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

梁摘要：项目3 BEAMS旨在了解环境和个人微生物群的差异如何决定 通过探索一个独特的人类模型来研究哮喘患病率的差异： 居住在亚利桑那州图森市和墨西哥州诺加莱斯市相距70英里的祖先，但在儿童哮喘发病率方面存在很大差异 （MX低4倍）和儿童粪便、饮用水和室内灰尘中的微生物组成。项目3 基于我们的发现，1）富含微生物的环境[例如，传统的阿米什（AM）农场]保护哮喘; 2)吸入AM房屋灰尘足以保护小鼠免于过敏性哮喘; 3） 健康的学龄前AM儿童，而不是高危的Hutterite儿童，保护相关的无菌（GF）小鼠免受 哮喘通过选定的微生物类群和新的先天机制; 4）个别AM粪便代谢物， 足以保护无特定病原体（SPF）小鼠免于过敏性肺部炎症;和5）美国和墨西哥 环境样品（室内灰尘和饮用水）不同地保护小鼠免于过敏性哮喘。 这些数据表明，环境和肠道微生物群在自然条件下对哮喘保护至关重要。 人群，并导致我们假设暴露于不同的环境微生物群（特别是来自 房屋灰尘和饮用水）不同形状的组成和肠道的代谢概况 美国和墨西哥孕妇的肠道微生物群，从而差异化地塑造肠道微生物群，免疫 哮喘的发展和轨迹。更具体地说，我们假设微生物 墨西哥家庭中普遍存在的环境，以及肠道微生物群，特别是怀孕的墨西哥人 妇女及其幼儿富含抑制2型反应的分类群和代谢物， 哮喘 我们将使用结合环境和个人直觉的创新方法来测试我们的假设 单一实验框架内的微生物：环境暴露对肠道微生物的影响 将在怀孕或年轻的GF小鼠中研究发育、免疫应答和哮喘， 通过与40个母亲/婴儿二对体（每个位置20个）的粪便相关联来“人源化”，然后将暴露于配对的 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，我们建议评估来自美国或墨西哥孕妇的粪便微生物群的垂直传播， 妇女和早期暴露于环境微生物群差异影响哮喘的发展，免疫 相关GF小鼠后代中的反应和肠道微生物组（目标1）;微生物群如何在 美国或墨西哥新生儿的胎粪和早期暴露于成对环境微生物群的差异 影响相关年轻GF小鼠的哮喘、免疫反应和肠道微生物组的发展 (Aim 2）;婴儿粪便代谢物在体内保护哮喘（目的3）。我们的工作将阐明 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

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.