Cannabidiol as a treatment for alcoholic liver disease

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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.