Manipulation of the Endocannabinoid System in Colitis: A Comprehensive Review

Abstract

Background: Inflammatory bowel disease (IBD) is a lifelong disease of the gastrointestinal tract whose annual incidence and prevalence is on the rise. Current immunosuppressive therapies available for treatment of IBD offer limited benefits and lose effectiveness, exposing a significant need for the development of novel therapies. In the clinical setting, cannabis has been shown to provide patients with IBD symptomatic relief, although the underlying mechanisms of their anti-inflammatory effects remain unclear.

Methods: This review reflects our current understanding of how targeting the endocannabinoid system, including cannabinoid receptors 1 and 2, endogenous cannabinoids anandamide and 2-arachidonoylglycerol, atypical cannabinoids, and degrading enzymes including fatty acid amide hydrolase and monoacylglycerol lipase, impacts murine colitis. In addition, the impact of cannabinoids on the human immune system is summarized.

Results: Cannabinoid receptors 1 and 2, endogenous cannabinoids, and atypical cannabinoids are upregulated in inflammation, and their presence and stimulation attenuate murine colitis, whereas cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects. In addition, inhibition of endocannabinoid degradation through monoacylglycerol lipase and fatty acid amide hydrolase blockade can also attenuate colitis development, and is closely linked to cannabinoid receptor expression.

Conclusions: 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.

Figure 1. Colonic distribution of classical cannabinoid receptors CB₁ and CB₂

CB₁ receptors (CB₁R) are located in the intrinsic neurons, extrinsic neurons such as the cell bodies of sensory neurons in the dorsal root ganglia and nodose ganglion, and vagal efferent nerves within the enteric nervous system, as well as on epithelial cells. CB₂ receptors (CB₂R) are expressed on epithelial cells and immune cells including neutrophils, activated macrophages, and subsets of T and B cells.

Figure 2. Therapeutic targeting of the endocannabinoid system in murine colitis

A schematic overview of cannabinoid receptors, the endogenous cannabinoids that act on them, pathway of enzymatic degradation of endocannabinoids, and how manipulation of this pathway impacts colitis.