The enteric microbiome in HIV-associated chronic immune activation and cardiovascular disease

HIV相关慢性免疫激活和心血管疾病中的肠道微生物群

• 批准号: 9384899
• 负责人: Scott A. Handley
• 金额: $ 52.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384899
• 关键词: Address; Africa South of the Sahara; African; Animals; Ankle; Archaea; Atherosclerosis; Autoimmunity; Bacteria; Bacterial Translocation; Bile Acids; Biological Models; Blood Vessels; Botswana; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chronic; Clinical; Coculture Techniques; Collection; Communities; Data; Development; Diabetes Mellitus; Disease; Enteral; Enterobacteriaceae; Epithelial; Feces; Foam Cells; Functional disorder; Goals; HIV; HIV Infections; HIV Seropositivity; Health; High-Throughput Nucleotide Sequencing; Human; Immune; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Investigation; Kidney; Lactobacillus; Lead; Lecithin; Life Expectancy; Link; Lipid-Laden Macrophage; Lipids; Longevity; Macrophage Activation; Measures; Metabolic; Metadata; Metagenomics; Microbe; Modeling; Modernization; Organism; Outcome; Parasites; Participant; Pathogenesis; Pathology; Patients; Persons; Platelet Activation; Population; Prevalence; Process; Publishing; Quality of life; Reporting; Research Personnel; Role; Serum; Serum Markers; Structure; Symbiosis; Technology; Therapeutic Intervention; Thrombosis; Transplantation; Uganda; Viral; Virus; Work; antiretroviral therapy; atherogenesis; cardiovascular disorder risk; cohort; dietary constituent; effective therapy; enteric adenovirus infection; fungus; gut microbiome; immune activation; immune function; immunological status; improved; in vitro Assay; in vivo; in vivo Model; indexing; interest; intimal medial thickening; microbial; microbial community; microbiome; microbiota; mortality; mouse model; novel therapeutic intervention; pathogenic bacteria; success; trimethyloxamine

Project Summary Despite the success of antiretroviral therapy (ART), individuals infected with Human Immunodeficiency Virus (HIV) still have a greater mortality than those who are uninfected, mostly due to death from inflammation- related non-communicable diseases (NCDs), 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 HIV infection results in disruptions in the gut microbial community and these alterations are associated with gut barrier dysfunction, bacterial translocation, and systemic immune activation. However, published studies have primarily examined populations in the developed world, even though the greatest burden of HIV-infection and associated CVD exists in the developing world. We remain the only group to report on HIV-associated changes in the gut microbiome in populations living in sub-Saharan Africa. Our published studies and preliminary data indicate that there are clear shifts in the gut microbiome, both bacterial and viral, with HIV-infection 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 two sub-Saharan African populations and measure systemic immune activation and cardiovascular outcomes associated with these changes. These studies will identify microbial candidates that we will then use in in vitro and in vivo models to investigate the causative relationship between HIV-associated gut microbial community changes and CVD. We will expose gut and vascular cells to HIV- associated microbes of interest and measure the inflammatory response to these organisms. We will also use an established murine model of atherosclerosis to transplant candidate microbes and/or stool communities into animals to characterize the development of CVD induced by these microbes. The specific aims of this project are to: 1) Determine the associations between changes in enteric microbial communities, increased immune activation, and cardiovascular disease in HIV-infected individuals in sub-Saharan Africa and 2) Utilize both in vitro and in vivo models to assess mechanisms by which HIV-associated enteric microbial communities promote chronic inflammation and cardiovascular disease. The goal of the proposed work is to identify specific mechanisms by which HIV-associated alterations in the gut microbiome (including bacteria, viruses, fungi and parasites) contribute to CVD pathogenesis in chronic HIV infection and help inform the development of new therapeutic interventions that leverage the gut microbiome to extend lifespan and improve quality of life for HIV-infected individuals.

项目摘要 尽管抗逆转录病毒疗法(ART)取得了成功，但感染人类免疫缺陷病毒的人 (艾滋病毒)的死亡率仍然高于未感染的人，主要是由于炎症死亡- 相关的非传染性疾病，如心血管疾病和肾功能不全。 这种慢性免疫激活和相关的心血管疾病的驱动因素在很大程度上仍不清楚。最新研究 已经表明，艾滋病毒感染会导致肠道微生物群落的破坏，这些变化是 与肠道屏障功能障碍、细菌易位和全身免疫激活有关。然而， 已发表的研究主要考察了发达国家的人口，尽管最大的 发展中世界存在艾滋病毒感染和相关心血管疾病的负担。我们仍然是唯一一个报道 关于生活在撒哈拉以南非洲的人群肠道微生物群中与艾滋病毒相关的变化。我们出版的 研究和初步数据表明，肠道微生物群有明显的变化，包括细菌和病毒， 这与艾滋病毒感染有关，这与全身炎症的措施增加相对应。独立于 HIV，肠道微生物群落的变化已被证明会产生炎性代谢产物， 导致巨噬细胞和血小板活化、血栓形成和动脉斑块形成。我们建议研究 撒哈拉以南非洲两个人群中HIV相关肠道微生物的变化和系统免疫的测量 与这些变化相关的激活和心血管结果。这些研究将确定微生物 然后我们将在体外和体内模型中使用候选对象来研究 HIV相关肠道微生物群落变化与心血管疾病。我们将使肠道和血管细胞暴露于艾滋病毒- 相关的感兴趣微生物，并测量对这些微生物的炎症反应。我们还将使用 建立动脉粥样硬化的小鼠模型，将候选微生物和/或粪便群落移植到 来描述这些微生物引起的心血管疾病的发展。这个项目的具体目标是 是为了：1)确定肠道微生物群落的变化、增强的免疫力 撒哈拉以南非洲艾滋病毒感染者的激活和心血管疾病和2) 在以下两个方面同时利用 评估HIV相关肠道微生物群落机制的体外和体内模型 促进慢性炎症和心血管疾病。 拟议工作的目标是确定具体的 肠道微生物组(包括细菌、病毒、真菌和 寄生虫)在慢性HIV感染的心血管疾病发病机制中的作用，并有助于了解新的 利用肠道微生物群延长生命并提高患者生活质量的治疗干预措施 感染艾滋病毒的人。