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New research sheds light on the mechanisms by which exercise lowers inflammation. Artem Varnitsin/EyeEm/Getty Images
  • Endogenous cannabinoids, which the body produces, are cannabis-like compounds that play an important role in modulating metabolism and inflammation.
  • Microorganisms in the gut, collectively known as the gut microbiota, produce short-chain fatty acids upon the breakdown of dietary fiber.
  • Experts know that endogenous cannabinoids have anti-inflammatory effects, as do the short-chain fatty acids that the gut microbiota produces.
  • A new study reports that a 6-week exercise intervention reduced inflammatory marker levels and that this effect accompanied higher endocannabinoid and short-chain fatty acid levels.
  • These results suggest that the short-chain fatty acids that gut microorganisms produce may interact with endocannabinoids to exert anti-inflammatory effects.

Cannabis exerts its effects on the body by binding to cannabinoid receptors. These cannabinoid receptors also bind to endogenous cannabinoids that the body makes, called endocannabinoids.

Endocannabinoids are involved in the modulation of numerous biological processes, including metabolism, pain, inflammation, and transmission of information in the brain. The release of endocannabinoids, along with opioids, is also responsible for the feeling of euphoria that people generally experience after an intense workout.

A new study has shown that daily physical exercise is effective in lowering the levels of inflammation-related markers. Moreover, the study suggests that the endocannabinoid system may interact with gut microorganisms to produce such a reduction in inflammatory markers.

Researchers at the University of Nottingham led the research, which appears in the journal Gut Microbes.

Endocannabinoids bind to cannabinoid receptors present in the brain, peripheral nervous system, and immune system. The enteric nervous system, which controls the gut, also expresses cannabinoid receptors.

The dysregulation of the endocannabinoid system is associated with obesity and metabolic disorders.

Microorganisms present in the gut, which people collectively refer to as the gut microbiota, also have a significant influence on metabolism. Changes in the composition of these microorganisms, including reduced diversity of gut microorganisms, are associated with obesity and other metabolic disorders.

Studies suggest that the endocannabinoid system interacts with the gut microbiota to influence metabolism and energy homeostasis.

For instance, gut microbiota composition can influence endocannabinoid and cannabinoid receptor levels in the intestine. Specifically, changes in gut microbiome composition in obesity occur alongside lower endocannabinoid levels.

Obesity and other metabolic disorders are also associated with chronic, low grade inflammation. Both endocannabinoids and gut microbiota are involved in the modulation of inflammation, including in the aforementioned conditions.

Certain gut bacteria species can break down dietary fiber to produce short-chain fatty acids. These short-chain fatty acids have a link with lower inflammation and may exert protective effects against obesity.

Similarly, the endocannabinoid system can limit inflammation, and changes in the endocannabinoid system are observed in irritable bowel syndrome (IBS) and obesity.

Scientists do not fully understand whether the short-chain fatty acids that gut microorganisms produce can interact with the endocannabinoid system to produce anti-inflammatory effects.

The present study reports that the endocannabinoid system may mediate, in part, the anti-inflammatory effects of short-chain fatty acids that the gut microbiota produces, and vice versa.

Exercise is associated with an increase in endocannabinoid levels and long-term anti-inflammatory effects. The researchers used a 6-week exercise intervention to investigate further the association between endocannabinoids, inflammation, and short-chain fatty acids produced by gut microorganisms.

The researchers found that physical exercise was associated with lower inflammation, which higher short-chain fatty acid and endocannabinoid levels accompanied.

The study’s first author, Dr. Amrita Vijay, a research associate at the University of Nottingham, told Medical News Today:

“The findings from the current study highlight that simple lifestyle interventions such as exercise can modulate endocannabinoids, and this is a timely discovery, especially in the time when there is increasing interest around the use of cannabidiol and other related supplements in reducing levels of inflammation.”

The present study involved two cohorts. The first cohort consisted of 78 adults who were aged over 45 years, living with knee arthritis, and residing in a community setting.

