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

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特征。 有趣的是，慢性阿片类药物滥用也被很好地记录下来，会导致肠道渗漏和持续的全身 发炎。静脉注射海洛因的艾滋病毒患者表现出加速了艾滋病毒疾病的进展。虽然 通过现代抗逆转录病毒治疗方案抑制HIV感染者的HIV复制微生物易位 在外周CD4+T细胞恢复后很长时间内持续。由此产生的先天和后天的激活 据报道，接受抗逆转录病毒治疗的HIV患者的免疫系统与炎症和 是发病率和死亡率的独立预测因子。ART在推动炎症过程中的作用有 没有记录在案。到目前为止，人们对导致这种现象的潜在机制知之甚少。 阿片类药物滥用者或正在接受抗逆转录病毒治疗的艾滋病毒患者的肠道渗漏和微生物易位。 越来越多的研究强烈支持这样一个概念，即肠道微生物区系在 维持肠道内环境平衡和肠道屏障功能。在动态平衡和疾病条件下， 微生物区系通过几种方式影响免疫功能，包括代谢产物的释放和直接 微生物相互作用。尽管少数研究已经将HIV感染患者的宿主微生物群与 代谢组、“组学”水平分析与肠道屏障功能之间的相互作用 抗逆转录病毒治疗(ART)的前景在很大程度上仍未得到探索。没有关于两国之间相互作用的数据 阿片类药物滥用背景下艾滋病毒患者的微生物-代谢-肠道屏障。这项研究的目标是 开发一条综合管道，用于识别微生物组代谢组和肠道之间的新联系 艾滋病毒感染后的屏障功能和药物滥用背景下的艾滋病毒感染。我们将进一步 研究抗逆转录病毒治疗是否能恢复体内平衡或加剧生物失调。 具体目标1：a)确定肠道微生物组中符合以下条件的独特生物标志物和特征图谱 与阿片类药物滥用和ART b)相关的艾滋病毒疾病进展 签名特征与新陈代谢和免疫激活有关。 特定目标2.建立肠道生物失调、代谢组改变和屏障之间的因果关系 在艾滋病毒感染后的中断以及在阿片类药物滥用和ART使用无菌和 经过抗生素处理的人源化小鼠。 具体目标3.确定益生菌将恢复肠道内稳态并延缓艾滋病毒疾病进展 阿片类药物滥用和艺术的背景。 这些研究的结果将允许开发一条新的治疗策略的管道 在HIV感染者和HIV患者中减弱免疫激活和逆转HIV疾病进展 被感染的药物滥用人群。

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.