This project will characterize the microbiome and endocannabinoid system (ECS) in people with HIV (PWH) and how they relate to neuroinflammation and blood-brain barrier (BBB) function. The study hypothesizes that pathogenic alterations in the gut microbiota (dysbiosis) and impaired gut barrier integrity (leaky gut) are mediators between the ECS, neuroinflammation and BBB dysfunction in HIV. The 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. The investigators 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 shotgun 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 central nervous system (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 cluster of differentiation 4 (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 EC systems in the gut, brain and immune system, may be therapeutic. The existing literature suggests that the two principal constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have differential effects on the ECS.
This study has the potential to contribute to a more complete understanding of the independent and combined effects of cannabis use and HIV on the brain and on inflammation. Such knowledge may inform future strategies for treating brain disease and inflammation. Participants will be randomly assigned to one of two groups, both of which will receive the same treatment in a different order over a period of about 6 weeks. The visits include physical examinations, blood tests, and other procedures designed to monitor subject safety and measure the effects of the study drug.