A study from Weill Cornell Medicine found that pain-sensing neurons protect the gut from inflammation and the damage that comes with it by controlling the bacteria that live in the intestines.
In a preclinical model, the researchers discovered that pain-sensing neurons in the stomach emit a chemical known as substance P, which appears to protect against gut inflammation and related tissue damage by increasing the population of beneficial microorganisms in the gut. In people with inflammatory bowel disease, these pain-sensing nerves are significantly reduced in number, and their pain-signaling genes are significantly altered (IBD).
Dr. David Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease, director of the Friedman Center for Nutrition and Inflammation, and the Michael Kors Professor of Immunology at Weill Cornell Medicine, is the study’s senior author. “These findings change the way we think about chronic inflammatory diseases and suggest a whole new way to treat them.”
Dr. Wen Zhang, the study’s first author and a postdoctoral researcher in the Artis group, said, “Defining a previously unknown sensory function for these specific neurons in regulating the microbiota brings a new level of insight to host-microbiota interactions.”
IBD encompasses two different conditions, Crohn’s disease and ulcerative colitis, and is believed to impact millions of Americans. Typically, it is treated with medications that directly target immune system components. Scientists now know that bacteria and other microorganisms that live in the gut help control inflammation in the gut.
In recent years, Dr. Artis’s team and others have demonstrated that the nervous system, which is “wired” into most organs, appears to be an additional potent immune regulator at the body’s barrier surfaces. In the latest study, Dr. Artis and his colleagues focused on the pain-sensing neurons that innervate the gastrointestinal tract.
The cell bodies of these gut-innervating pain neurons are located in the lower spine, and they contain a surface protein called TRPV1 that functions as a receptor for pain-related signals. For instance, TRPV1 can be activated by intense heat, acid, and capsaicin from chili peppers, for instance, and the brain interprets this activation as a sensation of burning pain. In IBD mouse models, suppressing these TRPV1 receptors in gut nerves or deleting TRPV1-expressing neurons significantly exacerbated inflammation and tissue damage, but activating the receptors had a protective effect.
The researchers noticed that the increased inflammation and tissue damage in TRPV1-deficient animals were linked to alterations in the relative populations of certain kinds of gut bacteria. When this changed bacterial population was transplanted into normal mice, the same increased sensitivity to inflammation and injury was observed. In contrast, therapy with broad-spectrum antibiotics could reverse this susceptibility in TRPV1-deficient mice. This showed that TRPV1-expressing nerves protect the gut mainly by making sure there are enough healthy gut microbes.
The scientists discovered compelling evidence that a significant portion of the microbe-influencing action of TRPV1-expressing neurons stems from a chemical called substance P that is secreted by the nerves. They noticed that substance P could reverse most of the detrimental consequences of inhibiting TRPV1. Experiments also showed that communication between neurons and microorganisms went both ways, with some types of bacteria being able to make nerves that express TRPV1 release more substance P.
To make sure this also works for people, the researchers looked at the gut tissue of IBD patients and found that the TRPV1 and substance P genes were not working right and that there were fewer TRPV1 nerves in general.
Dr. Zhang said, “These patients had damaged nerves that sensed pain, which may have caused their ongoing inflammation.”
How substance P exerts its effects on the population of gut microorganisms and how these microbes “speak back” are topics that researchers are attempting to answer through current research. But based on what we know so far, the next generation of anti-inflammatory drugs for IBD and other diseases may be aimed at the nervous system.
Dr. Artis stated, “Many existing anti-inflammatory medications only function in a subset of patients, and pharma companies have no idea why.” “Perhaps it’s because, when it comes to chronic inflammation, we’ve only been able to view a portion of the picture; however, the remainder, including the role of the nervous system, is now coming into focus.”
