Scientists discover ‘chain reaction’ that leads to pain in ulcerative colitis

People with inflammatory bowel disease (IBD) experience gut pain that can be severe, and it doesn’t always go away when their inflammation is under control and their colonoscopy looks normal. Now, in a new laboratory study, researchers found a previously unknown pain pathway that may explain this phenomenon.

The findings, published Oct. 23 in the journal Science Immunology, also point to a potential way to block that pain.

“Inflammation in the gut has always been thought of like a fire: the sensory nerves alarm because of the smoke and the heat, and when the fire is put out the alarm should stop,” said study co-author Dr. Heng Xu, a physician at Ninth People’s Hospital in Shanghai. Xu and his colleagues set out to try to isolate what could be causing the pain even when there’s no visible “fire” or “smoke.”

“What we found is that the tissue itself changes consistency,” Xu told Live Science in an email. “It becomes stiff and less elastic, a bit like a scar, and that stiffness alone keeps triggering the alarm even after the fire is out.”

In ulcerative colitis, the most common form of IBD, inflammation causes ulcers in the gut, as well as symptoms like bloody diarrhea and abdominal cramping. Several medications can help quell this inflammation, but that doesn’t necessarily eliminate patients’ pain. The researchers wondered if immune cells that live in the gut might contribute to that ongoing pain.

They zoomed in on a protein called Piezo1; in immune cells, it’s known to play a role in inflammation, and in neurons, it contributes to pain signals. The team looked at whether this protein’s activity changed in the context of colitis.

“We started with sequencing data that reads cells one at a time, from the gut tissue of patients with ulcerative colitis and from mice with the disease,” Xu said. “One cell type stood out: an immune cell that lives permanently in the gut wall, rather than arriving from the bloodstream when there’s trouble.” The quantity of these cells was higher in colitis than in healthy guts, and the cells carried more Piezo1 than the other cells analyzed.

“They sit touching the nerve endings,” Xu added.

In several experiments with lab mice with colitis, the team used a probe to press on the gut tissue and measure how hard it was. This showed that, compared with healthy mice, the gut was stiffer in two models of disease: one with visible inflammation and another with almost none.

They also measured pain levels in both sets of mice. “In mice with almost no visible gut inflammation, the pain was still there, which is why a colonoscopy can look normal while the patient hurts,” Xu said.

They then looked at Piezo1 in both sets of mice. The protein sits in the immune-cell membrane, and when the stiffened tissue around it is pulled or squeezed, it’s as if a button were pressed and a channel opens, Xu said. This sets off a chain reaction that leads to pain, Xu said.

That’s because calcium ions rush into the cell via the channel, and that surge sends a protein called NF-kB from the cell’s interior fluid into its nucleus — the control center where DNA is stored. There, NF-kB plugs into a gene, ordering the cell to manufacture nerve growth factor (NGF) that then exits the immune cell.

This NGF, which is known to amplify pain signals in the body, interacts with nearby pain-sensing neurons. These nerve endings grow denser and become hypersensitive, which makes ordinary gut activity painful, the study suggests.

The researchers used chemicals as on-off switches for Piezo1 in immune cells, opening the channel with one and closing it with another. As they did this, they tracked calcium signals and NGF production, and both rose and fell in step with the switch. This result suggests that Piezo1 activity is both necessary for this response and, on its own, enough to trigger it in these cells, Xu said.

Blocking this chain of events abolished the pain hypersensitivity in both sets of mice. The researchers tried completely removing the Piezo1 gene from the gut immune cells and found that this eliminated the pain. Removing the gene also caused no problems in healthy mice, they noted.

The study was “well controlled,” said Hongzhen Hu, the scientific director for the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine at Mount Sinai, who was not involved in the research. Future research should address the chemical messengers that coordinate inflammation, called cytokines, and determine whether the same chain reaction occurs in human cells, he said in an email.

The mouse experiments also may not reflect long-term, chronic disease in patients, given the mice experienced symptoms only transiently, Xu said.

Xu and his colleagues are now aiming to develop a drug that can target Piezo1 to switch off gut pain locally without suppressing the entire immune system. This would be a more targeted treatment than current options, such as immunosuppressants or opioids.

Other scientists have explored using anti-NGF treatments for other chronic pain conditions but not for ulcerative colitis, Xu noted. Fully blocking NGF might have downsides, he said, since NGF also helps to maintain nerves.

So more work is needed to translate these findings into a treatment. But for now, the work sheds new light on how immune cells can detect a physical change — such as tissue becoming stiff — and convert it to a pain signal.

“For the pain field, that’s a conceptual shift,” Xu said.