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What Does the Gut Microbiome have to do with Cannabinoids?

All humans and plants have evolved with a symbiotic relationship with microorganisms. Humans are no exception and the role our microbiome, principally our intestinal microbiota and its metabolic output, appears to significantly impact human biology. The human gut microbiome (GM) is composed of between 10 trillion and 100 trillion microorganisms, which is 10 times the number of our own cells and is made up of more than 1000 bacterial species. It is therefore understandable that the medical and research communities are paying a lot of attention to the GM as it relates to overall health. (de Almada et al., 2015)


The GM begins to form even before we are born and it is influenced by our dietary habits. In the modern, industrialized world, our high fat, high processed food diets create a “dysbiosis” in our GM that is tilted toward higher numbers of “bad” bacteria and lower numbers of health-promoting bacteria. This imbalance leads to numerous diseases of low-grade inflammation, including obesity, type 2 diabetes mellitus, heart disease, autoimmune disorders, and cancer. (Cani et al., 2016)


The endocannabinoid system (ECS) is a complex system with components expressed ubiquitously throughout the body, including the central nervous and immune systems. It was identified in the early 1990s by researchers exploring THC in marijuana. The discovery of the endocannabinoid system is revolutionizing medicine because it has been implicated in so many physiological functions, ranging from mood and anxiety disorders, movement disorders, such as Parkinson’s and Huntington’s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis. (Pacher et al., 2006)


Interestingly enough, it’s now being recognized that the endocannabinoid system (ECS) is involved in the process of inflammation and immune system modulation that is driven by the GM. Researchers have discovered the GM controls the ECS via “crosstalk” between the two. (Cani, 2012)

Both the GM and the ECS are critical in human health and wellness, and the “crosstalk” that occurs between them is an example of synergy exemplifying the adage from Aristotle that “the whole is greater than the sum of its parts”. This synergy is comparable to the entourage effect by which the cannabinoids and other phytocompounds in cannabis act synergistically to modulate the ECS.

This synergy and cooperation opens the door for therapeutic approaches that target both the GM and the ECS, simultaneously. It is already well established that the ECS modulates gut motility. When cannabinoid receptors are activated in the gut, motility and gastric acid secretion are reduced while desire for food intake is enhanced. In the face of ECS dysfunction or deficiency, individuals often develop conditions such as irritable bowel syndrome often characterized by pain from excessive motility and the “misperception” of pain, which is also modulated by the ECS. (Russo, 2004) These interactions between the brain and the gut create new opportunities to treat gastrointestinal disorders by taking advantage of phytocannabinoids that act upon the ECS. (Sharkey and Wiley, 2016)

What’s more, the earlier described “crosstalk” between the GM and the ECS reveals that, in addition to utilizing the ECS directly for therapeutic uses, the GM can also be targeted to address inflammatory health disorders. Research has documented that obesity is associated with increased ECS activity and higher plasma endocannabinoid levels. (Ginsberg and Woods, 2009)Therefore, blocking the ECS at the CB1 receptor is protective against obesity and low grade inflammation by improving the integrity of the gut barrier by preventing “leaky gut” linked to multiple diseases, particularly autoimmune disorders. Manipulation of the GM and ECS are being considered as therapeutic strategies for autoimmune disorders such inflammatory bowel disease, rheumatoid arthritis and particularly, multiple sclerosis (MS). (Mestre et al., 2018)


Interestingly, the ECS controls gut permeability through interactions with the GM. These same researchers found that the use of prebiotics can normalize the ECS function in both the gut and fatty tissues addressing gut permeability but also reducing fat mass accumulation.(Cani et al., 2016)

Prebiotics are non-digestible plant fibers that stimulate the growth of healthy bacteria in the gut. Conversely, probiotics are live bacteria of varying species that are part of a healthy GM. Both pre- and probiotics are found in food and supplements. (Lisko et al., 2017) The modern industrial dietary pattern is often deficient in prebiotics (fiber) and probiotic supplements tend to vary in efficacy, as their live bacteria numbers are often questionable. (Fenster et al., 2019) However, you cannot have a probiotic without a prebiotic and vice versa. Probiotic organisms are often short-lived and require a quality food source (prebiotic) to reproduce and flourish.


