ECS & the GI tract

Cannabis has been used for the treatment of inflammatory and functional disorders of the gastrointestinal (GI) tract for the past millenniums. Amongst others, the effects are based on the fact that the endocannabinoid system regulates communication between the brain, the gut and the immune system. Cannabinoid receptors can be found in large numbers on nervous cells of the peripheral nervous system (the “gut brain”), on intestinal epithelial cells as well as on hormone-secreting cells of the GI tract. Mutations of the gene coding for CB1 receptor seem to be responsible for some forms of irritable bowel syndrome. Furthermore, the composition of the intestinal flora influences the function of the endocannabinoid system.

Cannabis has been used for the treatment of inflammatory and functional disorders of the gastrointestinal (GI) tract (i.e. stomach pain, cramps, diarrhea, nausea and vomiting) for the past millennia. But what is the underlying physiologic basis for the various positive clinical effects?

The knowledge about the endocannabinoid system (ECS) has increased exponentially over the past years. Today its role for the homeostasis of the brain-gut-axis – that stands in close mutual exchange with the HPA-stress-axis, amongst other systems – as well as for other processes of the intestinal pathophysiology is undisputed. The central as well as decentral effects of the ECS substantially contribute to the regulation of motility and inflammatory events in the GI tract. Moreover, as neuromodulatory system the ECS is involved in the (central) control of nausea and vomiting as well as of visceral sensation of pain.3

Many patients suffering from visceral chronic pain report that stress exacerbates their symptoms. There is increasing evidence that the ECS is capable of influencing stress-related visceral hyperalgesia in a positive manner (Fig. 1).  It is well known that chronic stress has an impact on hormone metabolism and thereby also fundamentally on the energy turnover of the body. Apparently, the most important physiological mechanism in this context seems to be the stress-hormone-axis, the so called HPA-axis. It controls the release of the stress hormones adrenaline, noradrenaline and cortisol and subsequently other endocrine signals (e.g. sex hormones, hormones of the circadian rhythm, thyroid hormones). During chronic stress the body is in a constant state of alertness that can lead to many damaging effects according to neuro-endocrinologists, e.g. reduced immune function, hypertension, sleep disturbances, depression, cognitive disorders, catabolic shift of the metabolism, changes in glucose metabolism or sexual dysfunction. Due to dysregulated hormonal control loops and accompanying diseases a constantly intensifying vicious circle develops.

The graphic declares how the endocannabinoid-system communicate with the person's gut.
Figure 1 (adapted from Sharkey & Wiley 2016 Effects of chronic stress on peripheral endocannainoid pathways in visceral primary afferent neurons)

Under conditions of chronic stress, levels of 2-AG and AEA increase and endocannabinoid degradation enzymes COX-2 and FAAH are decreased in nociceptive dorsal root ganglion neurons that innervate the colon and pelvis. Along with this, levels of CB1 are reduced and there is an increase in TRPV1 expression and phosphorylation in nociceptive primary afferent neurons. These effects are mediated by corticosteroids from the HPA pathway.

The ECS also influences appetite and food intake via central and peripheral mechanisms and is able to stimulate lipogenesis and accumulation of fatty tissue.2

From animal models it is well established that the G-protein coupled CB1 and CB2 receptors are highly expressed in the gastrointestinal tract, e.g. in the enteric nervous system (“gut brain”) – excluding inhibitory motor neurons – as well as in the gut epithelium that also contains immune cells. Furthermore, CB1 receptors were found on some enteroendocrine cells, hence a direct effect of the ECS on the secretion of tissue hormones of the GI tract seems likely.3

Polymorphisms in CNR1 (the gene that encodes for CB1 receptor) seem to be responsible for some forms of irritable bowel syndrome. In this context, chronic stress also seems to have an impact by epigenetic regulation of the gene.3 Especially for the non-psychotropic phyto-cannabinoids cannabidiol (CBD) and cannabigerol (CBG), mechanisms of action for the treatment of intestinal inflammation have been revealed.4,5

The microbiome is defined as the entirety of microbes that colonize the human body. A single adult is colonized by approximately 100 trillion microbes that are mostly found in the gastrointestinal tract. The composition of the microbiome not only seems to influence general energy turnover but also to play an important role in the development of obesity, diabetes and even psychological disorders. The function of the endocannabinoid system in the GI tract also seems to depend on the composition of the microbiome: intestinal bacteria locally modulate the basic tone of the ECS which in turn regulates permeability of the intestine and plasma lipopolysaccharide (LPS) levels, thereby affecting inflammatory processes and overall metabolic function.6,7

Stimulation of hepatic CB2 receptors shows positive effects on alcohol-related fatty liver, liver inflammation, lesions, regeneration and fibrosis. The effect of CB1 receptors is evident in the pathogenesis of alcoholic and metabolic steatosis, liver fibrogenesis and circulatory failure in connection with cirrhosis.8

In addition, malignant tumors of the gastrointestinal tract might be treated with cannabinoids in the future.9,10,11

With this said, it is desirable that scientists investigate the promising effects of the endocannabinoid system and plant-based ligands for treatment of GI tract disorders in more detail in the future in order to enable more patients to benefit from the therapeutic potential of cannabinoid medicine, which has only few side effects.

[1] Sharkey KA, Wiley JW. The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology. 2016;151(2):252-266. doi:10.1053/j.gastro.2016.04.015

[2] Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005;8(5):585-589. doi:10.1038/nn1457

[3] Hong S, Zheng G, Wiley JW. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology. 2015;148(1):148-157.e7. doi:10.1053/j.gastro.2014.09.032

[4] De Filippis D, Esposito G, Cirillo C, et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One. 2011;6(12):e28159. doi:10.1371/journal.pone.0028159

[5] Borrelli F, Fasolino I, Romano B, et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol. 2013;85(9):1306-1316. http://linkinghub.elsevier.com/retrieve/pii/S0006295213000543

[6] Harsch IA, Konturek PC. The Role of Gut Microbiota in Obesity and Type 2 and Type 1 Diabetes Mellitus: New Insights into “Old” Diseases. Med Sci (Basel, Switzerland). 2018;6(2). doi:10.3390/medsci6020032

[7] Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010;6:392. doi:10.1038/msb.2010.46

[8] Mallat A, Teixeira-Clerc F, Deveaux V, Manin S, Lotersztajn S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br J Pharmacol. 2011;163(7):1432-1440. doi:10.1111/j.1476-5381.2011.01397.x

[9] Vara D, Salazar M, Olea-Herrero N, Guzmán M, Velasco G, Díaz-Laviada I. Anti-tumoral action of cannabinoids on hepatocellular carcinoma: role of AMPK-dependent activation of autophagy. Cell Death Differ. 2011;18(7):1099-1111. doi:10.1038/cdd.2011.32

[10] Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis. 2014;35(12):2787-2797. doi:10.1093/carcin/bgu205

[11] Ferro R, Adamska A, Lattanzio R, et al. GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine. Oncogene. July 2018:1. doi:10.1038/s41388-018-0390-1