Microbiome in Asthma Induced by Environmental Particle Exposure

环境颗粒暴露诱发哮喘的微生物组

基本信息

批准号：
10088448
负责人：
ALEXEY V FEDULOV
金额：
$ 68.9万
依托单位：
J. CRAIG VENTER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-02 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088448
关键词：
Address Affect Air Air Pollution Allergens Allergic Animal Model Animals Antibiotics Asthma Cells Child Health Cosmetics DNA Methylation Data Dendritic Cells Developed Countries Development Diesel Exhaust Disease Dose Environmental Exposure Environmental Health Epigenetic Process Etiology Exposure to Extrinsic asthma Female Fetal Development Flying body movement Future Generations Health Human Hypersensitivity Immune Immunology Incidence Industrialization Inflammation Inflammatory Response Inhalation Knowledge Lead Life Link Lung Maternal Exposure Mediating Metabolic Metabolism Metagenomics Microbe Modeling Mothers Mus Neonatal Oils Organism Particulate Particulate Matter Phenotype Play Predisposition Pregnancy Pregnant Women Public Health Public Policy Pulmonary Inflammation Readiness Reporting Research Research Design Residual state Ribosomal RNA Risk Role Route Scientist Seeds Severities Signal Transduction Source T-Lymphocyte Taxonomy Testing Therapeutic Transplantation Urban Population Vagina Vancomycin Volatile Fatty Acids Work airway inflammation asthma model base disease phenotype dysbiosis environmental agent epigenome epigenomics experimental study exposed human population fecal transplantation food consumption gut microbiome gut microbiota human model immunoregulation improved in utero lung microbiome maternal microbiome metabolomics metagenomic sequencing methylome microbial microbiome microbiome alteration microbiome research microbiota mouse model neonatal mice neonate novel offspring particle particle exposure pregnant prenatal exposure pup response titanium dioxide transcriptome vaginal microbiome

项目摘要

Asthma is triggered or worsened by environmental exposures and is associated with epigenetic changes in humans and animal models. Microbial dysbiosis in the gut and the lung is increasingly being associated with the incidence and severity of asthma, however causality studies are lacking. We have adapted a mouse model that focuses on the ONSET of allergic asthma early in life after an in utero exposure to environmental particles to study how microbiome may lead to the asthma onset. In this model, we have shown that maternal exposures (to allergen or particulate matter, e.g. concentrated urban air particles (CAP), diesel exhaust particles (DEP) and titanium dioxide particles (TiO2), trigger increased asthma risk in several generations of the offspring. Humans are widely exposed to these particulates, especially in urban and industrial settings, where the incidence of asthma is also higher. We found that the increased ‘preparedness’ for asthma in these neonates is associated with DNA methylation changes in key immune cells – dendritic cells (DC) that are essential in asthma origin. Important unanswered questions are why these epigenetic changes occur, and whether there is a causative link to the aberrant microbiome seen in asthma. We hypothesize that in utero exposures to particles alter the microbiome of the pregnant mice and their offspring, which then signals to the immune cells in a way that predisposes the offspring to allergy. In Specific Aim 1, we will test what happens to the maternal microbiome (gut, lung and vaginal) after the gestational particle exposure, as it is the maternal flora that largely seeds the neonate’s microbiome. Longitudinal profiling will employ a multifaceted approach, including 16S/ITS taxonomic profiling, metagenomic sequencing and targeted metabolomics, for the comprehensive analysis of the composition and metabolism of the microbes. In Specific Aim 2, we will examine the neonatal gut microbiome via similar longitudinal profiling, including their response to allergen and establishment of the asthma phenotype. Importantly, we will perform causality experiments by transferring the hypothetically aberrant flora from the “asthma-at-risk” donor pups (born to the dams treated with particles) to normal recipients, and vice versa: fecal microbiota transplant (FMT). Finally, we will test the effect of the FMT on the recipient’s DC epigenome. In Specific Aim 3, we will similarly profile neonatal lung microbiome and will test the effect of antibiotic- based alteration of the aberrant lung microflora on asthma preparedness. Significance: Here we postulate two, potentially interconnected, mechanisms in asthma onset: epigenetics and the microbiome. Both the epigenetic alterations in immune cells and the dysbiosis in the gut and lung have been linked to asthma in humans and mouse models but causality studies are lacking. The proposed research addresses this gap in knowledge in a study designed to test basic mechanisms of relatively common environmental exposures.

哮喘是通过环境暴露触发或恶化的，与表观遗传变化有关在人类和动物模型中。肠道和肺中的微生物营养不良越来越多地与哮喘的事件和严重程度，但是缺乏因果关系。我们已经改编了鼠标模型这重点是在子宫内暴露于环境颗粒后生命早期的过敏性哮喘发作研究微生物组如何导致哮喘发作。在此模型中，我们已经表明了Mater的暴露（对于过敏原或颗粒物，例如浓缩的城市空气颗粒（盖），柴油排气颗粒（DEP）和二氧化钛颗粒（TIO2），触发了几代后代的哮喘风险。人类广泛暴露于这些细节，尤其是在城市和工业环境中哮喘也更高。我们发现，这些新生儿中哮喘的“备忘性”相关随着哮喘起源至关重要的关键免疫细胞（DC）的DNA甲基化变化。重要的未解决的问题是为什么这些表观遗传变化发生，以及是否存在严重链接到哮喘中看到的异常微生物组。我们假设在子宫中暴露于颗粒的情况会改变怀孕小鼠及其后代的微生物组，然后以某种方式向免疫细胞发出信号使后代易过过敏。在特定目标1中，我们将测试母体微生物组（肠，肺和阴道）发生的情况妊娠颗粒的暴露，因为Mater Flora在很大程度上将新生儿的微生物组播种。纵向分析将采用多方面的方法，包括16秒/其分类学分析，元基因组测序和靶向代谢组学，以全面分析微生物的组成和代谢。在特定目标2中，我们将通过类似的纵向分析检查新生儿肠道微生物组，包括他们对过敏原的反应和哮喘表型的建立。重要的是，我们将执行因果关系通过从“哮喘风险”供体幼犬中转移假设异常的植物群（出生于用颗粒处理的水坝）给正常的接受者，反之亦然：粪便菌群移植（FMT）。最后，我们将测试FMT对接受者DC表观基因组的影响。在特定的目标3中，我们将类似地介绍新生儿肺微生物组，并将测试抗生素 - 基于异常肺微生物洛拉在哮喘准备度上的基于改变。意义：在这里，我们假设哮喘发作中的两个可能相互联系的机制：表观遗传学和微生物组。免疫细胞中的表观遗传改变和肠道的营养不良，肺与人类和小鼠模型中的哮喘有联系，但缺乏随意性研究。提议研究在一项旨在测试相对常见的基本机制的研究中解决了知识的差距环境暴露。