Effects of Cannabidiol and Tetrahydrocannabinol on the Microbiome, Endocannabinoids and Neuroinflammation in HIV

摘要 该项目将构成以微生物组和内源性大麻素系统为特征的人类研究 HIV感染者(PWH)的(ECS)及其与神经炎症和血脑屏障(BBB)的关系 功能。基于这里描述的令人兴奋的新的初步发现，我们认为肠道的变化 微生物区系(微生物群失调)和肠道屏障完整性受损(肠漏)是ECS和 HIV患者的神经炎症和血脑屏障功能障碍。我们的主要目标是(1)描述肠道微生物区系和 威斯康星医院和未感染艾滋病毒人群对外源性大麻素暴露的反应；(2) 描述血液和脑脊液中HIV相关炎症(先天、获得性、T细胞、B细胞)的类型 体液(CSF)对受控大麻暴露的反应；(3)评估大麻素暴露对这些因素的影响 模式以及它们是如何通过ECS、肠道微生物区系和肠道屏障功能的变化来调节的。我们 将进行一项临床试验，以随机交叉方式暴露于50PWH和50PWoH，至14天 分别口服THC和CBD以确定使用植物大麻素治疗是否减少炎症和 改善肠道功能。实验方法将使用粪便幕府元基因组测序来 描述肠道微生物群，特别注意耐氧细菌，促炎物种， Prevotea spp.、双歧杆菌和类杆菌。以及产丁酸的细菌。我们将评估如何 微生物区系和肠漏与神经炎症和血脑屏障功能受损有关，后者可能导致 增加中枢神经系统对微生物产生的促炎配体的暴露。这项研究的基本原理是 抗逆转录病毒治疗(ART)的病毒学抑制不能使肠道淋巴组织CD4T细胞正常化 衰竭、肠漏、生物失调、慢性肠炎和微生物抗原易位(MAT)。这些 改变最终会导致全身和中枢神经系统炎症。肠道屏障功能因改变而受损 紧密连接、细胞凋亡和上皮细胞增殖和修复减少使PWH容易增加 肠道微生物区系产生的促炎配体对组织的暴露对HIV很重要 神经发病机制。这里特别相关的是最近的发现，即大肠中的ECS相互作用 与肠道微生物群一起调节上皮屏障的通透性。因此，大麻的成分，通过 肠道EC系统可能具有治疗作用，现有文献表明，肠道EC系统的两个主要成分 大麻，Δ，9-四氢大麻酚(THC)和大麻二酚(CBD)，对ECS有不同的影响。

SUMMARY This project will constitute human research characterizing the microbiome and endocannabinoid system (ECS) in people with HIV (PWH) and how they relate to neuroinflammation and blood-brain barrier (BBB) function. Based on exciting new preliminary findings described here, we propose that alterations in the gut microbiota (dysbiosis) and impaired gut barrier integrity (leaky gut) are mediators between the ECS and neuroinflammation and BBB dysfunction in HIV. Our major goals are to (1) characterize the gut microbiota and ECS in response to exogenous cannabinoid exposure in both PWH and people without HIV (PWoH); (2) characterize patterns of HIV-associated inflammation (innate, adaptive, T-cell, B-cell) in blood and cerebrospinal fluid (CSF) in response to controlled cannabis exposure; (3) assess effects of cannabinoid exposure on these patterns and how they are mediated through changes in the ECS, gut microbiota and gut barrier function. We will perform a clinical trial of 50 PWH and 50 PWoH exposed in a randomized, cross-over fashion to 14 days each of oral THC and CBD to determine if treatment with either phytocannabinoid reduces inflammation and improves gut function. The experimental approach will use fecal shogun metagenomic sequencing to characterize the gut microbiome, with particular attention to aerotolerant bacteria, pro-inflammatory species, Prevotella spp., Bifidobacterium and Bacteroides spp. and butyrate-producing bacteria. We will evaluate how the microbiota and leaky gut relate to neuroinflammation and impaired BBB function, the latter potentially leading to increased CNS exposure to microbially-produced pro-inflammatory ligands. The rationale for the study is that virologic suppression on antiretroviral therapy (ART) does not normalize gut lymphoid tissue CD4+ T cell depletion, leaky gut, dysbiosis, chronic gut inflammation, and microbial antigen translocation (MAT). These alterations ultimately drive systemic and CNS inflammation. Compromised gut barrier function due to altered tight junctions, apoptosis and reduced epithelial cell proliferation and repair render PWH susceptible to increased tissue exposure to pro-inflammatory ligands produced by gut microbiota and are important in HIV neuropathogenesis. Of particular relevance here are recent findings that the ECS in the large intestine interacts with the gut microbiota to regulate epithelial barrier permeability. Thus constituents of cannabis, acting through the gut EC system, may be therapeutic, and the existing literature suggests that the two principal constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have differential effects on the ECS.