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

大麻二酚和四氢大麻酚对 HIV 微生物组、内源性大麻素和神经炎症的影响

基本信息

批准号：
10634642
负责人：
RONALD J. ELLIS
金额：
$ 89.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634642
关键词：
Apoptosis Attention Authorization documentation B-Lymphocytes Bacteria Bacteroides Bifidobacterium Biological Markers Blood Blood - brain barrier anatomy Blood brain barrier dysfunction Butyrates CD4 Positive T Lymphocytes CNR2 gene Cannabidiol Cannabinoids Cannabis Cellular Immunology Cerebrospinal Fluid Chronic Clinical Clinical Investigator Clinical Trials Conduct Clinical Trials Controlled Clinical Trials Data Disease Dronabinol Endocannabinoids Epidiolex Epithelial Cell Proliferation Epithelium Exposure to Formulation Functional disorder Gastrointestinal tract structure Goals HIV Human Immunologist Impairment Inflammation Inflammation Mediators Inflammatory Intervention Studies Intestinal permeability Large Intestine Leaky Gut Ligands Link Literature Lymphocyte Lymphoid Tissue Measures Mediating Mediation Mediator Modeling Multiple Sclerosis Neurologist Neuropathogenesis Oral Oral Administration Outcome Outcome Measure Pathway interactions Pattern Permeability Persons Pharmaceutical Preparations Predisposition Prevotella Production Publishing Randomized Research Research Personnel Syndrome System T-Cell Depletion T-Lymphocyte Tetrahydrocannabinol Therapeutic Tight Junctions Tissues Viral Work antiretroviral therapy authority blood-brain barrier function blood-brain barrier permeabilization cannabinoid receptor dysbiosis efficacy evaluation endogenous cannabinoid system exogenous cannabinoid experience gut dysbiosis gut inflammation gut microbiome gut microbiota improved marijuana use metagenomic sequencing microbial microbiome microbiota microorganism antigen monocyte neuroinflammation phytocannabinoid preclinical study remediation repaired response

项目摘要

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.

总结