Investigating the Role of the Endocannabinoid System in Intestinal Inflammation

Inflammatory Bowel Disease (IBD) is an umbrella term for relapsing and remitting disorders, including Crohn’s Disease (CD) and Ulcerative Colitis (UC), resulting in chronic inflammation of the gastrointestinal tract. According to the European Federation of Crohn’s and Ulcerative Colitis Associations, there are approximately 10 million people worldwide living with IBD and annual incidence rates continue to rise significantly. Characterised by the recruitment and infiltration of immune cells into the gut, it is widely accepted that the process of immune cell gut-homing is pivotal in disease pathogenesis. Central to immune cell gut-homing is 47, a heterodimeric surface integrin expressed on circulating immune cells mediating trafficking through interactions with its gut-specific ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Studies assessing immune cell gut-homing have led to the development of multiple anti-trafficking agents, most notably vedolizumab, a monoclonal antibody targeting 47 which works to a great extent by reducing the accumulation of T cells in the gut and subsequent intestinal inflammation. However, due to limited benefits, declining efficacies and associated risks with such options, strides have been made to develop novel therapeutic strategies. Recently cannabis has gained popularity as a potential option for the treatment of IBD. Numerous studies have indicated its increased use among IBD patients as a method of self-medication for its supposed symptomatic relief. However, clinical trials assessing cannabis and cannabinomimetics in the treatment of IBD have failed to show any empirical evidence for disease improvement, with one study indicating that its chronic use can lead to worsened disease outcome. Cannabis exerts its biological effect through the endocannabinoid system (ECS), a lipid-based signalling system with multiple regulatory functions. T cells exclusively rely on cannabinoid receptor 2 (CB2R) for canonical cannabinoid signalling, a receptor that is significantly increased in expression in IBD. As a result, attention has shifted to the role of this receptor in intestinal inflammation. Herein, we show CB2R signalling to have a major regulatory role in normal T cell functioning. Specifically, CB2R activation drives the expression of the gut-homing integrin 47 on T cells in a manner that is dependent on the Ras/Raf/MEK/ERK signalling cascade, thus facilitating the development of gut-homing T cells. This provides a much needed counter argument to balance the messaging regarding the use of cannabis in treating intestinal disease, partly explaining why cannabis has been found to worsen disease outcome. Furthermore, we assessed T cell glucose metabolism following CB2R manipulation. Different T cell subpopulations utilise distinct metabolic pathways to meet their functional demands, with alterations in cellular metabolism having significant impacts on T cell fate determination. In these studies we show CB2R activation to induce a metabolic shift in T cells, away from glycolysis towards the pentose phosphate pathway (PPP) and oxidative phosphorylation (OXPHOS), potentially facilitating the development of long-lived memory T cells. As a result, we hypothesise that CB2R activation on T cells drives the development of gut-homing, long-lived memory T cells. The work in this thesis not only outlines the risks associated with the use of cannabis in the context of intestinal inflammation, but is also highly suggestive that CB2R blockade may offer a potential novel therapeutic avenue for the treatment of IBD. Furthermore, these studies have the potential to lead future studies in the development of novel IBD therapeutics with the hope of improving the lives of millions of individuals worldwide.