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：
10462104
负责人：
Jesus Antonio Araujo
金额：
$ 6.73万
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：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10462104
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 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 therapeutically effective 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.

抽象的累积流行病学和实验数据表明，暴露于环境特定物质（PM）导致心血管发病率和死亡率增加。 PM暴露之间的因果关系并建立了动脉粥样硬化。不幸的是，致病机制仍然未知防止开发有效的治疗策略。我们发现对超细的暴露颗粒（UFP，PM，空气动力学直径<0.2 µm）和柴油排气导致脂质增加肺和全身组织的过氧化，伴有血脂异常和促性血浆脂蛋白剖面，由LDL颗粒组成，更容易氧化和功能失调的HDL颗粒随着其血管保护特性的丧失。但是，吸入UFP的机制导致系统性脉管系统的影响仍然未知。我们和其他人表明，暴露于PM导致肠道微生物组的明显变化，该体系已知会调节宿主代谢，免疫学和炎症反应导致病理状况，包括心血管疾病。这个项目将评估新型微生物组介导的胃肠道（GI）途径是否介导PM诱导的血脂血症和动脉粥样硬化。我们的初步数据表明口服UFP或继承柴油排气诱导肠道菌群多样性的变化，这与脂质氧化相关肠道和血液，血脂异常和肝脏脂肪变性以及肝PPARα表达的改善，这可能介导一些UFP介导的心脏代谢作用。我们的中心假设是吸入暴露于环境UFP会诱导血脂异常和动脉粥样硬化，部分原因是肠道的变化导致肝脏PPARα失调的微生物群组成。我们将通过三个具体目的：1）确定肺暴露后肠道菌群组成的变化 Ultrafine PM。我们将同时执行UFP吸入和口服瘤研究，以表征相对变化在LDLR KO和C57BL/6小鼠中的微生物群中。 2）检查UFP诱导的血脂异常和动脉粥样硬化是由肠道微生物组介导的。 UFP暴露的小鼠的微生物群将被转移进入无菌和抗生素处理的LDLR KO和C57BL/6受体，以在UFP-之间建立因果关系诱导的肠道菌群作用，脂质代谢和动脉粥样硬化。 3）确定UFP介导的是否肠道微生物群的变化通过调节来促进脂质代谢作用和动脉粥样硬化在肝脏中的表达。我们将确定UFP诱导的肝PPARα的变化是否介导了诱导的效果使用PPARαKO小鼠在脂质和动脉粥样硬化上暴露于UFP。结果有望增强我们的了解一种新型肠道微生物组介导的途径，UFP会诱导不良全身效应。如果预计成功的，从该项目获得的结果将对预防性产生重大影响以及改善空气污染的健康影响的治疗努力。