Role of Intestinal Microbiota in Dyslipidemia and Atherosclerosis Induced by Ambient Ultrafine Particles

肠道菌群在环境超细颗粒诱导的血脂异常和动脉粥样硬化中的作用

基本信息

批准号：
10010319
负责人：
Jesus Antonio Araujo
金额：
$ 4.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2019-12-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010319
关键词：
Air Pollutants Air Pollution Animals Antibiotics Arterial Fatty Streak Atherosclerosis Blood Blood Vessels C57BL/6 Mouse Caliber Cardiovascular Diseases Cardiovascular system Cells Cessation of life Cholesterol Data Deglutition Deposition Development Diesel Exhaust Disease Dyslipidemias Epidemiology Exhibits Exposure to Fatty Liver Food Future Gastrointestinal tract structure Germ-Free Goals Health Hepatic High Density Lipoproteins Immunity Individual Inflammation Inflammatory Inflammatory Response Inhalation Inhalation Exposure Intestines Knockout Mice Knowledge Lead Link Lipid Peroxidation Lipids Lipoproteins Liver Liver diseases Low-Density Lipoproteins Lung Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolism Morbidity - disease rate Mus Myocardial Infarction Oral Oral Administration Oral Ingestion Oropharyngeal Oxidative Stress PPAR alpha Particulate Matter Pathogenicity Pathologic Pathway interactions Phase Plasma Play Preventive Process Property Public Health Publishing Reporting Research Risk Role Stroke Testing Therapeutic Tissues Toxic effect Treatment Efficacy Triglycerides Water Western World atherogenesis base cardiometabolism cardiovascular health design dysbiosis fatty acid oxidation gastrointestinal gut microbiome gut microbiota lipid metabolism microbiome microbiota mortality novel oxidation particle particle exposure prevent stem ultrafine particle vascular inflammation volatile organic compound

项目摘要

ABSTRACT Cumulative epidemiological and experimental data have shown that exposure to ambient particulate matter (PM) leads to increased cardiovascular morbidity and mortality. A causal association between PM exposure and atherosclerosis has been established. Unfortunately, the pathogenic mechanisms remain unknown preventing the development of effective therapeutic strategies. We have found that exposures to ultrafine particles (UFP, PM with an aerodynamic diameter < 0.2 µm) and diesel exhaust lead to increased lipid peroxidation in the lungs and systemic tissues, accompanied by dyslipidemia and a proatherogenic plasma lipoprotein profile, consisting of LDL particles more susceptible to oxidation and dysfunctional HDL particles with loss of their vascular protective properties. However, the mechanisms by which inhalation of UFP lead to effects in the systemic vasculature remain unknown. We and others have shown that exposure to PM lead to marked changes in the gut microbiome, which is known to modulate host metabolism, immunity, and inflammatory responses resulting in pathological conditions, including cardiovascular diseases. This project will evaluate whether a novel microbome-mediated gastrointestinal (GI) pathway mediates PM-induced dyslipidemia and atherosclerosis. Our preliminary data indicate that oral administration of UFP or inhaled diesel exhaust induces changes in gut microbiota diversity, which associates with lipid oxidation in the intestines and blood, dyslipidemia, and liver steatosis together with decreased expression of hepatic PPARα, which may mediate some of the UFP-mediated cardiometabolic actions. Our central hypothesis is that inhalation exposure to ambient UFP induces dyslipidemia and atherosclerosis partly due to changes in gut microbiota composition that lead to dysregulation of PPARα in the liver. We will test this hypothesis via three specific aims: 1) To determine the changes in gut microbiota composition following pulmonary exposure to ultrafine PM. We will perform both UFP inhalation and oral gavage studies to characterize the relative changes in microbiota in Ldlr KO and C57BL/6 mice. 2) To examine whether UFP-induced dyslipidemia and atherosclerosis are mediated by the gut microbiome. The microbiota of UFP-exposed mice will be transferred into germ-free and antibiotic-treated Ldlr KO and C57BL/6 recipients to establish a causal link between UFP- induced gut microbiota effects, lipid metabolism, and atherosclerosis. 3) To determine whether UFP-mediated changes in gut microbiota promote lipid metabolic effects and atherosclerosis via modulation of PPARα expression in the liver. We will determine if UFP-induced changes in hepatic PPARα mediate effects induced by UFP exposure on lipid and atherosclerosis using PPARα KO mice. The results are expected to enhance our understanding of a novel gut microbiome-mediated pathway by which UFP induce adverse systemic effects. If successful, results derived from this project are expected to have a significant impact in developing preventive and therapeutic efforts to ameliorate the health impact of air pollution.

抽象的累积的流行病学和实验数据表明，暴露于环境颗粒物 (PM) 导致心血管发病率和死亡率增加 PM 暴露之间存在因果关系。不幸的是，动脉粥样硬化的致病机制仍不清楚。我们发现，接触超细颗粒会阻碍有效治疗策略的制定。颗粒物（UFP，空气动力学直径 < 0.2 µm 的 PM）和柴油机尾气导致脂质增加肺部和全身组织的过氧化，伴有血脂异常和促动脉粥样硬化血浆脂蛋白谱，由更容易氧化的 LDL 颗粒和功能失调的 HDL 颗粒组成然而，吸入 UFP 导致血管保护特性丧失的机制。我们和其他人已经证明，接触 PM 会导致全身脉管系统的影响。肠道微生物组发生显着变化，众所周知，肠道微生物组可以调节宿主代谢、免疫和炎症反应导致病理状况，包括心血管疾病。评估一种新的微生物介导的胃肠道 (GI) 途径是否介导 PM 诱导的我们的初步数据表明，口服或吸入UFP可治疗血脂异常和动脉粥样硬化。柴油机尾气会引起肠道微生物群多样性的变化，这与肠道中的脂质氧化有关肠道和血液、血脂异常、肝脏脂肪变性以及肝脏 PPARα 表达降低，它可能介导一些 UFP 介导的心脏代谢行为。吸入暴露于环境 UFP 会诱发血脂异常和动脉粥样硬化，部分原因是肠道变化导致肝脏 PPARα 失调的微生物群组成我们将通过三个方面来检验这一假设。具体目标： 1) 确定肺部暴露后肠道微生物群组成的变化我们将进行 UFP 吸入和口服灌胃研究来表征相对变化。 2) 检查 UFP 是否诱导血脂异常和动脉粥样硬化是由肠道微生物介导的，暴露于 UFP 的小鼠的微生物群将会发生转移。进入无菌且经过抗生素治疗的 Ldlr KO 和 C57BL/6 受体，以建立 UFP- 肠道诱导的微生物群影响、脂质代谢和动脉粥样硬化 3) 确定 UFP 是否介导。肠道微生物群的变化通过调节 PPARα 促进脂质代谢效应和动脉粥样硬化我们将确定 UFP 诱导的肝脏 PPARα 变化是否介导诱导效应。通过使用 PPARα KO 小鼠进行 UFP 暴露对脂质和动脉粥样硬化的影响，预计结果将增强我们的研究成果。了解 UFP 诱导不良全身效应的新型肠道微生物介导途径。该项目取得成功，预计将对制定预防性措施产生重大影响以及改善空气污染对健康影响的治疗努力。