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

梁摘要：项目3 Beans试图了解环境和个人微生物区系的差异是如何决定 通过探索一种独特的人类模型来研究哮喘患病率的差异：可比墨西哥人的人群 居住在亚利桑那州图森和密歇根州诺加莱斯相距70英里的祖先在儿童哮喘发病率上存在巨大差异 (MX降低4倍)和儿童粪便、饮用水和房屋灰尘的微生物组成。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]可以预防哮喘； 2)吸入AM室内粉尘足以保护小鼠免受过敏性哮喘；3)未经处理的粪便 健康的学龄前AM儿童，但不是高危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分类群和新的先天机制；4)个别AM粪便代谢产物 足以保护无特定病原体(SPF)的小鼠免受过敏性肺部炎症；以及5)美国和墨西哥 环境样本(房屋灰尘和饮用水)可以不同地保护小鼠免受过敏性哮喘的侵袭。 这些数据表明，环境微生物区系和肠道微生物区系对天然哮喘的保护至关重要。 种群，并导致我们假设暴露于不同的环境微生物群(特别是来自 家庭灰尘和饮用水)不同地影响肠道的组成和代谢 美国和墨西哥孕妇的微生物区系，从而形成不同的肠道微生物区系，免疫 他们的孩子的发展和哮喘的轨迹。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，特别是怀孕的墨西哥人的肠道微生物区系 妇女及其年幼子女体内富含抑制2型反应的类群和代谢物 哮喘。 我们将使用一种结合了环境和个人直觉的创新方法来验证我们的假设 单一实验框架内的微生物区系：环境暴露对肠道微生物区系的影响 将首先在怀孕或年轻的GF小鼠身上研究发育、免疫反应和哮喘 通过与40个母婴二元组(每个位置20个)的大便相关联来进行人性化，然后将暴露在配对的 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。 具体地说，我们建议评估美国或墨西哥孕妇粪便微生物区系的垂直传播 女性与早期接触环境微生物区系不同影响哮喘的发生、免疫 相关GF小鼠后代的反应和肠道微生物群(目标1)；微生物区系如何在 美国或墨西哥新生儿的胎粪和早期暴露于配对环境微生物区系的差异 对相关幼龄GF小鼠哮喘发生、免疫反应及肠道微生物群的影响 (目标2)；体内哪些婴儿粪便代谢物可预防哮喘(目标3)。我们的工作将阐明 环境暴露与肠道微生物区系发育、免疫反应和哮喘的联系机制 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.