Cannabidiol as a treatment for alcoholic liver disease

ANSTRACT 大麻二酚（CBD）是大麻中主要的非精神活性大麻素。最近，美国FDA 批准Epidiolex，一种口服CBD制剂，用于治疗两种形式的儿科癫痫综合征。在 此外，CBD目前正在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）模型中向小鼠腹膜内注射CBD减轻了 肝脏脂肪变性、代谢失调、氧化应激、炎症和嗜酸性粒细胞介导的损伤， 这表明CBD对ALD具有保护潜力。然而，目前尚不清楚CBD是否可以管理 口服，以实现其对ALD的保护作用，如果CBD具有治疗作用，除了其预防作用外， 对ALD的潜力。此外，肠道机制的CBD的保护作用， ALD未知。 GPR 3是我们最近发现的一种新的CBD孤儿G蛋白偶联受体（GPCR 受体的在初步研究中，我们发现GPR 3在用酒精喂养的小鼠的回肠中上调。 此外，我们的初步数据表明，CBD提高了claudin-1的水平， 抑制肠上皮Caco-2细胞中酒精诱导的屏障功能障碍。这些初步数据 这表明通过作用于GPR 3，CBD可以恢复ALD中破坏的肠屏障功能。芳基 碳氢化合物受体（AhR）是在肠3型先天性巨噬细胞中表达的配体激活的核受体， 淋巴样细胞（ILC 3）。我们和其他人最近的研究表明，AhR配体，如 有益细菌的色氨酸代谢产物通过肠道保护小鼠模型免受ALD AhR-IL 22-Reg 3通路。有趣的是，最近的报道已经确定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可能通过以下途径对ALD发挥保护作用： 肠AhR以改善肠屏障功能障碍和肠生态失调。 先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 GPR 3和/或AhR介导的肠道屏障功能和生态良好的恢复。两个目标旨在测试我们的 假设：（1）研究口服CBD对酒精诱导的肠道损伤的潜在治疗作用 微生物群失调、肠屏障功能障碍和肝损伤。我们将用长期酒精喂养 小鼠模型在这方面。(2)为了探索潜在的GPR 3和AhR介导的机制， 口服CBD对酒精诱导的肠道和肝脏损伤的影响。我们将使用两种GPR 3敲除小鼠 和肠ILC 3特异性AhR敲除小鼠来测试我们的假设。预计完成这项研究后， 显著影响口服CBD治疗酒精相关肝病的发展。

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.