Leaky Gut Syndrome: Cannabinoids and the Endocannabinoid System (ECS) as a therapeutic target.

Transcription

1 Leaky Gut Syndrome: Cannabinoids and the Endocannabinoid System (ECS) as a therapeutic target. By Kyle Boyar What is Leaky Gut Syndrome and how is it diagnosed? Leaky Gut Syndrome (LGS) is an ailment characterized by a variety of symptoms including abdominal pain, fatigue, inflammation, gas, bloating, and intolerance to certain foods. It is thought to be caused by increased permeability of the intestinal lining, which is made up of structures called tight junctions. These structures are comprised of tightly knit cells that are essentially impermeable to fluids preventing the passage of undigested food particles, toxic waste products, bacteria, and viruses into the bloodstream. Researchers believe that this disruption of the seal of tight junctions allows the leakage of these substances into the bloodstream leading to inflammation throughout the body [1]. To determine if a patient has a leaky gut, physicians will usually employ a mannitollactulose test in which a solution with these sugars is consumed and the urine

2 produced is collected. The intestine easily absorbs mannitol while lactulose is only slightly absorbed. In a healthy individual urinalysis should indicate low levels of mannitol and high levels of lactulose however in a patient with a leaky gut both sugars will be present in high concentrations. What processes go awry in LGS? It has been hypothesized that LGS can be caused by problems with the body s immune system. In the immune systems of patients with LGS there is a failure in the recognition of bodily structures as self, leading to attack of the host s tissues by its own immune cells. While not all the factors have been assembled in the understanding of intestinal permeability there are some key factors that have been identified. Immune cells present in the gut called mast cells have been shown to have an influence on intestinal permeability because they release the cytokine TNF-alpha. In patients suffering from LGS this signaling protein is improperly regulated which leads to inflammation of the gut [2]. In addition there are alterations in what is known as the zonulin pathway in patients with autoimmune disorders. Zonulin signaling is an event in the gut that regulates the structure of tight junctions by modifying the expression of its components and hence altering the permeability of the intestinal barrier. In many autoimmune diseases zonulin is overexpressed leading to a compromised intestinal barrier [3]. How might cannabis alleviate the symptoms of Leaky Gut Syndrome? Cannabis has a myriad of medicinal effects that have potential applications for alleviating the discomfort associated with LGS. Its ability to act as an antioxidant, influence intestinal permeability, as well as reduce nausea, inflammation, and pain response can be attributed to the relief it provides. 1. Cannabinoids have an influence on intestinal permeability

3 A study performed in 2011 published in the British Journal of Pharmacology showed that phytocannabinoids, specifically THC and CBD, cause a decrease in intestinal permeability in vitro using measurements of transepithelial electrical resistance (TEER) [4]. In addition the application of these cannabinoids to intestinal epithelial cells caused an increase in the expression of the tight junction protein claudin- 1, which is involved in cell-to-cell adhesion. This increase in expression could explain the overall observed decrease in intestinal permeability. 2. Cannabinoids are capable of suppressing the immune system As previously mentioned dysregulation of immune responses can be partially attributed to the cause of leaky gut. The cannabinoid receptor CB2 is found on the surface of many types of immune cells that cause inflammation. The use of CB2 agonists like THC can result in suppression of the immune system, which could help mitigate some of the autoimmune problems that are associated with LGS [5]. 3. Cannabinoids reduce inflammation Compounds that act as CB1 receptor antagonists such as cannabidiol (CBD) are able of decreasing the expression of a cell signaling protein called tumor necrosis factor alpha (TNF-α) [6]. The production of TNF-α leads to pro-inflammatory responses in the body therefore a reducing its production could greatly reduce intestinal inflammation [7]. Acidic cannabinoids are also capable of reducing inflammation by inhibiting cyclooxygenase (COX) enzymes. These enzymes are responsible for the production of compounds that mediate inflammatory responses such as prostaglandins and thrombaxanes [8] and are also the targets of over the counter non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and acetaminophen.

4 4. Cannabinoids act as antioxidants Reactive oxygen species (ROS), compounds with unpaired electrons are prevalent in oxidative stress resulting in cell damage and inflammatory responses. The damaging effects of these compounds can be mitigated by cannabinoids which act as antioxidants in the body and stabilize these reactive molecules. Specifically, the cannabinoids THC and CBD have both been shown to exhibit antioxidant activity capable of neutralizing ROS [9]. 5. Cannabinoids produce analgesia Cells in the gut express the cannabinoid receptor CB2, which is partially responsible for producing the pain-relieving and anti-inflammatory effects of cannabis. In particular cannabis strains high in the terpene β- caryophyllene could provide the most benefit as this compound has been shown to be a functional CB2 agonist [10-11]. Some studies have also suggested that the probiotic L. acidophilus may also be a promising means to heighten these effects as the presence of these bacteria in the gut have been shown to cause an elevation in the expression of the CB2 receptor as well as have a protective role on the intestinal barrier [12-13]. Future Studies The studies presented suggest that the ECS could be a potential therapeutic target in treating patients with LGS however further studies are needed to confirm these benefits. The evidence shown begs the question of the state of the ECS in patients with LGS. Are irregularities in endocannabinoid signaling part of the pathology of the disease as with other gastrointestinal and autoimmune ailments or are the findings that targeting the ECS could provide relief merely coincidence? Additionally could the use of the probiotic L. acidophilus enhance these therapeutic benefits? Until the federal government truly acknowledges the

5 potential of this miraculous plant for the treatment of this crippling ailment these questions will remain unanswered. References 1. Farhadi, A., Banan, A., Fields, J. and Keshavarsian, A. (2003), Intestinal barrier: An interface between health and disease. Journal of Gastroenterology and Hepatology, 18: doi: /j x 2. O Sullivan M, Clayton N, Breslin NP et al. Increased mast cells in the irritable bowel syndrome. Neurogastro- enterol. Motil. 2000; 12: Sapone A, De magistris L, Pietzak M, et al. Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes. 2006;55(5): Alhamoruni A, Lee AC, Wright KL, Larvin M, O'sullivan SE. Pharmacological effects of cannabinoids on the Caco-2 cell culture model of intestinal permeability. J Pharmacol Exp Ther. 2010;335(1): Hegde VL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells with potent immunosuppressive properties. Eur J Immunol. 2010;40(12): Mechoulam R. Cannabinoids in models of chronic inflammatory conditions. Phytochem Rev : Hollander D. Crohn's disease, TNF-alpha, and the leaky gut. The chicken or the egg?. Am J Gastroenterol. 2002;97(8): Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol Pharm Bull. 2011;34(5):774-8.

6 9. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9- tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA. 1998;95(14): Klauke AL, Racz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014;24(4): Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA. 2008;105(26): Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13(1): García-lafuente A, Antolín M, Guarner F, Crespo E, Malagelada JR. Modulation of colonic barrier function by the composition of the commensal flora in the rat. Gut. 2001;48(4): ICC International Cannabis Community