The role of CB ₁ in intestinal permeability and inflammation

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-α and IFN-γ and oxygen deprivation. Permeability changes were measured by transepithelial electrical resistance. The role of the CB receptor was explored using CB-knockdown (CBKd) 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 CB ( < 0.0001) and decreased cytokine production. Basolateral application of JZL184 decreased permeability CB ( < 0.0001). URB597 and JZL184 increased the enhanced (worsened) permeability caused by inflammation and hypoxia ( < 0.0001 and < 0.05). CBKd cells showed reduced permeability response to inflammation ( < 0.01) but not hypoxia. 2-AG levels were increased in response to inflammation and hypoxia in Caco-2 cells. In human mucosal tissue, inflammation increased the secretion of granulocyte macrophage-colony stimulating factor, IL-12, -13, and -15, which was prevented with treatment with URB597 and JZL184, and was inhibited by a CB antagonist. The results of this study show that endogenous AEA and 2-AG production and CB activation play a key modulatory roles in normal intestinal mucosa permeability and in inflammatory and hypoxic conditions.-Karwad, M. A., Couch, D. G., Theophilidou, E., Sarmad, S., Barrett, D. A., Larvin, M., Wright, K. L., Lund, J. N., O'Sullivan, S. E. The role of CB in intestinal permeability and inflammation.

Protective Effect of Akkermansia muciniphila against Immune-Mediated Liver Injury in a Mouse Model

“…It was reported that endocannabinoid (eCB) system plays a role in gut homeostasis including motility, inflammation and permeability, of which the underlying mechanisms remains to be elucidated ( Lee et al, 2016 ; Karwad et al, 2017 ). CB1 blockage was shown to improve gut barrier function and reduce systemic LPS levels, while the other member of eCB system-CB2 seemed unrelated with permeability ( Muccioli et al, 2010 ).…”

NAPE‐PLD controls OEA synthesis and fat absorption by regulating lipoprotein synthesis in anin vitromodel of intestinal epithelial cells

“…2C). Further, the report suggested that the increased endogenous AEA enhanced permeability in the Caco-2 cells (45). Therefore, the increase in endogenous AEA could be involved in the cellular phenotype in the NAPE-PLD-deleted cells.…”

“…AEA has been shown to play roles in biologic activities, such as cell adhesion and migration, permeability, inflammation, and apoptosis in the in vitro experiments (41)(42)(43)(44)(45). Especially, the inhibitory effect on cell proliferation was exerted by AEA treatment in human colon cancer cell lines (42), implicating a mechanism underlying the slow growth rate of the NAPE-PLD-deleted cells (Fig.…”

Role of cannabis in inflammatory bowel diseases

“…In one study, administration of CB2 agonists (JWh133, AM1241) upregulated the CB2 receptors and reduced colonic inflammation in trinitrobenzene sulfonic acid-induced colitis in a murine model [49]. The role of CB1 receptors in inflammation is still under investigation, though some research suggests that they help combat inflammation by modulating the release of other neurotransmitters and producing an "entourage effect" in peripheral nerve terminals [50]. It has been shown that the co-activation of CB1 and CB2 receptors is essential for effective emesis control by endocannabinoids, possibly by blocking the endocannabinoid reuptake by CB2 [51].…”