The Gut-Endocannabinoid Axis

 

The gut microbiome plays a critical role in harvesting energy from food, strengthening the protective gut lining, synthesizing vitamins, and developing the immune system.1 Both the gut microbiota and the endogenous endocannabinoid system (ECS) have a systemic influence on the human body. Because their effects span multiple different systems and organs, both are critical for normal and healthy functioning of the human body.

Though the gut microbiome has been well studied, research into the ECS continues to evolve as interest in cannabis and its impact on the body grows.

The ECS is a physiologic system that’s deeply involved in several pathways within the body. It’s composed of a network of neuromodulators (organic compounds called endocannabinoids), receptors, and enzymes—all of which respond to cannabinoids. Endocannabinoids and their receptors are found in tissues throughout the body, including in connective tissues, immune cells, glands, the brain, and other organs.2 Though knowledge of the ECS is still developing, research indicates that the system plays a role in regulating pain, addiction, mood, memory, motor learning, and appetite.

The two main cannabinoid receptors that have been identified are CB1 (found predominantly in the nervous system, gonads, glands, organs, and connective tissue) and CB2 (found predominantly within the immune system). The body produces endogenous endocannabinoids to stimulate the CB1 and CB2 receptors. Of these endocannabinoids, research has highlighted anandamide and 2-arachidonoylglyceral (2-AG), which are arachidonate-based lipids and ligands. Though the body’s own endocannabinoids stimulate ECS receptors, exogenous cannabinoids (phytocannabinoids) also stimulate receptors. The two most well-known phytocannabinoids are THC and CBD, and most of the phytocannabinoids consumed are extracted from Cannabis sativa.3

The Relationship Between the Gut Microbiome and ECS
Though the gut microbiome and ECS each play a unique role in the body, researchers are interested in their integrated functioning. The connection between gut bacteria and endocannabinoid signaling was first explored in 2010 by Muccioli and colleagues, who focused on the influence the relationship exerted over adipogenesis.4 Though research has found that mice with obesity and diabetes have microbiomes with compositions different from those of their counterparts without these conditions, mice with obesity specifically have been found to have an imbalance in gut flora (with higher levels of harmful bacteria than beneficial bacteria). Such imbalances in microbiota may affect fat metabolism, as the higher ratio of harmful bacteria can encourage fat storage in fat cells via enzyme activation. The skewed ratio of harmful to beneficial bacteria in mice with obesity has also been shown to modify endocannabinoid signaling, increasing gut permeability as well as obesity-associated inflammation and adipogenesis. Researchers found that the provision of prebiotics (foods that feed beneficial bacterial in the gut) led to favorable alterations in the gut microbiome of mice with obesity, which seemed to alter ECS expression in fat tissues, improving lipid metabolism and fat cell formation. Though the exact mechanism of the ECS on adipogenesis remains unclear, the authors concluded that the composition of gut bacteria, through endocannabinoid signaling, influences adipogenesis.

Furthermore, a scientific literature review published by Cani and colleagues in 2015 found a possible link between the ECS and the gut microbiome. The authors suggested that gut flora can affect levels of the endocannabinoids anandamide and 2-AG not only by acting on CB1 receptors but also by influencing the enzymes that break down the endocannabinoids. This review also found that lifestyle factors (such as high-fat diets, intake of prebiotics and/or probiotics, and antibiotic use) that alter the gut microbiome will subsequently affect expression of CB1 and CB2 receptors.5

The reports published by Cani et al in 2015 and Muccioli et al in 2010 explored the relationship between the ECS and the gut microbiome alone, without the administration of exogenous cannabinoids. Exogenous intake of cannabinoids may also affect gut microbiota, a possibility explored by an in vivo study published by Cluny and colleagues in 2015. Researchers experimented on mice to study the link between THC intake and gut microbiota. More specifically, the study investigated the influence of chronic THC administration on both gut microbiota and body weight in diet-induced obese mice and lean mice. Mice received either a lean or high-fat diet paired with either daily THC or a placebo over the course of six weeks.6

Researchers found that while the mice fed a high-fat diet paired with a placebo increased body mass by almost 20%, mice on a high-fat diet paired with THC didn’t gain any body mass on average. In fact, the ratio of “good” to “bad” gut bacteria in mice fed a high-fat diet paired with THC improved to resemble that of mice fed a more balanced, lean diet. That is, the researchers in this study found that THC may restore the skewed ratio of bacteria resulting from a high-fat diet, altering the gut microbiota and reversing obesity. Interestingly, the mice on the high-fat diet paired with THC had increased levels of a specific bacteria in their guts—Akkermansia muciniphila—compared with all the other groups of mice (even those on a lean diet). A muciniphila is a probiotic bacterium that may control adipose tissue metabolism. Essentially, the researchers concluded that pairing THC with a high-fat diet in mice prevented the growth of excess harmful bacteria, which thereby prevented obesity in lean mice and reversed obesity in diet-induced obese mice.6

The findings of this study were similar to those of a 2013 study by Everard et al, which found that adding A muciniphila to the diets of mice limited the amount of fat the mice gained and improved fat metabolism. The probiotic also increased CB2 receptors, which assist in controlling inflammation within the body by reducing levels of the cytokine interferon gamma. The suppression of interferon gamma has been shown to improve glucose tolerance and control of glucose metabolism, which may also play a role in adipose tissue metabolism.7

Interestingly, the gut microbiota play a role that goes beyond simply breaking down fat and regulating adipogenesis. Gut bacteria also regulate the epithelial barrier, a protective layer that lines the inside walls of the gastrointestinal tract. A report published in 2012 suggests that the critical role of gut bacteria on this protective barrier may be partly influenced by the interaction of gut bacteria with the ECS—with the CB1 receptors in particular. The findings indicate that the interaction of gut bacteria with the CB1 receptors is critical to maintaining the integrity of the gut lining.8 The epithelial barrier plays an important role in maintaining overall health and homeostasis within the body, so the relationship between CB1 receptors and gut microbiota is significant.

