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 病毒直接靶向并大量消耗肠道 CD4+ T 细胞，因此 HIV 感染为研究适应性免疫在塑造人类肠道（微生物群）微生物组成中的作用提供了独特的机会。我们和其他人发现，艾滋病毒感染者的肠道微生物群组成发生了深刻的改变，并且具有高度特征性，这与适应性免疫在决定哪些细菌能够成功定植方面发挥着核心作用的观点相一致。微生物群失衡（生态失调）与代谢疾病有关，HIV 感染者通常存在代谢异常，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、四肢和臀部脂肪萎缩，伴或不伴内脏脂肪堆积）有关。然而，并非所有接受抗逆转录病毒治疗的人都会患上疾病，而且其他影响因素尚不清楚。我们观察到，肠道微生物群通常不会恢复到长期接受 ART 的健康美国成年人的典型状态，这表明肠道微生物群有可能导致 ART 相关疾病的病理学。在本次拨款的具体目标 (SA)1 中，我们将对接受或未接受 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高通量测序，以确定患有代谢性疾病的个体是否更有可能患有 HIV 相关的生态失调和肠道炎症。 SA2 和 SA3 的目标是超越建立肠道微生物群与 HIV 感染代谢疾病之间的关联，以了解潜在的机制。我们要解决的核心问题是 1) 为什么 HIV 感染会导致我们观察到的特定微生物群组成变化？ 2）这些成分变化可能驱动代谢疾病的机制是什么？ 3）涉及哪些具体的分子因素？为此，我们将通过识别在其基因组 (SA2) 中选择的基因/操纵子，并通过实验确定其免疫调节特性，探索 HIV 感染和 LD 的相对丰度不同的细菌物种的特性。 SA3）。我们的初步数据表明，依赖于 FoxP3+ CD4+ T 调节细胞 (Treg) 诱导而持续存在的有益“共生”细菌会随着 HIV 感染而优先消失。我们假设 这可能反过来导致促炎细菌的生长、慢性炎症和代谢疾病的发展。因此，我们期望发现缺乏 HIV 感染和/或 LD 的物种更有可能刺激 Treg，并且更有可能在其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毒力相关因子。这项工作将确定肠道炎症细菌驱动因素/抑制因素的增加/减少是否会导致艾滋病毒感染者的代谢疾病。