Cannabidiol as a treatment for alcoholic liver disease

大麻二酚治疗酒精性肝病

• 批准号: 10753729
• 负责人: WENKE FENG
• 金额: $ 41.13万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753729
• 关键词: Acute; Address; Agonist; Alcoholic Liver Diseases; Alcohols; Aryl Hydrocarbon Receptor; Bacteria; Bacterial Translocation; Caco-2 Cells; Cannabidiol; Cannabinoids; Cannabis; Cells; Childhood; Chronic; Clinical Trials; Data; Development; Disease; Disease model; Dose; Endotoxemia; Epidiolex; Epilepsy; Epithelial Attachment; Fatty Liver; Formulation; Foundations; Functional disorder; G-Protein-Coupled Receptors; GPR3 gene; Hepatic; Immune; Immunologic Surveillance; Inflammation; Injury; Intestines; Intraperitoneal Injections; Knockout Mice; Kupffer Cells; Ligands; Literature; Lymphoid Cell; Mediating; Metabolic; Modeling; Mucous Membrane; Mus; Nuclear Receptors; Oils; Oral; Oral Administration; Orphan; Outcome Study; Oxidative Stress; Pathway interactions; Patients; Preventive; Proteins; Refractory; Reporting; Research; Route; Syndrome; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Tryptophan; United States; United States Food and Drug Administration; alcohol abuse therapy; alcohol exposure; aryl hydrocarbon receptor ligand; beta-arrestin; chronic liver disease; claudin-1 protein; design; dysbiosis; feeding; gut dysbiosis; gut microbiota; ileum; interleukin-22; intestinal barrier; intestinal epithelium; intestinal injury; liver injury; mouse model; neutrophil; novel; oral supplementation; pre-clinical; protective effect; receptor; recruit; restoration

ANSTRACT Cannabidiol (CBD) is the major non-psychoactive cannabinoid in cannabis. Recently US FDA has approved Epidiolex, an oral CBD formulation, for the treatment of two forms of pediatric epileptic syndromes. In addition, CBD is currently in clinical trials for a variety of diseases. Two recent studies have demonstrated that intraperitoneal injection of CBD to mice in a binge-on-chronic alcoholic liver disease (ALD) model alleviated liver steatosis, metabolic dysregulation, oxidative stress, inflammation, and neutrophil-mediated injury, indicating CBD has protective potentials against ALD. However, it is unknown if CBD can be administered orally to achieve its protective effects against ALD, and if CBD has therapeutic, in addition to its preventive potentials against ALD. Furthermore, intestinal mechanisms underlying the protective effects of CBD against ALD is unknown. GPR3 is an orphan G protein-coupled receptor (GPCR) recently identified by us to be a novel CBD receptor. In preliminary studies, we found that GPR3 is upregulated in the ileum of mice fed with alcohol. Furthermore, our preliminary data demonstrated that CBD enhanced the level of claudin-1 and significantly inhibited alcohol-induced barrier dysfunction in intestinal epithelial Caco-2 cells. These preliminary data suggest that by acting on GPR3, CBD may restore the intestinal barrier function disrupted in ALD. Aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear receptor expressed in intestinal type 3 innate lymphoid cells (ILC3). Recent studies by us and others have demonstrated that AhR ligands such as tryptophan metabolites from beneficial bacteria protect against ALD in mouse models through the intestinal AhR-IL22-Reg3 pathway. Interestingly, recent reports have identified CBD as a ligand for AhR with therapeutic potentials. These previous studies imply that CBD may exert its protective effects against ALD through intestine AhR to ameliorate intestinal barrier dysfunction and gut dysbiosis. Previous literature and our preliminary studies provide the foundation for our central hypothesis for this R21 project: oral CBD treatment has preventive and therapeutic potential against ALD through intestinal GPR3- and/or AhR-mediated restoration of gut barrier function and eubiosis. Two aims are designed to test our hypothesis: (1) To investigate the potential therapeutic effects of oral CBD against alcohol-induced gut microbiota dysbiosis, intestinal barrier dysfunction, and liver injury. We will use a chronic alcohol feeding mouse model in this aim. (2) To explore the potential GPR3- and AhR-mediated mechanisms underlying the effects of oral CBD against alcohol-induced intestine and liver injury. We will use both GPR3 knockout mice and intestinal ILC3 specific AhR knockout mice to test our hypothesis. Completion of this study is expected to significantly impact the development of oral CBD in the treatment of alcohol-associated liver diseases.

anttract 大麻二醇（CBD）是大麻中主要的非精神活性大麻素。最近美国FDA有 批准的Epidiolex是一种口服CBD配方，用于治疗两种形式的小儿癫痫综合征。在 此外，CBD目前正在针对各种疾病进行临床试验。最近的两项研究表明 腹膜内注射CBD向小鼠饮食中的酒精性肝病（ALD）模型减轻 肝脂肪变性，代谢失调，氧化应激，炎症和中性粒细胞介导的损伤， 表明CBD具有针对ALD的保护潜力。但是，未知是否可以管理CBD 口头以对ALD实现保护作用，如果CBD具有治疗性，除了预防性 反对ALD的潜力。此外，CBD的保护作用背后的肠道机制 ALD是未知的。 GPR3是我们最近确定为新型CBD的孤儿G蛋白偶联受体（GPCR） 受体。在初步研究中，我们发现GPR3在喂养酒精的小鼠的回肠中被上调。 此外，我们的初步数据表明，CBD提高了Claudin-1的水平，并且显着 抑制酒精诱导的肠上皮CACO-2细胞中的屏障功能障碍。这些初步数据 建议通过在GPR3上作用，CBD可能会恢复ALD中破坏的肠道屏障功能。芳基 碳氢化合物受体（AHR）是一种配体激活的核受体，该受体在肠道3先天性 淋巴样细胞（ILC3）。我们和其他人最近的研究表明，AHR配体等 来自有益细菌的色氨酸代谢物通过肠模型预防小鼠模型中的ALD AHR-IL22-REG3途径。有趣的是，最近的报告将CBD确定为具有治疗性的AHR的配体 潜力。这些先前的研究表明，CBD可能会对ALD发挥保护作用 肠AHR可以改善肠道屏障功能障碍和肠道营养不良。 以前的文献和我们的初步研究为我们的中心假设奠定了基础 R21项目：口服CBD治疗具有针对ALD通过肠道的预防和治疗潜力 gpr3-和/或AHR介导的肠道障碍功能和卵巢疾病的恢复。两个目标旨在测试我们 假设：（1）研究口服CBD对酒精诱导的肠道的潜在治疗作用 微生物群营养不良，肠道屏障功能障碍和肝损伤。我们将使用慢性酒精喂养 鼠标模型在此目标中。 （2）探索潜在的GPR3和AHR介导的机制 口服CBD对酒精引起的肠道和肝损伤的影响。我们将使用两只GPR3淘汰小鼠 和肠道ILC3特异性AHR敲除小鼠以检验我们的假设。这项研究的完成有望 显着影响口服CBD在治疗酒精相关肝病方面的发展。