Endocannabinoid Mechanism Found to Mellow Out Intestinal Inflammation

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Source: 400tmax/Getty Images
Source: 400tmax/Getty Images

Cannabis users report that the drug relieves symptoms of inflammatory bowel disease (IBD). Although the drug’s soothing effects may seem real enough to cannabis users, scientists have struggled to pin down a molecular mechanism that could explain how cannabis could calm the sometimes-harsh intestinal environment. In particular, scientists have sought a “counterbalance pathway,” a molecular mechanism that could resolve the kind of inflammation that occurs in ulcerative colitis and Crohn’s disease. According to a new paper, such a counterbalance pathway may have been found by a researcher from the University of Massachusetts Medical School and the University of Bath.

The researchers discovered that gut inflammation is regulated by two important processes, which are constantly in flux and responding to changing conditions in the intestinal environment. The first process, identified in previous scientific research, promotes an aggressive immune response in the gut that destroys dangerous pathogens, but which can also damage the lining of the intestine when immune cells attack indiscriminately.

The second pathway, first described in the new paper, turns off the inflammation response via special molecules transported across the epithelial cells lining the gut by the same process already known to remove toxins from these cells into the intestine cavity. Crucially, this response requires a naturally produced molecule called an endocannabinoid, which is very similar to cannabinoid molecules found in cannabis.

Details appeared August 13 in the Journal of Clinical Investigation, in an article titled, “Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis.” According to this article, certain endocannabinoids aren’t present, inflammation isn't kept in balance. In fact, inflammation can run unchecked as the body's immune cells attack the intestinal lining.

“We identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen,” wrote the article’s authors. “These results define a key role for epithelial cells in balancing the constitutive secretion of anti-inflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.”

The researchers hope that their findings will lead to the development of drugs and treatments for gut disorders, which affect millions of people around the world and are caused when the body's immune defenses mistakenly attack the lining of the intestine.

“There's been a lot of anecdotal evidence about the benefits of medical marijuana, but there hasn't been a lot of science to back it up,” said Beth A. McCormick, Ph.D., the article’s senior author and vice chair and professor of microbiology and physiological systems at UMass Medical School. “For the first time, we have an understanding of the molecules involved in the process and how endocannabinoids and cannabinoids control inflammation. This gives clinical researchers a new drug target to explore to treat patients that suffer from inflammatory bowel diseases, and perhaps other diseases, as well.”

The new mechanism, which was uncovered through knockdown experiments that explicated the link between endocannabinoid secretion and neutrophil influx in models of acute intestinal inflammation, has the potential to be therapeutically exploited.

“We need to be clear that while this is a plausible explanation for why marijuana users have reported cannabis relieves symptoms of IBD, we have thus far only evaluated this in mice and have not proven this experimentally in humans,” cautioned article co-author Randy Mrsny, a professor at the University of Bath’s Department of Pharmacy and Pharmacology. “We hope, however, that these findings will help us develop new ways to treat bowel diseases in humans.”








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