How cannabinoids regulate immune responses in the digestive system

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Courtesy of Lift Magazine

The gut is exposed to all kinds of strange bugs and other bad stuff on a daily basis. Just as an airport has security staff, the gut employs an immune system to scan for dangerous elements—such as toxins, bacteria and viruses—and promptly neutralize them.

Since immune responses always pose a cost to healthy tissue (inflammatory responses and destruction of compromised cells), the gut must be capable of returning to a non-alert status as soon as the threat has been diffused. Diabetes type 1 is a tragic example of what happens when the immune system fails to execute this step. In this condition, a group of pancreatic cells that produce insulin is continuously destroyed by the activity of the gut immune system.

The system that dials the level of immune activity in the gut is not yet fully understood, but according to a recent publication, the endocannabinoid system (eCS) could play a major role in it. The work studied rats and was led by Sreyashi Basu and Pramod Srivastava from the University of Connecticut School of Medicine, and was published in the Proceedings of the National Academy of Sciences.

The researchers’ work elegantly shows how the eCS activates a group of cells known as mononuclear phagocytes, which exists in abundance in the small intestine, and is vital for the fine balance between inflammation and tolerance responses in the gut.

The first piece of evidence came from the finding that two eCS receptors—CB2 and TRPV1—are greatly expressed in the membranes of these mononuclear phagocytes. Importantly, this pattern of expression was higher than in any other population of gut immune cells, suggesting a specific role of the eCS.

Next, the authors looked at what happened to the population of mononuclear phagocytes in mutant rats that lack either CB2 or TRPV1 receptors. In both cases, these cells were found in much fewer numbers in the intestine. Other similar cells that play different roles in the gut immune system were unaltered.

Having ascertained what happens in the absence of cannabinoid receptors, the next step was to ascertain what happens when they are stimulated. As expected, when the rats were administered the endocannabinoid anandamide, the same pattern in immune cell recruitment was observed. This effect was replicated in mice that lacked the FAAH enzyme that metabolizes anandamide in the body.

But how is the gut eCS activated under natural circumstances? Without exhausting other possibilities, the researchers showed that ingestion of capsaicin (the active ingredient in chili peppers) led to anandamide production by activation of TRPV1 receptors. The latter then activated CB2 receptors in the gut that recruited the immunosuppressive phagocyte cells mentioned earlier.

Finally, the authors tested the ability of anandamide to protect against type 1 diabetes in mice. Sure enough, the mice treated with anandamide coped better with their condition (as measured by blood glucose), and were found to express several tolerogenic and anti-inflammatory substances in higher quantities than those diabetic mice that did not receive the cannabinoid. This effect was most probably due to

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