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

摘要 累积的流行病学和实验数据表明，接触环境颗粒物 (PM)导致心血管发病率和死亡率增加。PM暴露与 动脉粥样硬化已经形成。不幸的是，致病机制仍然未知 阻碍了有效治疗策略的发展。我们发现暴露在超细 颗粒（UFP，空气动力学直径< 0.2 µm的PM）和柴油机废气导致脂质增加 肺和全身组织中的过氧化，伴有血脂异常和致动脉粥样硬化血浆 脂蛋白谱，由更易氧化的LDL颗粒和功能障碍的HDL颗粒组成 血管保护功能丧失。然而，吸入UFP导致 对全身血管系统的影响仍然未知。我们和其他人已经表明，接触PM会导致 肠道微生物组的显著变化，已知其调节宿主代谢、免疫力和 炎症反应导致病理状况，包括心血管疾病。该项目将 评估是否有一种新的微生物组介导的胃肠道（GI）途径介导PM诱导的 血脂异常和动脉粥样硬化。我们的初步数据表明，口服UFP或吸入 柴油机尾气诱导肠道微生物群多样性的变化，这与肠道中的脂质氧化有关。 肠和血液、血脂异常和肝脏脂肪变性以及肝脏PPARα表达降低， 其可介导某些UFP介导的心脏代谢作用。我们的核心假设是 吸入暴露于环境UFP诱导血脂异常和动脉粥样硬化部分是由于肠道的变化 微生物群组成，导致肝脏中的PPARα失调。我们将通过以下三个方面来检验这一假设： 具体目的：1）确定肺部暴露于以下物质后肠道微生物群组成的变化： 超细粉末我们将进行UFP吸入和经口灌胃研究，以表征相对变化 在Ldlr KO和C57 BL/6小鼠的微生物群中。2)检查UFP是否诱导血脂异常， 动脉粥样硬化由肠道微生物组介导。UFP暴露小鼠的微生物群将被转移到 无菌和驱虫处理的Ldlr KO和C57 BL/6受体，以建立UFP- 诱导的肠道微生物群效应、脂质代谢和动脉粥样硬化。3)为了确定UFP介导的 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 在肝脏中的表达。我们将确定UFP诱导的肝脏PPARα变化是否介导诱导的效应， 通过UFP暴露对脂质和动脉粥样硬化的影响，使用PPARα KO小鼠。预计结果将提高我们的 了解一种新的肠道微生物组介导的途径，UFP通过该途径诱导不良全身效应。如果 该项目取得的成果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。

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.