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: 8799703
• 负责人: Catherine Lozupone
• 金额: $ 38.77万
• 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/8799703
• 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; High Density Lipoprotein Cholesterol; High Prevalence; High-Throughput Nucleotide Sequencing; Human; Hypertriglyceridemia; Immune; Immune response; 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; Relative (related person); 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; monocyte; public health relevance; 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（由申请人提供）：由于HIV病毒直接靶向肠道CD4+ T细胞，因此HIV感染提供了一个独特的机会，可以研究适应性免疫在塑造微生物组成的作用，以使肠道（Microtobiota）在人类中。与自适应免疫性在确定哪些细菌将成功定殖的核心作用的观念一致，我们和其他人发现，感染HIV的个体已经深刻改变了且高度特征性的肠道肠道菌群组成。微生物群（营养不良）与代谢性疾病有关，HIV感染的个体通常具有代谢异常，包括高甘油三酸酯血症，低密度脂蛋白胆固醇和胰岛素抵抗。抗逆转录病毒疗法（ART）药物与这些异常以及脂肪营养不良（LD；面部，四肢和臀部的脂肪植物（有或没有内脏脂肪积累）相关。但是，并不是每个人都在艺术发展疾病，而其他促成因素并不能很好地理解。我们观察到，肠道微生物群通常不会恢复到具有长期艺术的健康成年人的典型状态，这表明有可能有助于与ART连接疾病的病理。在该赠款的特定目的（SA）中，我们将使用有或没有LD和ART的HIV阳性受试者的粪便和直肠活检样本的高通量测序来确定患有代谢疾病的人是否可能更有可能患有HIV相关的营养不良和肠炎症。 SA2和SA3的目标是超越肠道菌群与艾滋病毒感染中代谢疾病之间建立关联，以了解基本机制。我们将要解决的中心问题是1）为什么艾滋病毒感染会导致我们观察到的特定微生物群的组成变化？ 2）这些组成变化可能导致代谢疾病的机制是什么？ 3）涉及哪些特定分子因素？为此，我们将通过鉴定在其基因组中选择的基因/操纵子（SA2）以及通过实验确定其免疫调节特性（SA3）（SA3）来探索与HIV感染和LD相对丰度不同的细菌物种的性质。我们的初步数据表明，依赖于Foxp3+ CD4+ T调节细胞（Tregs）持续性的有益的“共生”细菌优先丢失了HIV感染。我们假设 这可能导致促炎细菌，慢性炎症和代谢疾病的发展的生长。因此，我们期望发现，因HIV感染和/或LD耗尽的物种会更有可能刺激Treg，并且更有可能知道Treg在其基因组中诱导分子因子。相反，我们预计艾滋病毒和与LD相关的物种将刺激相对较高的促炎性细胞因子，并在其基因组中选择与毒力相关的因子选择。这项工作将确定肠道炎症的细菌驱动因素/抑制因素是否有助于艾滋病毒感染者的代谢疾病。