- A study in mice suggests that pain neurons in the gut help to regulate the secretion of protective mucus.
- The neurons responded to painful gut inflammation by signaling other cells to increase mucus production.
- In a healthy gut, friendly bacteria also appeared to interact with the neurons to regulate how much mucus was produced.
- The authors of the study speculate that some pain relief medications may interfere with the neurons’ ability to boost mucus production.
Pain — however unpleasant it can be — is necessary. It warns us about potentially harmful stimuli and motivates us to take evasive action. Pain in the gut, for example, might signal that we should avoid a particular type of food.
However, when pain is intense and unavoidable — such as a migraine headache — it makes sense to take a drug to help relieve it. But what if pain itself somehow contributes to bodily regulation and healing?
This is the tentative suggestion from a study led by researchers at Harvard Medical School in Boston, MA.
When the researchers simulated a painful inflammatory condition called colitis in mice, pain nerves in the animals’ gut triggered increased production of mucus — a slippery, gel-like substance made of proteins and sugars.
The scientists speculate that this response to painful stimuli may help to clear harmful substances from the gut.
The researchers also found that, even in the absence of painful stimuli, gut bacteria interacted with the pain neurons to help regulate mucus secretion.
“It turns out that pain may protect us in more direct ways than its classic job to detect potential harm and dispatch signals to the brain,” said senior author Isaac Chiu, Ph.D., an associate professor of immunobiology at Harvard’s Blavatnik Institute.
Prof. Chiu told Medical News Today that pain nerves in the gut “talk” to nearby mucus-secreting cells in the lining of the intestines.
“This means that the nervous system has a major role in the gut beyond just giving us an unpleasant sensation and that it’s a key player in gut barrier maintenance and a protective mechanism during inflammation,” he added.
The results were recently published in the journal Cell.
The importance of mucus
A mucus layer protects the linings of the intestines and airways from abrasion and other kinds of damage. In both the lungs and the gut, cup-shaped “goblet” cells produce mucus.
In the gut, the mucus helps to prevent its contents from leaking into the underlying tissue and also acts as a protective barrier against pathogens.
At the same time, mucus supports friendly or “commensal” gut bacteria, which play a vital role in our health.
The researchers discovered that the guts of mice that lacked pain neurons produced less mucus. In addition, there was an imbalance of beneficial and harmful gut microbes, known as “dysbiosis.”
The study revealed that pain neurons communicate directly with mucus-producing goblet cells through a signaling molecule called CGRP.
In response to painful stimuli, the nerve cells produce more CGRP. This molecule then binds to RAMP1, a receptor found on the surface of goblet cells in mice and humans.
The researchers found that this molecular signal triggers the goblet cells to churn out more mucus whenever the gut is inflamed, as happens in colitis.
But they also found that in the absence of any painful stimuli, friendly bacteria could stimulate the pain neurons to release small quantities of CGRP.
“This finding tells us that these nerves are triggered not only by acute inflammation but also at baseline,” Prof. Chiu said. “Just having regular gut microbes around appears to tickle the nerves and causes the goblet cells to release mucus.”
This ensures that these friendly or “commensal” gut microbes have a steady supply of mucus to help them thrive.
Particular substances in food — such as capsaicin, which gives chili peppers their intense heat — may also trigger mucus production. The researchers showed that capsaicin activated pain neurons in the gut of mice and promoted mucus production.
The regulatory role of pain
According to the researchers, there may be a link between gut dysbiosis, pain neurons, and inflammatory bowel diseases, such as ulcerative colitis.
They found that mice lacking either pain neurons or RAMP1 (the receptor for CGRP on goblet cells) were more prone to colitis. The condition was also more severe.
But if the scientists gave CGRP to mice without any pain neurons in their gut, it quickly restored mucus production.
“Pain is a common symptom of chronic inflammatory conditions of the gut, such as colitis, but our study shows that acute pain plays a direct protective role as well,” said Daping Yang, a postdoctoral researcher in the Chiu Lab and first author of the study.
In their paper, the authors suggest that acute pain helps to maintain the gut barrier in inflammatory bowel diseases.
When they simulated colitis in mice, animals without pain receptors in their gut experienced more severe disease.
“In people with inflammation of the gut, one of the major symptoms is pain, so you might think that we’d want to treat and block the pain to alleviate suffering,” Prof. Chiu said.
“But some part of this pain signal could be directly protective as a neural reflex, which raises important questions about how to carefully manage pain in a way that does not lead to other harms.”
Certain pain-relieving drugs could have unintended consequences.
“Opioids are known to cause significant microbial dysbiosis in the gut,” Prof. Chiu said.
Doctors also use drugs that block CGRP to treat and prevent chronic migraine. The authors speculate that over time this could interfere with their mucosal gut barrier and disturb the balance of gut bacteria.
Currently, there is no evidence that these drugs cause increased gut inflammation or dysbiosis, Prof. Chiu explained. But surveys have found that anti-CGRP migraine drugs cause constipation in more than 50% of patients who take them.
“It would be important to investigate if other gut issues arise, including inflammation and microbiome changes,” Prof. Chiu said.
Qasim Aziz, Ph.D., FRCP, professor of neurogastroenterology at the Queen Mary University of London in the U.K., not involved in the study, said the mechanism proposed by the researchers was “plausible” and so anti-CGRP therapies could, in theory, increase gut inflammation in humans.
“However, this is hypothetical at this stage and needs to be tested experimentally,” he told MNT. “This study, however, does provide an important point for consideration for future research, particularly for drug development.”
Limitations of the study
It’s important to note that the new study had some limitations.
For example, the authors write that in their simulation of colitis, some mice may have had less severe inflammation because they drank less water.
To recreate colitis, researchers add a noxious chemical called DSS to the animals’ drinking water, which could inadvertently condition some of the mice to avoid it.
Future studies in humans are still needed to better understand how pain neurons in the gut help regulate the secretion of protective mucus.
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