Why Gut Pain Can Persist in IBD After Inflammation Fades: Stiff Tissue May Be Why

Many people with inflammatory bowel disease (IBD) keep having severe gut pain even when medication has calmed their inflammation and a colonoscopy looks normal. A new laboratory study in mice points to a possible reason: the gut wall becomes stiff, and that stiffness alone can set off pain signals, according to Live Science.

The work was published Oct. 23 in the journal Science Immunology. It is early research in animals, and it has not been shown to work the same way in people.

What did the researchers find?

The team, which includes Dr. Heng Xu of Ninth People's Hospital in Shanghai, studied colitis, an inflammatory condition of the gut. Ulcerative colitis, the most common form of IBD, causes ulcers, bloody diarrhea and abdominal cramping. Drugs can reduce the inflammation, but that does not always end the pain.

Xu compared the old view of gut inflammation to a fire: the nerves sound an alarm because of smoke and heat, and the alarm should stop once the fire is out. The new results suggest that the tissue itself changes. It becomes stiff and less elastic, somewhat like scar tissue, and that stiffness keeps the alarm going, Xu told Live Science.

How does stiffness turn into pain?

The researchers first looked at single-cell sequencing data from patients with ulcerative colitis and from mice with the disease. One type of immune cell stood out. It lives permanently in the gut wall, sits against nerve endings and was more abundant in colitis. It also carried more of a protein called Piezo1 than the other cells analyzed.

In mice, the team pressed a probe on the gut tissue and found it was stiffer than in healthy animals. That held in two disease models, one with visible inflammation and one with almost none. Pain was present in both, including the model with little inflammation.

Xu described Piezo1 as a button on the immune cell's surface. When the stiff tissue around the cell is stretched or squeezed, a channel opens and calcium rushes in. That moves a protein called NF-kB into the cell's nucleus, where it switches on production of nerve growth factor, or NGF. NGF is known to amplify pain signals. According to the study, it makes nearby pain-sensing nerve endings grow denser and more sensitive, so ordinary gut activity hurts.

How strong is the evidence?

The researchers used chemicals to open and close the Piezo1 channel in immune cells. Calcium signals and NGF production rose and fell along with the switch. Xu said this suggests Piezo1 activity is both necessary for the response and enough to trigger it in these cells.

Blocking the chain of events removed the pain hypersensitivity in both sets of mice. Deleting the Piezo1 gene from the gut immune cells also eliminated the pain, and it caused no problems in healthy mice, the team reported.

Hongzhen Hu of the Icahn School of Medicine at Mount Sinai, who was not involved, called the study well controlled. He said future work should look at cytokines, the chemical messengers that coordinate inflammation, and test whether the same sequence occurs in human cells. Xu added that the mice had symptoms only temporarily, so the experiments may not reflect long-term chronic disease in patients.

Why does it matter for people with IBD?

If the findings hold up in humans, they could help explain why pain can continue when scans and tests show little inflammation. Current options for easing the pain include immunosuppressants and opioids. Xu said his group is now trying to develop a drug that targets Piezo1 to switch off gut pain locally without suppressing the whole immune system.

Blocking NGF is another idea that has been explored for other chronic pain conditions, but not for ulcerative colitis, Xu noted. Shutting it off completely could carry downsides, since NGF also helps maintain nerves.

What happens next?

More work is needed before any treatment could result. Beyond the clinical questions, Xu said the study shows how immune cells can sense a physical change, such as tissue turning stiff, and convert it into a pain signal. He called that “a conceptual shift” for the pain field.

Live Science noted that its article is for information only and is not medical advice.

Around Prague, based on reporting by Live Science