The latest star on the GM market is, EpiCor, which acts as a prebiotic and affects the immune system by increasing the levels of beneficial bacteria (bifidobacteria and lactobacilli). EpiCor is derived from Saccharomyces cerevisiae and has been evaluated for its modulating effect on the GM in human trials revealing a significant decrease in pro-inflammatory cytokines with EpiCor administration.(Possemiers et al., 2013)


The endocannabinoid system has also been found in animals. (Silver, 2019) More veterinary researchers are studying the use of cannabinoids and their relevance to pain, osteoarthritis and hip dysplasia. (Gamble et al., 2018) One clinical trial suggested that 2 mg/kg of CBD twice daily can improve activity and well-being in dogs with osteoarthritis. The GM is also of vital importance to the health of livestock in prevention of disease and resistance to stressors. (Kogut and Arsenault, 2016) Given the fact that growth-promoting antibiotics (AGPs) have increasingly received bad publicity as a contributor to antibiotic resistant infections and are even banned in some countries, alternatives to antibiotics like pre and probiotics for sustainable livestock production is warranted.

As we gain a better understanding of the complex and intricate interplay between the GM and the ECS, it will lead to new, safer, and desperately needed treatments for a multitude of human and animal health disorders.




References:

1. Cani, P.D., 2012. Crosstalk between the gut microbiota and the endocannabinoid system: impact on the gut barrier function and the adipose tissue. Clin. Microbiol. Infect. 18, 50–53. https://doi.org/10.1111/j.1469-0691.2012.03866.x

2. Cani, P.D., Plovier, H., Van Hul, M., Geurts, L., Delzenne, N.M., Druart, C., Everard, A., 2016. Endocannabinoids — at the crossroads between the gut microbiota and host metabolism. Nat. Rev. Endocrinol. 12, 133–143. https://doi.org/10.1038/nrendo.2015.211

3. de Almada, C.N., Nunes de Almada, C., Martinez, R.C.R., Sant’Ana, A. de S., 2015. Characterization of the intestinal microbiota and its interaction with probiotics and health impacts. Appl. Microbiol. Biotechnol. 99, 4175–4199. https://doi.org/10.1007/s00253-015-6582-5

4. Fenster, K., Freeburg, B., Hollard, C., Wong, C., Rønhave Laursen, R., Ouwehand, A.C., 2019. The Production and Delivery of Probiotics: A Review of a Practical Approach. Microorganisms 7, 83. https://doi.org/10.3390/microorganisms7030083

5. Gamble, L.-J., Boesch, J.M., Frye, C.W., Schwark, W.S., Mann, S., Wolfe, L., Brown, H., Berthelsen, E.S., Wakshlag, J.J., 2018. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Front. Vet. Sci. 5, 165–165. https://doi.org/10.3389/fvets.2018.00165

6. Ginsberg, H.N., Woods, S.C., 2009. The endocannabinoid system: potential for reducing cardiometabolic risk. Obes. Silver Spring Md 17, 1821–1829. https://doi.org/10.1038/oby.2009.107

7. Kogut, M.H., Arsenault, R.J., 2016. Editorial: Gut Health: The New Paradigm in Food Animal Production. Front. Vet. Sci. 3, 71–71. https://doi.org/10.3389/fvets.2016.00071

8. Lisko, D.J., Johnston, G.P., Johnston, C.G., 2017. Effects of Dietary Yogurt on the Healthy Human Gastrointestinal (GI) Microbiome. Microorganisms 5, 6. https://doi.org/10.3390/microorganisms5010006

9. Mestre, L., Carrillo-Salinas, F.J., Mecha, M., Feliú, A., Guaza, C., 2018. Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis. Cannabinoid Pharmacol. Ther. Spain 157, 51–66. https://doi.org/10.1016/j.bcp.2018.08.037

10. Pacher, P., Bátkai, S., Kunos, G., 2006. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462. https://doi.org/10.1124/pr.58.3.2

11. Possemiers, S., Pinheiro, I., Verhelst, A., Van den Abbeele, P., Maignien, L., Laukens, D., Reeves, S.G., Robinson, L.E., Raas, T., Schneider, Y.-J., Van de Wiele, T., Marzorati, M., 2013. A Dried Yeast Fermentate Selectively Modulates both the Luminal and Mucosal Gut Microbiota and Protects against Inflammation, As Studied in an Integrated in Vitro Approach. J. Agric. Food Chem. 61, 9380–9392. https://doi.org/10.1021/jf402137r

12. Russo, E.B., 2004. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol. Lett. 25, 31–39.

13. Sharkey, K.A., Wiley, J.W., 2016. The Role of the Endocannabinoid System in the Brain–Gut Axis. Gastroenterology 151, 252–266. https://doi.org/10.1053/j.gastro.2016.04.015

14. Silver, R.J., 2019. The Endocannabinoid System of Animals. Animals 9, 686. https://doi.org/10.3390/ani9090686





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