Furthermore, a study published in 2020 demonstrated that altering the gut microbiome led to significant changes in gene expression and signaling within what’s known as the endocannabinoidome, which is the broader system of enzymes, receptors, and lipid mediators related to the ECS. Researchers studied germ-free mice (mice that lacked any gut microbiota) and conventional mice, assessing ECS genetic expression and the lipid profiles of both types of mice. They found that germ-free mice exhibited specific modifications in intestinal ECS genetic expression as well as in lipid mediator levels. The scientists then reintroduced a functional gut microbiome into the germ-free mice via fecal microbiota transplant, using samples from the conventional mice. After fecal transplant, the scientists found that the modifications that existed prior to fecal transplant in the germ-free mice (particularly within the jejunum and ileum) were reversed after only one week. The findings suggest that the gut microbiome directly affects the ECS, possibly influencing ECS signaling and subsequent physiopathologic functions.9

Cannabis, Gut Bacteria, and Neurodegenerative Disease
Multiple sclerosis (MS) is a debilitating neurodegenerative disease characterized by brain inflammation and symptoms including tremors, spasticity, and paralysis. In 2019, Al-Ghezi and colleagues published a report exploring the impact of cannabis on an animal model of MS using experimental autoimmune encephalomyelitis (EAE). This animal model closely mimics the conditions observed within a human brain afflicted by MS. A drug comprising a combination of THC and CBD is used as a treatment for muscle spasticity in human MS patients. This study sought to explore the mechanism of reduced neuroinflammation in MS patients utilizing cannabis, assessing the possible role of the gut microbiome in reducing signs of paralysis and inflammation observed in cannabis-using MS patients.10

Investigators found that the combination of THC and CBD attenuated EAE (reducing tremors and spasticity) and significantly decreased inflammatory cytokines while promoting anti-inflammatory cytokines. The investigators also found that mice with EAE showed high levels of A muciniphila, the probiotic both used and found in the studies discussed earlier with regard to the ECS, gut bacteria, and adipogenesis. A muciniphila, despite its favorable effects on lipid metabolism, is a mucin-degrading bacteria that has been indicated in the exacerbation of MS symptoms in humans. Levels of this bacteria were reduced after treatment with the THC and CBD combination. The mice with EAE who were treated with THC and CBD also demonstrated higher levels of short-chain fatty acids, which have a demonstrated anti-inflammatory role within the body, regulating the body’s inflammatory response through the suppression of proinflammatory proteins. Ultimately, the data from this study suggest that exogenous cannabinoids may attenuate EAE and its symptoms while also suppressing neuroinflammation. Exogenous cannabinoids may prevent the microbial dysbiosis observed in EAE and promote a healthy microbiome within the gut. Interestingly, the study found that THC or CBD alone weren’t effective in attenuating EAE.10

Cannabis, Gut Bacteria, and Cognition
A study published in 2017 explored the impact of cannabis on cognition, studying the link between gut dysbiosis and cognitive deficiency. Researchers compared the fecal microbiota between 19 chronic cannabis users and 20 nonusers and assessed the presence of two types of bacteria: Prevotella and Bacteroides. Prevotella is associated with a plant-based diet, while Bacteroides is associated with an animal-based diet. Gut bacteria in individuals following plant-based diets tend to have a higher ratio of beneficial bacteria compared with their animal-consuming counterparts. Researchers found that nonusers had a higher ratio of Prevotella to Bacteroides. The higher levels of Prevotella correlated positively with mitochondrial function and cognition. The researchers found that the lower Prevotella to Bacteroides ratio observed in cannabis users, combined with a diet low in antioxidants and fiber, may depress mitochondrial function and short-chain fatty acid production, possibly leading to cognitive deficiencies.11

Conclusion
A growing body of evidence supports an integrated relationship between the gut microbiome and the ECS, sometimes referred to as the gut-endocannabinoid axis. Though research affirms that there’s indeed a connection between the ECS and gut microbiota, the exact mechanism remains unclear. Because of this ambiguity, the impact of the gut microbiota on ECS genetic expression (and vice versa) and the resulting effect on lipid metabolism warrants further research. Moreover, the relationship between the ECS and gut microorganisms seems to play a critical role in maintaining the integrity of the gut barrier; further research may uncover the true extent of the systematic influence of this integrated relationship. Finally, exogenous cannabis intake can serve as a bridge between the ECS and the gut microbiome, affecting the body’s functioning on a level as innocuous as adipogenesis or as life-altering as neurodegenerative disease.

— Sandeep Kaur Dhillon, MS, RDN, received her master’s degree in nutrition and exercise physiology from Columbia University. She completed her dietetic training in New York City and practices as a dietitian in Los Angeles.

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