Gut transporter protein mediates beneficial endocannabinoid release

Last Updated: 2018-08-15

By Will Boggs MD

NEW YORK (Reuters Health) - Intestinal P-glycoprotein promotes the release of endocannabinoids into the gut, where they reduce inflammation and maintain homeostasis, researchers report.

"There has been extensive, but to date mostly anecdotal, support for a beneficial role for cannabinoids and cannabis-derived agents to provide benefit for symptoms in individuals suffering from intestinal inflammatory disease (IBD)," said Dr. Beth A. McCormick of the University of Massachusetts Medical School, in Worcester.

"Our studies have provided one possible rationale for these previous findings: that there is a constitutively active efflux system at the luminal surface of cells that line the intestine that pumps out one class of lipids of the family known as endocannabinoids," she told Reuters Health by email.

Dr. McCormick's team investigated the mechanisms by which epithelial cells in the intestine regulate trans-epithelial neutrophil migration during inflammation and homeostasis.

Defects in P-glycoprotein expression or function are associated with IBD, and mice lacking the gene that encodes P-glycoprotein develop spontaneous intestinal inflammation.

The researchers discovered strong signals for agonist activity at the peripheral cannabinoid receptor in response to P-glycoprotein, suggesting that the mediator was one or more endocannabinoids.

Mass spectrometry results were consistent with the hypothesis that P-glycoprotein specifically secretes endocannabinoids of the N-acyl ethanolamine class, the team reports in the Journal of Clinical Investigation, online August 13.

In further experiments, cannabinoid-receptor expression contributed to inhibition of neutrophil transmigration, supporting an anti-inflammatory and homeostatic role for the P-glycoprotein/endocannabinoid pathway.

"Our studies are the first demonstration of a mechanism used by endocannabinoids for secretion from cells," Dr. McCormick said. "This is a significant advance to further understanding endocannabinoid biology that can lead to advances in improving medicinal applications of cannabis-derived agents."

"There is the immediate opportunity to use this research to identify new therapeutic strategies to treat individuals suffering from IBD that could include either agents extracted from marijuana plants or novel molecules selected based upon superior properties made obvious by this newly defined mechanism," she said. "However, it should not go unnoticed that a secondary significant aspect of our work involves an improved understanding of P-glycoprotein function with regard to endocannabinoids."

"This information could be directed towards better treatments for solid tumors, where the resistance to anti-cancer agents is mediated by the over-expression of P-glycoprotein," Dr. McCormick said. "Additionally, many promising therapeutics to treat conditions, such as Alzheimer's and Parkinson's diseases, are limited by their active exclusion by P-glycoprotein expressed in the blood vessels of the brain. Thus, our data provides the potential to improve treatments in oncology and neurology."

Dr. Pramod K. Srivastava of the University of Connecticut School of Medicine, in Farmington, told Reuters Health by email, "They confirm the fact that endocannabinoids play a critical role in tamping down inflammation in the gut. Our paper (https://bit.ly/2MxBneA) was the first to formally show this."

He said these findings suggest "the possibility of formally testing the utility of endocannabinoids, given orally (not inhaled) in IBD, colitis, etc. (This) should be of interest to academic physicians interested in clinical trials."

Dr. Srivastava added, "This is still in the domain of research, including clinical research. It has no relevance to clinical medicine as practiced today."

Dr. McCormick and another author are coinventors on a patent application related to these findings.

SOURCE: https://bit.ly/2Mq6wQW

J Clin Invest 2018.