Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis

Rose L. Szabady, Christopher Louissaint, Anneke Lubben, Bailu Xie, Shaun Reeksting, Christine Tuohy, Zachary Demma, Sage E. Foley, Christina S. Faherty, Alejandro Llanos-Chea, Andrew J. Olive, Randall J. Mrsny, and Beth A. McCormick  (August 2018)

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Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine–type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.

Cannabis for the treatment of Crohn’s disease

Tahir S Kafil, Tran M Nguyen, John K MacDonald, Nilesh Chande  (November 2017)

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Usual treatment options for CD include anti-inflammatory and immunosuppressant agents (Friedman 2012). Commonly used drugs are 5-ASA, sulfasalazine, corticosteroids, thiopurine drugs, methotrexate and biologic therapies such as anti-TNF-α agents (Friedman 2012). Management includes control of acute exacerbations, induction of remission, and maintenance of remission. It is important to do this review to evaluate the strength of evidence for the use of cannabis and cannabinoids as treatment for CD. It will help clarify if this therapy leads to objective physiological improvement beyond subjective and psychotropic scores. Further, we hope to evaluate various modes of consumption and assess for adverse effects.

Cannabinoid Receptor-2 Ameliorates Inflammation in Murine Model of Crohn’s Disease

Kristina L Leinwand, Ashleigh A Jones, Rick H Huang, Paul Jedlicka, Daniel J Kao, Edwin F de Zoeten, Soumita Ghosh, Ruin Moaddel,  Jan Wehkamp,  Maureen J Ostaff, Jutta Bader,  Carol M Aherne and Colm B Collins  (October 2017)

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In summary, the endocannabinoid system is induced in murine ileitis but is downregulated in chronic murine and human intestinal inflammation, and CB2R activation attenuates murine ileitis, establishing an anti-inflammatory role of the endocannabinoid system.

Modulation of the Endocannabinoid System by the Fatty Acid Amide Hydrolase, Monoacylglycerol and Diacylglycerol Lipase Ihibitors as an Attractive Target for Secretory Diarrhoea Therapy

A. Wasilewski, A. Misicka, M. Sacharczuk, J. Fichna  (August 2017)

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Secretory diarrhoea is a leading cause of mortality and morbidity worldwide. Our aim was to characterize the effect of inhibition of selected enzymes involved in the synthesis or degradation of endocannabinoids on electrolyte equilibrium in the mouse colonic tissue. The aim of this study was to evaluate the effects of PF-3845, JZL-184 and RHC-80267, as inhibitors of fatty acid amide hydrolase (FAAH), monoacylglycerol (MAGL) and diacylglycerol lipase (DAGL), respectively on epithelial ion transport in isolated mouse colon stimulated by forskolin (FSK), veratridine (VER) and bethanechol (BET).

G protein-coupled receptor 55 (GPR55) expresses differently in patients with Crohn’s disease and ulcerative colitis

Marcin Włodarczyk, Aleksandra Sobolewska-WłodarczykAdam I. Cygankiewicz, Damian Jacenik, Wanda M. Krajewska, Krystyna Stec-Michalska, Aleksandra Piechota-Polańczyk, Maria Wiśniewska-Jarosińska and Jakub Fichna  (March 2017)
Different patterns of GPR55 expression at mRNA level were observed in IBD patients. We speculate that GPR55 is crucial for the mucosal inflammatory processes in IBD, particularly in CD and its expression may affect disease severity, and response to treatment. The GPR55 receptors may become an attractive target for novel therapeutic strategies in IBD.

Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review

Kristina L. Leinwand, DO; Mark E. Gerich, MD; Edward J. Hoffenberg, MD; Colm B. Collins, PhD  (February 2017)

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Although manipulation of the endocannabinoid system in murine colitis has proven to be largely beneficial in attenuating inflammation, there is a paucity of human study data. Further research is essential to clearly elucidate the specific mechanisms driving this anti-inflammatory effect for the development of therapeutics to target inflammatory disease such as IBD.

The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity

Alhouayek, M; Muccioli, GG  (July 2012)

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Anandamide and 2-arachidonoylglycerol are endogenous bioactive lipids that bind to and activate the cannabinoid receptors, and together with the enzymes responsible for their biosynthesis and degradation [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)] constitute the endocannabinoid system (ECS). The ECS is implicated in gut homeostasis, modulating gastrointestinal motility, visceral sensation, and inflammation, as well as being recently implicated in IBD pathogenesis. Numerous subsequent studies investigating the effects of cannabinoid agonists and endocannabinoid degradation inhibitors in rodent models of IBD have identified a potential therapeutic role for the ECS.