Members of the endocannabinoid system are distinctly regulated in inflammatory bowel disease and colorectal cancer

Abstract

Preclinical studies have demonstrated that the endocannabinoid system (ECS) plays an important role in the protection against intestinal inflammation and colorectal cancer (CRC); however, human data are scarce. We determined members of the ECS and related components of the ‘endocannabinoidome’ in patients with inflammatory bowel disease (IBD) and CRC, and compared them to control subjects. Anandamide (AEA) and oleoylethanolamide (OEA) were increased in plasma of ulcerative colitis (UC) and Crohn’s disease (CD) patients while 2-arachidonoylglycerol (2-AG) was elevated in patients with CD, but not UC. 2-AG, but not AEA, PEA and OEA, was elevated in CRC patients. Lysophosphatidylinositol (LPI) 18:0 showed higher levels in patients with IBD than in control subjects whereas LPI 20:4 was elevated in both CRC and IBD. Gene expression in intestinal mucosal biopsies revealed different profiles in CD and UC. CD, but not UC patients, showed increased gene expression for the 2-AG synthesizing enzyme diacylglycerol lipase alpha. Transcripts of CNR1 and GPR119 were predominantly decreased in CD. Our data show altered plasma levels of endocannabinoids and endocannabinoid-like lipids in IBD and CRC and distinct transcript profiles in UC and CD. We also report alterations for less known components in intestinal inflammation, such as GPR119, OEA and LPI.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…ECS controls gastrointestinal (GI) tract (GIT) motility, sensitivity, and inflammatory processes, and thus appears to be an interesting target in the treatment of GI diseases, with a significant role in inflammatory bowel disease (IBD) [303]. Although the data on ECS tone in IBD is not consistent, the eCBs level is generally increased, from which LPI, an endogenous GPR55 agonist, may exert a pro-inflammatory effect, based on clinical observations [304]. A number of CB1 and CB2 agonists were proven to be effective in ameliorating IBD symptoms in animal models.…”

Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases

“…Activation of cannabinoid receptors (CBs) by endocannabinoids influences a great number of digestive and intestinal functions, suggesting a possible treatment with cannabinoids for these pathologies in humans (Di Sabatino et al, 2011). A recent work by Grill et al (2019) described the circulating levels of endocannabinoids in patients with IBD, and they found increased AEA and OEA, suggesting nonspecific regulation by the Endogenous Cannabinoid System (ECS) in IBD. NAE analogues with PPAR and/or dual cannabinoid/PPAR activity would be good targets in order to restore several features where homeostasis is altered, as in the case of UC.…”

The Interplay between Cancer Biology and the Endocannabinoid System—Significance for Cancer Risk, Prognosis and Response to Treatment

“…Despite all invested efforts, colorectal cancer (CRC) is still the third most common malignant disease in the world with around 1.8 million new cases in 2018, and in second place by mortality induced by cancer with around 0.9 million deaths [59]. The ECS's involvement in the development, progression and treatment of CRC has been evaluated in terms of the implication of cannabinoid receptors, endo-and synthetic cannabinoids, as well as various ECS-induces signalling molecules [60,61].…”