Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial

Abstract

Background and aims
We aimed to examine, for the first time, the effect of cannabidiol (CBD) and palmitoylethanolamide (PEA) on the permeability of the human gastrointestinal tract in vitro, ex vivo, and in vivo.
Methods
Flux measurements of fluorescein-labeled dextrans 10 (FD10) and fluorescein-labeled dextrans 4 (FD4) dextran across Caco-2 cultures treated for 24 hours with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα) (10 ng·mL−1) were measured, with or without the presence of CBD and PEA. Mechanisms were investigated using cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), transient receptor potential vanilloid 1 (TRPV1), and proliferator activated receptors (PPAR) antagonists and protein kinase A (PKA), nitric oxide synthase, phosphoinositide 3-kinases, extracellular signal–regulated kinases (MEK/ERK), adenylyl cyclase, and protein kinase C (PKC) inhibitors. Human colonic mucosal samples collected from bowel resections were treated as previously stated. The receptors TRPV1, PPARα, PPARδ, PPARγ, CB1, CB2, G-coupled protein receptor 55 (GPR55), G-coupled protein receptor 119 (GPR119), and claudins-1, -2, -3, -4, -5, -7, and -8 mRNA were measured using multiplex. Aquaporin 3 and 4 were measured using enzyme-linked immunosorbent assay (ELISA). A randomized, double-blind, controlled-trial assessed the effect of PEA or CBD on the absorption of lactulose and mannitol in humans taking 600 mg of aspirin. Urinary concentrations of these sugars were measured using liquid chromatography mass spectrometry.
Results
In vitro, PEA, and CBD decreased the inflammation-induced flux of dextrans (P < 0.0001), sensitive to PPARα and CB1 antagonism, respectively. Both PEA and CBD were prevented by PKA, MEK/ERK, and adenylyl cyclase inhibition (P < 0.001). In human mucosa, inflammation decreased claudin-5 mRNA, which was prevented by CBD (P < 0.05). Palmitoylethanolamide and cannabidiol prevented an inflammation-induced fall in TRPV1 and increase in PPARα transcription (P < 0.0001). In vivo, aspirin caused an increase in the absorption of lactulose and mannitol, which were reduced by PEA or CBD (P < 0.001).
Conclusion
Cannabidiol and palmitoylethanolamide reduce permeability in the human colon. These findings have implications in disorders associated with increased gut permeability, such as inflammatory bowel disease.

Citation

Couch, D. G., Cook, H., Ortori, C., Barrett, D., Lund, J. N., & O’Sullivan, S. E. (2019). Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial. Inflammatory Bowel Diseases, 25(6), 1006-1018. https://doi.org/10.1093/ibd/izz017

• Journal Article Type: Article
• Acceptance Date: Feb 19, 2019
• Online Publication Date: Feb 19, 2019
• Publication Date: Feb 19, 2019
• Deposit Date: Mar 6, 2019
• Publicly Available Date: Feb 20, 2020
• Journal: Inflammatory Bowel Diseases
• Print ISSN: 1078-0998
• Electronic ISSN: 1536-4844
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 6
• Pages: 1006-1018
• DOI: https://doi.org/10.1093/ibd/izz017
• Keywords: Immunology and Allergy; Gastroenterology
• Public URL: https://nottingham-repository.worktribe.com/output/1601054
• Publisher URL: https://academic.oup.com/ibdjournal/advance-article/doi/10.1093/ibd/izz017/5341970
• Additional Information: This is a pre-copyedited, author-produced version of an article accepted for publication in Inflammatory Bowel Diseases following peer review. The version of record Daniel G Couch, Hollie Cook, Catherine Ortori, Dave Barrett, Jonathan N Lund, Saoirse E O’Sullivan; Palmitoylethanolamide and Cannabidiol Prevent Inflammation-induced Hyperpermeability of the Human Gut In Vitro and In Vivo—A Randomized, Placebo-controlled, Double-blind Controlled Trial, Inflammatory Bowel Diseases, , izz017, is available online at: https://academic.oup.com/ibdjournal/advance-article/doi/10.1093/ibd/izz017/5341970 .