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.

哮喘是由环境暴露引发或加剧的，并且与表观遗传变化有关在人类和动物模型中，肠道和肺部的微生物失调越来越与此相关。哮喘的发病率和严重程度，但缺乏因果关系研究，我们已经采用了小鼠模型。重点关注在子宫内暴露于环境颗粒后生命早期过敏性哮喘的发生研究微生物组如何导致哮喘发作在这个模型中，我们证明了母亲的暴露。（过敏原或颗粒物，例如浓缩城市空气颗粒 (CAP)、柴油机尾气颗粒 (DEP) 和二氧化钛颗粒（TiO2）会增加人类后代的哮喘风险。广泛暴露于这些颗粒物，特别是在城市和工业环境中，我们发现这些新生儿对哮喘的“准备”程度也较高。关键免疫细胞——树突状细胞 (DC) 中的 DNA 甲基化发生变化，这对于哮喘起源至关重要。尚未解答的重要问题是为什么会发生这些表观遗传变化，以及是否存在因果关系我们勇敢地承认，在子宫内暴露于颗粒物会改变哮喘中出现的异常微生物组。怀孕小鼠及其后代的微生物组，然后以以下方式向免疫细胞发出信号：使后代容易过敏。在具体目标 1 中，我们将测试母体微生物组（肠道、肺和阴道）在妊娠期颗粒物暴露，因为母体菌群主要为新生儿的微生物组播下种子。分析将采用多方面的方法，包括 16S/ITS 分类分析、宏基因组测序以及靶向代谢组学，对微生物的组成和代谢进行综合分析。在具体目标 2 中，我们将通过类似的纵向分析来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，我们将进行因果关系。通过从“有哮喘风险”的供体幼崽（出生于将经过颗粒处理的母猪）移植到正常受体，反之亦然：粪便微生物移植（FMT）。将测试 FMT 对受体 DC 表观基因组的影响。在具体目标 3 中，我们将类似地分析新生儿肺部微生物组，并测试抗生素的效果异常肺部微生物群的改变对哮喘准备的影响。意义：在这里，我们假设哮喘发病有两种可能相互关联的机制：表观遗传学和微生物组：免疫细胞的表观遗传学改变和肠道菌群失调。在人类和小鼠模型中，肺与哮喘有关，但缺乏因果关系研究。研究解决了这一知识差距，旨在测试相对常见的基本机制环境暴露。