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.

摘要 大麻二酚（CBD）是大麻中主要的非精神活性大麻素。近期美国FDA 批准 Epidiolex 是一种口服 CBD 制剂，用于治疗两种形式的小儿癫痫综合征。在 此外，CBD目前正在针对多种疾病进行临床试验。最近的两项研究表明 在慢性酒精性肝病（ALD）模型中向小鼠腹腔注射 CBD 可缓解 肝脏脂肪变性、代谢失调、氧化应激、炎症和中性粒细胞介导的损伤， 表明 CBD 对 ALD 具有保护潜力。然而，CBD是否可以施用尚不清楚 口服以达到对 ALD 的保护作用，如果 CBD 除了预防作用外还具有治疗作用 对抗 ALD 的潜力。此外，CBD 保护作用背后的肠道机制 酒精性肝病未知。 GPR3是一种孤儿G蛋白偶联受体（GPCR），最近被我们鉴定为新型CBD 受体。在初步研究中，我们发现喂食酒精的小鼠回肠中 GPR3 表达上调。 此外，我们的初步数据表明 CBD 提高了claudin-1的水平，并显着 抑制酒精诱导的肠上皮 Caco-2 细胞屏障功能障碍。这些初步数据 表明通过作用于 GPR3，CBD 可以恢复 ALD 中受损的肠道屏障功能。芳基 碳氢化合物受体 (AhR) 是一种配体激活的核受体，在肠道 3 型先天性中表达 淋巴细胞（ILC3）。我们和其他人最近的研究表明，AhR 配体，例如 有益细菌的色氨酸代谢物可通过肠道预防小鼠模型中的 ALD AhR-IL22-Reg3 途径。有趣的是，最近的报告已确定 CBD 作为 AhR 的配体，具有治疗作用 潜力。这些先前的研究表明 CBD 可能通过以下方式发挥其对 ALD 的保护作用： 肠道 AhR 可改善肠道屏障功能障碍和肠道菌群失调。 之前的文献和我们的初步研究为我们的中心假设提供了基础 R21项目：口服CBD治疗具有通过肠道预防和治疗ALD的潜力 GPR3 和/或 AhR 介导的肠道屏障功能恢复和优生。有两个目标旨在测试我们的 假设：（1）研究口服 CBD 对酒精诱导肠道的潜在治疗作用 微生物群失调、肠道屏障功能障碍和肝损伤。我们将使用长期酒精喂养 小鼠模型就是为了这个目的。 (2) 探讨GPR3和AhR介导的潜在机制 口服 CBD 对酒精引起的肠道和肝脏损伤的作用。我们将使用两只 GPR3 敲除小鼠 和肠道 ILC3 特异性 AhR 敲除小鼠来检验我们的假设。预计完成这项研究 显着影响口服 CBD 在治疗酒精相关肝病方面的发展。