The endocannabinoid system in inflammatory bowel system

Crohn’s disease (CD) and ulcerative colitis (UC) constitute the two major forms of inflammatory bowel disease (IBD), which are disorders of chronic inflammation in the gastrointestinal tract that are associated with significant morbidity and socioeconomic burden. IBD patients with long-standing intestinal inflammation are more prone to developing colorectal cancer (CRC). Until now, none of the existing IBD treatments is able to heal the mucosal ulcerations satisfactorily. The endocannabinoid system (ECS), which comprises of endogenous cannabinoid ligands, their receptors, and metabolic enzymes, has been implicated in gut homeostasis, visceral sensation, inflammation and gastrointestinal motility. Available studies in rodent models of IBD suggest that enhancing the ECS tone may reduce inflammation and improve mucosal integrity. This evidence indicates that the components of the ECS seem well positioned to exert a protective role in IBD and also to offer a great opportunity for therapeutic exploitation. Despite the role of the ECS in the gut, the presence and function of the components of the ECS is not well characterised in human IBD. The primary aim of the study was to investigate the state of the major components of the ECS in human IBD and to establish whether IBD is associated with any changes of the components of the ECS. Cannabinoid CB1 and CB2 receptors, enzymes for endocannabinoid biosynthesis PLC, “LRAT”, NAPE-PLD and DAGL, and endocannabinoid metabolic enzymes FAAH and MAGL were analysed from colonic tissue samples of CD, UC and control patients by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to determine the relative mRNA expression of the above genes. The RT-qPCR analysis showed that the mRNA expression of PLC, LRAT, and NAPE-PLD were unchanged in both CD and UC, whiles DAGL mRNA was decreased in UC but was unchanged in CD. The endocannabinoid degradation enzymes, FAAH mRNA expression was also unchanged in CD but decreased in UC, whereas the mRNA expression of MAGL was significantly decreased in both CD and UC. NAPE-PLD/FAAH and DAGL/MAGL ratios, an estimation of the balance of AEA and 2-AG levels, showed that AEA and 2-AG levels could be increased and unchanged, respectively, in IBD. The mRNA expression of CB1 was significantly decreased in CD and UC whilst CB2 mRNA expression was unchanged in both forms of IBD. The study demonstrated that the components of the ECS which were investigated were present in colonic tissues of both IBD patients and healthy individuals, but they appear to be off balance in CD and UC patients. The decreased CB1 receptors in IBD patients could be an important modifier in the disease and could also provide a possible pathoaetiological mechanism linking IBD and CRC. Although these findings look promising, more studies with larger sample size are required to characterise the components of the ECS in human IBD