The role of CB1 in intestinal permeability and inflammation

Karwad, Mustafa A.; Couch, Daniel G.; Theophilidou, Elena; Sarmad, Sarir; Barrett, David A.; Larvin, Michael; Wright, Karen L.; Lund, Jonathan N.; O'Sullivan, Saoirse

Abstract

The endocannabinoid system has previously been shown to play a role in the permeability and inflammatory response of the human gut. The goal of our study was to determine the effects of endogenous anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) on the permeability and inflammatory response of intestinal epithelium under normal, inflammatory, and hypoxic conditions. Human intestinal mucosa was modeled using Caco-2 cells. Human tissue was collected from planned colorectal resections. Accumulation of AEA and 2-AG was achieved by inhibiting their metabolizing enzymes URB597 (a fatty acid amide hydrolase inhibitor) and JZL184 (a monoacylglycerol lipase inhibitor). Inflammation and ischemia were simulated with TNF-a and IFN-g and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB1 receptor was explored using CB1-knockdown (CB1Kd) intestinal epithelial cells. Endocannabinoid levels were measured using liquid chromatography–mass spectrometry. Cytokine secretion was measured using multiplex and ELISA. URB597 and JZL184 caused a concentration-dependent increase in permeability via CB1 (P < 0.0001) and decreased cytokine production. Basolateral application of JZL184 decreased permeability via CB1 (P < 0.0001). URB597 and JZL184 increased the enhanced (worsened) permeability caused by inflammation and hypoxia (P

Citation

Karwad, M. A., Couch, D. G., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., …O'Sullivan, S. (2017). The role of CB1 in intestinal permeability and inflammation. FASEB Journal, 31(8), 3267-3277. https://doi.org/10.1096/fj.201601346R

• Journal Article Type: Article
• Acceptance Date: Apr 1, 2017
• Online Publication Date: Apr 12, 2017
• Publication Date: 2017-08
• Deposit Date: Aug 22, 2017
• Publicly Available Date: Aug 22, 2017
• Journal: FASEB Journal
• Print ISSN: 0892-6638
• Electronic ISSN: 1530-6860
• Publisher: Federation of American Society of Experimental Biology
• Peer Reviewed: Peer Reviewed
• Volume: 31
• Issue: 8
• Pages: 3267-3277
• DOI: https://doi.org/10.1096/fj.201601346R
• Keywords: gut, endocannibinoids, anandamide, 2-ag
• Public URL: https://nottingham-repository.worktribe.com/output/855447
• Publisher URL: http://www.fasebj.org/content/31/8/3267