Microbiome in Asthma Induced by Environmental Particle Exposure

环境颗粒暴露诱发哮喘的微生物组

• 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
• 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

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恶化，并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生态失调越来越多地与 哮喘的发病率和严重程度，但缺乏因果关系研究。我们改造了一个小鼠模型 该研究关注的是在子宫内暴露于环境颗粒后， 来研究微生物是如何导致哮喘发作的。在这个模型中，我们已经表明， (to过敏原或颗粒物质，例如浓缩的城市空气颗粒（CAP）、柴油机排气颗粒（DEP），以及 二氧化钛颗粒（TiO 2）会增加几代后代的哮喘风险。人类 广泛暴露于这些颗粒物，特别是在城市和工业环境中， 哮喘也更高。我们发现，这些新生儿对哮喘的“准备”增加与 关键免疫细胞-树突状细胞（DC）中的DNA甲基化变化，这些细胞在哮喘起源中至关重要。 重要的未解问题是为什么这些表观遗传变化发生，以及是否存在因果联系 哮喘中异常的微生物组。我们假设，在子宫内暴露于粒子改变了 怀孕小鼠及其后代的微生物组，然后向免疫细胞发出信号， 使后代容易过敏 在具体目标1中，我们将测试在分娩后母体微生物组（肠道，肺部和阴道）发生了什么变化。 妊娠颗粒暴露，因为它是母体植物群，主要种子新生儿的微生物组。纵向 分析将采用多方面的方法，包括16 S/ITS分类分析，宏基因组测序， 和靶向代谢组学，用于微生物的组成和代谢的综合分析。 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 它们对变应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 通过将假设的异常植物群从“哮喘风险”供体幼仔（出生于 用颗粒处理的母鼠）与正常受体，反之亦然：粪便微生物群移植（FMT）。最后我们 将测试FMT对接受者DC表观基因组的影响。 在具体目标3中，我们将类似地描述新生儿肺部微生物组，并将测试抗生素的效果， 基于异常肺部菌群的改变对哮喘的预防。 意义：在这里，我们假设两个潜在的相互关联的哮喘发病机制： 表观遗传学和微生物组免疫细胞的表观遗传改变和肠道的生态失调， 在人类和小鼠模型中，肺与哮喘有关，但缺乏因果关系研究。拟议 一项旨在测试相对常见的癌症的基本机制的研究填补了这一知识空白。 环境暴露。