Impact of the Environment and Host Microbiome on Asthma Development: Mechanistic Studies

环境和宿主微生物组对哮喘发展的影响：机制研究

• 批准号: 10088093
• 负责人: Donata Vercelli
• 金额: $ 8.45万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10088093
• 关键词: Affect; Allergic; Amish; Asthma; Characteristics; Child; Childhood Asthma; Data; Development; Dust; Environment; Environmental Exposure; Environmental Impact; Exhibits; Exposure to; Extrinsic asthma; Farming environment; Feces; Genes; Germ-Free; Home environment; House Dust; Immune; Immune response; Individual; Infant; Inhalation; Lead; Life; Link; Location; Lung; Lung Inflammation; Meconium; Metabolic; Metabolism; Mexican; Mexico; Microbe; Mothers; Mus; Nursery Schools; Output; Pathway interactions; Phenotype; Population; Pregnant Women; Prevalence; Sampling; Shapes; Side; Testing; Time; Vertical Disease Transmission; Woman; Work; asthma model; design; drinking water; germ free condition; gut microbiome; gut microbiota; host microbiome; human model; hutterite; in vivo; innovation; male; metabolic profile; microbial; microbiome research; microbiota; neonate; novel; pregnant; response; trait

BEAMS ABSTRACT: Project 3 BEAMS seeks to understand how differences in environmental and personal microbiota determine differences in asthma prevalence by exploring a unique human model: populations of comparable Mexican ancestry that live 70 miles apart in Tucson, AZ, and Nogales, MX, but differ profoundly in childhood asthma rates (4-fold lower in MX) and the microbial composition of children’s stool, drinking water and house dust. Project 3 builds on our findings that 1) microbe-rich environments [e.g., traditional Amish (AM) farms] protect from asthma; 2) inhalation of AM house dust is sufficient to protect mice from allergic asthma; 3) unmanipulated stools of healthy preschool AM children, but not high-risk Hutterite children, protect associated germ-free (GF) mice from asthma through selected microbial taxa and novel innate mechanisms; 4) individual AM stool metabolites are sufficient to protect specific pathogen-free (SPF) mice from allergic lung inflammation; and 5) US and Mexican environmental samples (house dust and drinking water) differentially protect mice from allergic asthma. These data demonstrate that both environmental and gut microbiota are critical for asthma protection in natural populations, and lead us to hypothesize that exposure to distinct environmental microbiota (especially from house dust and drinking water) differentially shapes the composition and metabolic profile of gut microbiota in US and Mexican pregnant women, thereby differentially shaping gut microbiota, immune development and trajectory to asthma in their children. More specifically, we hypothesize that the microbial environments prevalent in Mexican homes, and the gut microbiota especially abundant in pregnant Mexican women and their young children, are enriched in taxa and metabolites that suppress type-2 responses and asthma. We will test our hypothesis using an innovative approach that combines environmental and personal gut microbiota within a single experimental framework: the impact of environmental exposures on gut microbiota development, immune responses and asthma will be studied in pregnant or young GF mice that first will be “humanized” by association with stools of 40 mother/infant dyads (20 per location), then will be exposed to paired dust and drinking water from the subjects’ homes, and finally will be tested in a classic allergic asthma model. Specifically, we propose to assess how vertical transmission of stool microbiota from US or Mexican pregnant women and early exposure to environmental microbiota differentially affect the development of asthma, immune responses and gut microbiome in the progeny of associated GF mice (Aim 1); how microbiota enriched in the meconium of US or Mexican neonates and early exposure to paired environmental microbiota differentially influence the development of asthma, immune responses and gut microbiome in associated young GF mice (Aim 2); which infant stool metabolites protect from asthma in vivo (Aim 3). Our work will elucidate the mechanisms that link environmental exposures to gut microbiota development, immune responses and asthma protection.

梁摘要：项目 3 BEAMS 试图了解环境和个人微生物群的差异如何决定 通过探索独特的人类模型来研究哮喘患病率的差异：可比较的墨西哥人群 居住在亚利桑那州图森和墨西哥州诺加利斯的祖先相距 70 英里，但儿童哮喘发病率却截然不同 （MX 降低 4 倍）以及儿童粪便、饮用水和室内灰尘的微生物成分项目 3。 基于我们的发现：1) 微生物丰富的环境 [例如传统的阿米什 (AM) 农场] 可预防哮喘； 2) 吸入 AM 室内灰尘足以保护小鼠免受过敏性哮喘的影响；3) 未经处理的粪便； 健康的学龄前 AM 儿童（但不是高危哈特派儿童）可以保护相关的无菌 (GF) 小鼠免受感染 通过选定的微生物分类群和新的先天机制来治疗哮喘；4) 个体 AM 粪便代谢物是 足以保护无特定病原体 (SPF) 小鼠免受过敏性肺部炎症的影响；5) 美国和墨西哥； 环境样本（房屋灰尘和饮用水）对小鼠免受过敏性哮喘有不同的保护作用。 这些数据表明，环境和肠道微生物群对于自然环境中的哮喘预防至关重要。 人口，并引导我们解决暴露于不同环境微生物群（特别是来自 房屋灰尘和饮用水）对肠道的组成和代谢特征有不同的影响 美国和墨西哥孕妇的微生物群，从而差异化地塑造肠道微生物群、免疫 更具体地说，我们与微生物作斗争。 墨西哥家庭中普遍存在的环境，墨西哥孕妇的肠道微生物群尤其丰富 妇女及其幼儿富含抑制 2 型反应的类群和代谢物， 哮喘。 我们将使用结合环境和个人直觉的创新方法来检验我们的假设 单一实验框架内的微生物群：环境暴露对肠道微生物群的影响 将在怀孕或幼年 GF 小鼠中研究发育、免疫反应和哮喘，首先将 通过与 40 名母亲/婴儿双人组（每个位置 20 名）的粪便相关联来“人性化”，然后将暴露于配对 来自受试者家中的灰尘和饮用水，最后将在经典的过敏性哮喘模型中进行测试。 具体来说，我们建议评估美国或墨西哥孕妇粪便微生物群的垂直传播方式 女性和早期接触环境微生物群对哮喘、免疫系统的发展有不同的影响 相关 GF 小鼠后代的反应和肠道微生物组（目标 1）； 美国或墨西哥新生儿的胎便和早期接触配对环境微生物群的差异 影响相关年轻 GF 小鼠的哮喘发展、免疫反应和肠道微生物组 （目标 2）；哪些婴儿粪便代谢物可预防体内哮喘（目标 3）。 将环境暴露与肠道微生物群发育、免疫反应和哮喘联系起来的机制 保护。