The role of the enteric microbiome in chronic HIV pathogenesis and cardiovascular disease in HIV-infected individuals

肠道微生物组在艾滋病毒感染者慢性艾滋病发病机制和心血管疾病中的作用

• 批准号: 9271428
• 负责人: David Benjamin Gootenberg
• 金额: $ 4.68万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271428
• 关键词: Address; Adenoviruses; Affect; Africa South of the Sahara; African; Archaea; Atherosclerosis; Bacteria; Bile Acids; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell model; Cells; Cessation of life; Chronic; Clinical; Coculture Techniques; Collection; Communities; Data; Data Set; Development; Diabetes Mellitus; Disease; Disease Outcome; Enteral; Epithelial; Feces; Foam Cells; Functional disorder; Goals; HIV; HIV Infections; HIV Seropositivity; Health; High-Throughput Nucleotide Sequencing; Human; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Intestines; Kidney; Lactobacillus; Lead; Lecithin; Life Expectancy; Link; Lipids; Longevity; Macrophage Activation; Measurement; Measures; Mediating; Metabolic; Metadata; Methods; Microbe; Modeling; Monitor; Mus; Obesity; Organism; Outcome; Parasites; Participant; Pathogenesis; Pathology; Patients; Permeability; Physiological; Platelet Activation; Population; Production; Quality of life; Reporting; Research Personnel; Role; Serum; Serum Markers; Symbiosis; System; Therapeutic Intervention; Thrombosis; Training; Transplantation; Ursidae Family; Viral; Virus; Work; antiretroviral therapy; career; cohort; computerized tools; cytokine; dietary constituent; effective therapy; gut microbiome; immune activation; improved; in vivo; in vivo Model; interest; intimal medial thickening; macrophage; microbial; microbial community; microbiome; microbiota; mortality; mouse model; novel; pathogenic bacteria; trimethyloxamine

Project Summary/Abstract Even with antiretroviral therapy, Human Immunodeficiency Virus (HIV)-infected individuals still have a greater mortality than uninfected individuals, mostly due to death from inflammation-related non-communicable diseases (NCD), such as cardiovascular disease (CVD) and kidney dysfunction. The drivers of this chronic immune activation and associated CVD remain largely unknown. Recent studies have shown that there might be significant HIV-associated disruptions in the gut microbial community, which is essential to human health and is involved in many metabolic and immune interactions. Our preliminary data from Sub-Saharan African populations, which bear a great burden of HIV and associated CVD, suggest that there are clear shifts in this microbial community and that these correspond to increased measures of systemic inflammation. Independent of HIV, changes in the gut microbial community have been shown to produce inflammatory metabolites that cause macrophage and platelet activation, thrombosis, and arterial plaque formation. We propose to study HIV-associated gut microbial changes in Sub-Saharan African populations and measure systemic immune activation and cardiovascular outcomes associated with these changes. We will then use in vitro and in vivo models to investigate the causative relationship between HIV-associated gut microbial community changes and CVD. To accomplish this goal, we will expose gut cell models to HIV-associated microbes of interest and measure the inflammatory response to these organisms. We will also transplant mouse models of atherosclerosis with stool microbial communities and then quantify the development of CVD induced by these communities. It is our hope that this work will identify mechanisms by which the gut microbial community might contribute to CVD pathogenesis in chronic HIV and provide opportunities for therapeutic interventions to extend lifespan and improve quality of life for HIV-infected individuals.

项目摘要/摘要 即使接受抗逆转录病毒疗法，人类免疫缺陷病毒（HIV）感染的个体仍然具有更大的 死亡率比未感染的个体，主要是由于与炎症相关的非传染性的死亡。 疾病（NCD），例如心血管疾病（CVD）和肾功能障碍。这个慢性的驱动力 免疫激活和相关的CVD在很大程度上仍然未知。最近的研究表明，可能 在肠道微生物群落中要大量与艾滋病毒相关的干扰，这对于人类健康至关重要 并参与许多代谢和免疫相互作用。我们来自撒哈拉以南非洲的初步数据 人口承担着艾滋病毒和相关CVD的重大负担，这表明这有明显的转变 微生物群落，这些对应于增加全身炎症的度量。独立的 在艾滋病毒中，肠道微生物群落的变化已被证明会产生炎症代谢产物 导致巨噬细胞和血小板激活，血栓形成和动脉斑块形成。我们建议学习 撒哈拉以南非洲人群中与HIV相关的肠道微生物变化并测量全身免疫 这些变化相关的激活和心血管结局。然后，我们将在体外和体内使用 研究与HIV相关的肠道微生物社区变化之间的因果关系的模型 和CVD。为了实现这一目标，我们将使肠道细胞模型暴露于感兴趣的艾滋病毒相关的微生物和 测量对这些生物的炎症反应。我们还将移植鼠标的模型 粪便微生物群落的动脉粥样硬化，然后量化这些诱导的CVD的发展 社区。我们希望这项工作将确定肠道微生物社区可能的机制 有助于慢性艾滋病毒的CVD发病机理，并为治疗干预提供机会 延长寿命并改善艾滋病毒感染者的生活质量。