The researchers examined the relationship between the endocannabinoid system, gut microbiota, and inflammation in this cohort at baseline. They then confirmed these results in a second cohort consisting of 35 individuals over 18 years of age.

The researchers also assessed the effects of a 6-week exercise intervention tailored to people with osteoarthritis on the relationship between the endocannabinoid system, inflammation, and gut microbiota in the first cohort. To do this, they divided the participants into a treatment group, consisting of 38 participants, and a control group, involving 40 individuals.

The researchers used blood samples from the participants to evaluate the serum levels of endocannabinoids, short-chain fatty acids, and inflammatory markers. The inflammatory markers included cytokines, a class of immune proteins that have either pro-inflammatory or anti-inflammatory effects.

The team used stool samples and conducted DNA sequencing to assess the abundance of various gut microbiota species.

Before the onset of the exercise intervention in the first cohort, the researchers found that endocannabinoid levels had a positive correlation with gut microbial diversity, short-chain fatty acids levels, and levels of gut microbiota species that produce these short-chain fatty acids.

In contrast, higher endocannabinoid levels were associated with lower levels of Collinsella, a gut bacteria genus that is linked with increased inflammation.

Consistent with these results, endocannabinoid levels were positively correlated with anti-inflammatory cytokines levels but had a negative relationship with pro-inflammatory cytokine levels. These results from the first cohort were similar to those that the team obtained from the second cohort.

The researchers then estimated the contribution of endocannabinoids to mediating the anti-inflammatory effects of short-chain fatty acids. They used a statistical method called mediation analysis, which can help estimate the extent to which a third factor plays a role in mediating the relationship between two variables.

They found that endocannabinoids mediated roughly one-third of the effects of short-chain fatty acids on inflammatory markers. This suggests that other biological factors or pathways, in addition to the endocannabinoid system, may play a role in mediating the anti-inflammatory effects of short-chain fatty acids that the gut microbiome produces.

Likewise, the researchers investigated the extent to which short-chain fatty acids mediated the effects of endocannabinoids on inflammation. They estimated that short-chain fatty acids mediated about half of these effects.

However, the authors caution that such estimates, which they obtained using mediation analysis, do not imply causality.

Next, the researchers examined how the 6-week exercise intervention affected the association between endocannabinoids levels on one hand and short-chain fatty acid levels, gut microbiome composition, and inflammatory markers on the other.

They found that endocannabinoid and short-chain fatty acid levels increased in the exercise group but did not show any changes in the control group. At the same time, there was a decline in the level of pro-inflammatory cytokines in the participants in the exercise group.

Changes in the levels of the endocannabinoid anandamide correlated with the short-chain fatty acid butyrate after 6 weeks across the two groups. Moreover, the researcher found a positive correlation between the changes in endocannabinoid levels and the increase in the abundance of short-chain fatty acid-producing bacteria.

On the other hand, changes in endocannabinoid levels were negatively correlated with the changes in the abundance of bacteria and cytokines associated with pro-inflammatory effects.

Lastly, the endocannabinoid levels were positively associated with the expression levels of the genes for the short-chain fatty acid receptor FFAR2 and the cannabinoid receptor CNR2.

The short-chain fatty acid receptor is associated with a lower risk of obesity, whereas CNR2 is associated with anti-inflammatory effects.

These results suggest that the anti-inflammatory effects resulting from physical exercise could potentially involve an interaction between endocannabinoids and short-chain fatty acids.

Highlighting the study’s salience, Dr. Vijay said, “The findings are novel, as we may have found a key link between how substances produced by gut microbes interact with the substances produced by our own bodies, which tell us how physical exercise reduces inflammation.”

The authors note that their findings are observational and do not establish causation. Furthermore, Dr. Vijay added, “The exercise intervention we carried out was performed in individuals with painful knee osteoarthritis and may not be directly relevant to other groups.”

“It would be interesting to test if different forms of exercise have different effects on our bodies in relation to the levels of these substances being produced and thereby influencing inflammation. It is also important to consider the effect of diet on these relationships.”

– Dr. Vijay