Factors mediating gut microbiota dysbiosis and metabolic disease in HIV patients

HIV患者肠道菌群失调和代谢性疾病的介导因素

• 批准号: 9117527
• 负责人: Catherine Lozupone
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117527
• 关键词: Address; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Bacteroides; Bacteroides fragilis; Biopsy; Biopsy Specimen; Blood; Buttocks; CD4 Positive T Lymphocytes; Cell Communication; Cells; Characteristics; Chronic; Colitis; Data; Development; Diet; Disease; Face; Fatty acid glycerol esters; Genes; Genome; Goals; Grant; Gut associated lymphoid tissue; HIV; HIV Infections; HIV Seropositivity; Health; High Density Lipoprotein Cholesterol; High Fat Diet; High Prevalence; High-Throughput Nucleotide Sequencing; Human; Hypertriglyceridemia; Immune; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory disease of the intestine; Informatics; Insulin Resistance; Interleukin-10; Lamina Propria; Lead; Limb structure; Link; Lipids; Lipoatrophy; Lipodystrophy; Measures; Mediating; Metabolic; Metabolic Activation; Metabolic Diseases; Metabolic Marker; Microbe; Modeling; Molecular; Mononuclear; Mucous Membrane; Mus; Operon; Pathologic; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Polysaccharides; Population; Prevotella; Property; RNA, Ribosomal, 16S; Regulatory T-Lymphocyte; Role; Sampling; Shapes; T cell response; T-Lymphocyte; Testing; Tissues; Triglycerides; Virulence; Visceral; Work; adaptive immunity; antiretroviral therapy; commensal microbes; cytokine; gut microbiota; immune activation; inflammatory marker; macrophage; microbiota; monocyte; therapeutic target

DESCRIPTION (provided by applicant): Since the HIV virus directly targets and substantially depletes gut CD4+ T cells, HIV infection provides a unique opportunity to study the role of adaptive immunity in shaping the composition of microbes that colonize the gut (the microbiota) in humans. Consistent with the notion that adaptive immunity plays a central role in determining which bacteria will successfully colonize, we and others have found that HIV-infected individuals have profoundly altered and highly characteristic gut microbiota composition. Microbiota inbalance (dysbiosis) has been associated with metabolic disease, and HIV-infected individuals often have metabolic abnormalities including hypertriglyceridemia, low high-density lipoprotein cholesterol, and insulin resistance. Antiretroviral therapy (ART) drugs are associated with these abnormalities and with lipodystrophy (LD; lipoatrophy in the face, extremities and buttocks with or without visceral fat accumulation). However not everyone on ART develops disease and other contributing factors are not well understood. We observed that gut microbiota is often not restored to a state typical of healthy US adults with long-term ART, indicating a potential to contribute to the pathology of ART-linked diseases. In Specific Aim (SA)1 of this grant, we will use high-throughput sequencing of fecal and rectosigmoid biopsy samples from HIV-positive subjects with and without LD and ART to determine whether individuals with metabolic disease will more likely have HIV-associated dysbiosis and gut inflammation. The goal of SA2 and SA3 is to go beyond the establishment of an association between gut microbiota and metabolic disease in HIV infection to understand underlying mechanisms. Central questions that we will address are 1) Why does HIV infection lead to the specific microbiota compositional changes that we observe? 2) What is the mechanism by which these compositional changes may drive metabolic disease? 3) What specific molecular factors are involved? To do this we will explore the properties of bacterial species that differ in relative abundance with HIV infection and LD, both by identifying genes/operons that are selected for in their genomes (SA2), and by experimental determination of their immune-modulatory properties (SA3). Our preliminary data suggest that beneficial "symbiotic" bacteria that depend on the induction of FoxP3+ CD4+ T regulatory cells (Tregs) for persistence are preferentially lost with HIV infection. We hypothesize that this may in turn lead to the outgrowth of pro-inflammatory bacteria, chronic inflammation and the development of metabolic disease. Thus, we expect to find that species depleted with HIV infection and/or LD will more likely stimulate Tregs and will more likely have known Treg inducing molecular factors in their genomes. Conversely we expect that HIV and LD-associated species will stimulate relatively high levels of pro-inflammatory cytokines and will have a selection for virulence-associated factors in their genomes. This work will establish whether gain/loss of bacterial drivers/suppressors of inflammation in the gut contributes to metabolic disease in HIV-infected individuals.

描述(申请人提供)：由于HIV病毒直接瞄准并大量消耗肠道中的CD4+T细胞，HIV感染提供了一个独特的机会来研究获得性免疫在塑造人类肠道(微生物区系)中的微生物组成中的作用。与适应性免疫在决定哪些细菌将成功定植方面发挥核心作用的概念一致，我们和其他人发现，艾滋病毒感染者的肠道微生物区系组成发生了深刻的变化，具有很高的特征。微生物区系失衡(微生物群失调)与代谢性疾病有关，HIV感染者通常会有代谢异常，包括高甘油三酯血症、低高密度脂蛋白胆固醇和胰岛素抵抗。抗逆转录病毒治疗(ART)药物与这些异常和脂肪营养不良(LD；面部、肢体和臀部的脂肪萎缩，伴有或不伴有内脏脂肪堆积)有关。然而，并不是每个接受抗逆转录病毒治疗的人都会患上疾病，其他致病因素也没有得到很好的了解。我们观察到，肠道微生物区系通常不能恢复到长期接受ART的健康美国成年人的典型状态，这表明有可能对ART相关疾病的病理做出贡献。在这项赠款的具体目标(SA)1中，我们将使用高通量测序技术对患有和不患有LD和ART的HIV阳性受试者的粪便和直肠乙状结肠活检样本进行测序，以确定患有代谢性疾病的患者是否更有可能出现HIV相关的生物失调和肠道炎症。SA2和SA3的目标是超越在肠道微生物区系和艾滋病毒感染中的代谢性疾病之间建立联系，以了解潜在的机制。我们将解决的中心问题是：1)为什么艾滋病毒感染会导致我们观察到的特定微生物区系的组成变化？2)这些组成变化可能驱动代谢性疾病的机制是什么？3)涉及哪些特定的分子因素？为此，我们将通过识别在它们基因组中选择的基因/操纵子(SA2)，以及通过实验确定它们的免疫调节特性(SA3)，来探索与艾滋病毒感染和LD相对丰度不同的细菌物种的特性。我们的初步数据表明，依赖于FoxP3+CD4+T调节细胞(Tregs)诱导持续存在的有益“共生”细菌更容易随着HIV感染而丢失。我们假设 这可能反过来导致促炎性细菌的生长、慢性炎症和代谢性疾病的发展。因此，我们希望发现，被HIV感染和/或LD耗尽的物种更有可能刺激Treg，并且更有可能在它们的基因组中具有已知的Treg诱导分子因子。相反，我们预计HIV和LD相关物种将刺激相对较高水平的促炎细胞因子，并在其基因组中选择与毒力相关的因子。这项工作将确定肠道内细菌炎症驱动/抑制因子的获得/丢失是否有助于艾滋病毒感染者的代谢性疾病。