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

总结 该项目将构成表征微生物组和内源性大麻素系统的人类研究 (ECS)艾滋病毒感染者（PWH）以及它们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，我们提出肠道的改变 微生物群（生态失调）和受损的肠道屏障完整性（肠道渗漏）是ECS和 神经炎症和血脑屏障功能障碍。我们的主要目标是（1）表征肠道微生物群， ECS在PWH和无HIV的人（PWoH）中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（先天性、适应性、T细胞、B细胞）的模式 流体（CSF）响应于受控大麻暴露;（3）评估大麻素暴露对这些 模式以及它们如何通过ECS，肠道微生物群和肠道屏障功能的变化介导。我们 将对50名PWH和50名PWO H进行临床试验，以随机、交叉方式暴露14天 口服THC和CBD的每一种，以确定用植物大麻素治疗是否减少炎症， 改善肠道功能。实验方法将使用粪便幕府宏基因组测序， 表征肠道微生物组，特别注意耐氧细菌，促炎物种， 普氏菌属，双歧杆菌和拟杆菌属。和丁酸盐产生菌。我们将评估如何 微生物群和肠道渗漏与神经炎症和受损的BBB功能有关，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CD 4 + T细胞正常化 消耗、漏肠、生态失调、慢性肠道炎症和微生物抗原易位（MAT）。这些 改变最终驱动全身和CNS炎症。肠道屏障功能受损，原因是 紧密连接、细胞凋亡和上皮细胞增殖和修复的减少使PWH对增加的 组织暴露于肠道微生物群产生的促炎配体，在HIV中很重要 神经发病机制特别相关的是最近的发现，大肠中的ECS相互作用， 与肠道微生物群一起调节上皮屏障通透性。因此，大麻的成分，通过 肠道EC系统，可能是治疗性的，现有的文献表明，两个主要成分的 大麻、Δ9-四氢大麻酚（THC）和大麻二酚（CBD）对ECS具有不同的作用。

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.