Role of Microbial dysbiosis and altered metabolomics in the context of Opioid abuse and ART in HIV disease progression

阿片类药物滥用和 ART 背景下微生物失调和代谢组学改变在 HIV 疾病进展中的作用

• 批准号: 9253611
• 负责人: Sabita Roy
• 金额: $ 59.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253611
• 关键词: Acquired Immunodeficiency Syndrome; Adaptive Immune System; Adult; Animals; Anti-Retroviral Agents; Antibiotics; Attenuated; Automobile Driving; Bacterial Translocation; Bile Acids; Biological Markers; CD4 Positive T Lymphocytes; Chronic; Data; Development; Disease; Disease Progression; Drug abuse; Epidemic; Genes; Germ-Free; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Health; Heroin; Homeostasis; Individual; Inflammation; Inflammatory; Intestines; Intravenous; Knowledge; Life Expectancy; Lipids; Metabolic; Metabolic Pathway; Metabolism; Microbe; Modernization; Morbidity - disease rate; Morphine; Opioid; Patients; Peripheral; Pharmaceutical Preparations; Play; Population; Probiotics; Process; Reporting; Residual state; Ribosomes; Role; Substance abuse problem; Therapeutic; Treatment Protocols; gut microbiome; gut microbiota; humanized mouse; immune activation; immune function; inflammatory marker; metabolome; metabolomics; microbial; microbiome; microbiota; microorganism interaction; mortality; mouse model; novel; novel therapeutic intervention; opioid abuse; restoration; statistics

Abstract/Project Summary Gut leakiness, microbial translocation and systemic inflammation are hallmarks of HIV disease progression. Interestingly, chronic opioid abuse is also well documented to induce gut leakiness and sustained systemic inflammation. HIV patients that use intravenous heroin display accelerated HIV disease progression. Although HIV replication is suppressed in HIV-infected adults on modern ART regimens microbial translocation continues long after peripheral CD4+ T cell restoration. The resulting activation of both the innate and adaptive immune systems in ART treated HIV individuals is reported to be associated with markers of inflammation and is an independent predictor of morbidity and mortality. The role of ART in driving the inflammatory process has not been documented. Thus far, very little is known regarding the underlying mechanisms that contribute to gut leakiness and microbial translocation in either opioid abusers or in HIV patients that are on ART. Increasing number of studies strongly support the concept that the gut microbiota, play a significant role in maintaining gut homeostasis and gut barrier function. Under both homeostatic and disease conditions the microbiota influences immune function in several ways, including the release of metabolites and direct microbial interactions. Although a few studies have correlated the host microbiome in HIV infected patients with the metabolome, the interaction between the ``omics'' level analysis and the gut barrier function in the context of antiretroviral treatment (ART) still remain largely unexplored. There is no data on the interaction of the microbiome-metabolome-gut barrier in HIV patients in the context of opioid abuse. The goal of this study is to develop an integrated pipeline for identifying novel connections between the microbiome-metabolome and gut barrier function following HIV infection and HIV infection in the context of Drug Abuse. We will further investigate if treatment with ART restores homeostasis or exacerbates dysbiosis. Specific Aim 1: a) Identification of unique biomarkers and signature profiles in the gut microbiome that are associated with HIV disease progression in the context of opioid abuse and ART b) Determine if altered signature profiles is associated with metabolic consequences and immune activation. Specific Aim 2. Establish a causal relationship between gut dysbiosis, altered metabolome and barrier disruption following HIV infection and in the context of opioid drug abuse and ART using germ free and antibiotic treated humanized mice. Specific Aim 3. Establish that Probiotics will restore gut homeostasis and delay HIV disease progression in the context of opioid abuse and ART. The results from these studies will allow for the development of a pipeline for new therapeutic strategies to attenuate immune activation and reverse HIV disease progression both in HIV infected patients and in HIV infected drug abusing population.

摘要/项目摘要 肠道渗漏、微生物易位和全身炎症是艾滋病毒疾病进展的标志。 有趣的是，慢性阿片类药物滥用也有充分证据表明会导致肠道渗漏和持续的全身性中毒。 炎。使用静脉注射海洛因的艾滋病毒患者表现出加速艾滋病毒疾病进展。虽然 采用现代 ART 疗法微生物易位的 HIV 感染成人中的 HIV 复制受到抑制 外周 CD4+ T 细胞恢复后仍持续很长时间。由此产生的先天性和适应性的激活 据报道，接受 ART 治疗的 HIV 个体的免疫系统与炎症和炎症标志物有关。 是发病率和死亡率的独立预测因子。 ART 在驱动炎症过程中的作用 没有被记录。迄今为止，人们对导致这一现象的潜在机制知之甚少。 阿片类药物滥用者或接受 ART 的 HIV 患者的肠道渗漏和微生物易位。 越来越多的研究强烈支持肠道微生物群在 维持肠道稳态和肠道屏障功能。在稳态和疾病条件下 微生物群通过多种方式影响免疫功能，包括代谢物的释放和直接作用 微生物相互作用。尽管一些研究将 HIV 感染患者的宿主微生物组与 代谢组、“组学”水平分析与背景下肠道屏障功能之间的相互作用 抗逆转录病毒治疗（ART）的作用在很大程度上仍未得到探索。没有关于相互作用的数据 阿片类药物滥用背景下艾滋病毒患者的微生物组-代谢组-肠道屏障。这项研究的目标是 开发一个综合管道来识别微生物组-代谢组和肠道之间的新联系 HIV 感染后和药物滥用情况下 HIV 感染后的屏障功能。我们将进一步 研究 ART 治疗是否可以恢复体内平衡或加剧生态失调。 具体目标 1：a) 鉴定肠道微生物组中独特的生物标志物和特征谱 b) 确定是否改变与阿片类药物滥用和 ART 背景下的 HIV 疾病进展相关 特征谱与代谢后果和免疫激活相关。 具体目标 2. 建立肠道菌群失调、代谢组改变和屏障之间的因果关系 HIV 感染后以及阿片类药物滥用和使用无菌和 ART 的情况下的破坏 抗生素治疗人源化小鼠。 具体目标 3. 确定益生菌能够恢复肠道稳态并延缓 HIV 疾病进展 阿片类药物滥用和 ART 的背景。 这些研究的结果将有助于开发新的治疗策略 减弱 HIV 感染者和 HIV 患者的免疫激活并逆转 HIV 疾病进展 受感染的吸毒人群。