Pain in the gut may be part of a protective cycle

In findings published October 14 in Cell, researchers from Harvard Medical School report that physical pain may do more than alert the conscious mind to injury. It may provide some of humanity’s most important partners, our symbiotic gut bacteria, with the environment they need to help us thrive.

The researchers raised a group of laboratory mice without pain neurons and discovered that they also suffered from dysregulation of both the production of mucus along the lumen of the intestine where gut bacteria live and of the bacteria themselves. This condition is called dysbiosis. It occurs the proportions of helpful and unhelpful bacterial species have changed so much that it makes the host ill.

“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.” 

—senior co-author and Blavatnik Institute associate professor of immunobiology Isaac Chiu

Further investigation showed that the pain neurons in questions could do double duting communicating with nearby goblet cells, the cup-shaped units in the intestine that produce mucus. The scientists identified the RAMP1 receptor, present on the goblet cells, and a neuropeptide called CGRP, released by the neurons, as likely mediators of this communication.

They also found that the neurons respond to the microbes themselves, completing a nerve-goblet-microbe triad that can produce either a positive or negative feedback loop: One step in the process can cause the other two to speed up or slow down. Because this process takes place in the gut, dietary factors can trigger it too.

“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.”

—lead author, post-doc Daping Yang

In other words, pain causes the neurons to release CGRP, which causes the goblet cells to produce mucus, which protects the microbes. Dr. Chiu pointed out that this may have some implications for the way we treat both gut pain and other conditions. Some medicines prescribed for migraines, for example, specifically suppress CGRP.

“Given that CGRP is a mediator of goblet cell function and mucus production, if we are chronically blocking this protective mechanism in people with migraine and if they are taking these medications long-term, what happens? … Are the drugs going to interfere with the mucosal lining and people’s microbiomes?”

—Chiu

Dr. Yang suggests that individuals predisposed to inflammatory bowel disease may suffer from malfunctions in the CGRP signaling pathway.

Read the full paper in Cell at 10.1016/j.cell.2022.09.024.