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，暴露在环境颗粒物中 (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 动脉粥样硬化已经确立。不幸的是，致病机制仍不清楚。 阻碍制定有效的治疗策略。我们发现暴露在超细粉尘中 颗粒物(空气动力学直径&0.2微米的UFP、PM)和柴油尾气会导致血脂升高 肺部和全身组织中的过氧化反应，并伴有血脂异常和致动脉粥样硬化的血浆 脂蛋白谱，由更易氧化的低密度脂蛋白颗粒和功能失调的高密度脂蛋白颗粒组成 随着它们血管保护性能的丧失。然而，吸入UFP导致 对全身血管系统的影响尚不清楚。我们和其他人已经证明，接触PM会导致 肠道微生物群的显著变化，已知的是调节宿主新陈代谢、免疫力和 导致病理状况的炎症反应，包括心血管疾病。这个项目将 评估一种新的微生物体介导的胃肠道(GI)途径是否介导PM诱导 血脂异常和动脉粥样硬化。我们的初步数据显示口服UFP或吸入UFP 柴油尾气引起肠道微生物区系多样性的变化，这与机体的脂质氧化有关 肠道和血液，血脂异常，肝脏脂肪变性，肝脏PPARα表达降低， 这可能介导了一些UFP介导的心脏代谢作用。我们的中心假设是 吸入暴露于环境中的UFP可导致血脂异常和动脉粥样硬化，部分原因是肠道的改变 导致肝脏中PPARα失调的微生物区系组成。我们将通过三个方面来检验这一假设 具体目标：1)确定肺暴露后肠道微生物区系组成的变化 超细粉末冶金我们将同时进行UFP吸入和口腔灌胃研究，以表征相关变化 在Ldlr KO和C57BL/6小鼠的微生物区系中。2)检测UFP诱导的血脂异常和 动脉粥样硬化是由肠道微生物群介导的。暴露于UFP的小鼠的微生物区系将被转移 无菌和抗生素治疗的Ldlr KO和C57BL/6受体之间的因果联系 诱导肠道微生物区系效应、脂类代谢和动脉粥样硬化。3)确定UFP介导的 肠道微生物区系变化通过调节PPARα促进脂代谢效应和动脉粥样硬化 在肝脏中的表达。我们将确定超微结构蛋白是否会引起肝脏PPARα介导效应的改变 用PPARαKO小鼠通过超氧化物歧化蛋白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 了解一种新的肠道微生物组介导的途径，通过该途径，UFP可引起不良全身效应。如果 成功，从这个项目中得到的结果预计将对制定预防措施产生重大影响 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.