediated signals and IL22 contribute to a Clostridia induced barrier protective response that prevents against an allergic response to food. Finally, Aim 2b will examine how Clostridia mediated activation of the innate and adaptive immune system impacts epithelial tight junction protein expression and function. The successful completion of the Aims proposed holds promise for the development of novel approaches to prevent or treat food allergy based on modulation of the composition of intestinal microbiota.

描述（由申请人提供）：在美国和其他发达国家，食物过敏的患病率正以惊人的速度上升。改变有益共生菌种群的环境刺激与这种增加有关。我们实验室的早期工作表明，无法通过 TLR4 发出信号的小鼠表现出对食物的过敏反应增强。我们假设共生细菌是 TLR4 配体的来源，并证明新生儿给予广谱抗生素 (Abx) 混合物会在 TLR4 充足小鼠中诱导过敏反应，与 TLR4 突变小鼠中所见的过敏反应相同。在本次修订后的申请中提供的初步数据中，我们建立了一种新的食物过敏知生模型，并表明直接源自健康小鼠肠道微生物群的明确细菌群落可以防止系统对食物过敏原的过度反应。我们证明梭状芽孢杆菌类细菌选择性诱导屏障保护反应，包括激活 IL-23/IL-22 轴、诱导抗菌肽 Reg3b 和 Reg3g 的表达以及肠道 Tregs 和 IgA 分泌的扩展B细胞；该反应的一部分依赖于 TLR4。我们假设含有梭菌的微生物群足以引发屏障保护反应，防止对食物的过敏反应。在提出的实验中，我们将研究过敏保护细菌群体如何在细胞和分子水平上向宿主传递信号。提供了七个新的初步数据，以支持本修订后的申请中概述的两个目标。目标 1 将确定哪些细胞与共生细菌的相互作用对于诱导屏障保护反应是必要且充分的。我们使用 Cre-Lox 技术培育出了 CD11c+ 树突状细胞 (DC) 和肠上皮细胞 (IEC) 中 MyD88 信号传导有针对性突变的小鼠。我们还将检查 Tregs 本身是否需要 TLR4 信号传导。肠上皮细胞的微阵列分析强调了梭菌定植小鼠上皮细胞中选择性上调的两个新基因/途径；抗微生物肽 Reg3b 和芳基碳氢化合物受体 (Ahr) 的靶基因。这两种途径都与肠道免疫的调节密切相关。目标 2a 将研究 Ahr 介导的信号和 IL22 如何促进梭菌诱导的屏障保护反应，从而防止对食物的过敏反应。最后，目标 2b 将研究梭菌介导的先天性和适应性免疫系统的激活如何影响上皮紧密连接蛋白的表达和功能。所提出目标的成功完成有望开发基于肠道微生物群组成的调节来预防或治疗食物过敏的新方法。