People with inflammatory bowel disease (IBD) can continue to experience severe bowel pain even after inflammation has been controlled and a colonoscopy appears normal. A new laboratory study identifies a previously unknown pain pathway in which stiffened intestinal tissue activates the Piezo1 protein in resident immune cells, prompting them to release nerve growth factor (NGF), which heightens pain signals. The findings may point to more targeted treatments for intestinal pain.
The study was published Oct. 23 in the journal Science Immunology.
A pain signal that persists after inflammation
“Inflammation in the gut has always been thought of as being like a fire; the smoke and heat should cause sensory nerves to sound an alarm, and when the fire goes out, the alarm should stop,” the study’s co-authors said. Dr. Heng Shu of Shanghai’s Ninth People’s Hospital and colleagues set out to identify what might cause pain even when there was no visible “fire” or “smoke.”
Ulcerative colitis, the most common form of IBD, causes inflammation and ulcers in the intestines. Symptoms can include bloody diarrhea and abdominal pain. Although some medications reduce inflammation, they do not necessarily eliminate pain.
“What we found is that the consistency of the tissue itself changes,” study co-author Xu told Live Science via email. “It hardens like a scar, loses its elasticity, and its hardness alone keeps the alarm going off even after the fire is extinguished.”
The researchers suspected that immune cells living in the gut could be contributing to this persistent pain. They focused on Piezo1, a protein known to participate in inflammatory responses in immune cells and to help transmit pain signals in neurons.
How stiff tissue may activate pain
The team began by analyzing sequencing data one cell at a time from intestinal tissue taken from people with ulcerative colitis and from mice with the disease. One cell type stood out: immune cells that permanently reside in the intestinal wall rather than arriving from the bloodstream in response to an injury or infection.
These cells were more abundant in colitis than in healthy intestinal tissue, and they contained more Piezo1 than the other cell types the researchers examined. “They’re sitting touching the nerve endings,” Schuh said.
In several experiments involving mice with colitis, the researchers used a probe to press against intestinal tissue and measure its stiffness. The intestines were stiffer in both disease models than in healthy mice. One model involved visible inflammation, while the other involved very little inflammation.
The researchers also measured pain in both groups. “Mice with little intestinal inflammation still had pain, which is why patients can appear normal on colonoscopies even when they are in pain,” Xu said.
Piezo1 is located in the membranes of immune cells. When the surrounding stiff tissue pulls on or compresses the cells, it appears to activate the protein as if pressing a button and opens a channel, Xu said. This triggers a chain of events that causes pain, Schuh said.
Calcium ions then flow into the cells through the channels. The resulting surge moves a protein called NF-κB from the cell’s internal fluid into the nucleus, where DNA is stored. NF-κB activates a gene that instructs the cells to produce NGF, which the immune cells release.
NGF is known to amplify pain signals and interact with nearby pain-sensing neurons. Research suggests that these nerve endings can become denser and more sensitive, making ordinary bowel movements painful.
Blocking the pathway reduced pain in mice
The researchers used a chemical switch to turn Piezo1 on and off in immune cells. As they opened or closed the channel, calcium signals and NGF production rose and fell accordingly. This suggests that Piezo1 activity is necessary for the response and is sufficient to trigger it in these cells, Xu said.
Blocking the sequence of events eliminated pain hypersensitivity in both mouse models. When the researchers removed the Piezo1 gene from intestinal immune cells, the mice no longer showed pain. Removing the gene did not cause problems in healthy mice, the researchers noted.
Hu Hongzhen, scientific director of the Mark Lebwohl Center for Neuroinflammation and Sensory at the Icahn School of Medicine at Mount Sinai, was not involved in the study and said it was “well controlled.” However, future research will need to examine cytokines — chemical messengers that regulate inflammation — to determine whether the same chain reaction occurs in human cells, he said in an email.
Xu also cautioned that the mouse experiments may not fully reflect the long-term chronic disease experienced by patients, because the mice had symptoms only temporarily.
Potential treatments
Xu and colleagues are now seeking to develop drugs that target Piezo1 and locally switch off intestinal pain without suppressing the entire immune system. Such an approach would be more targeted than current options, including immunosuppressants and opioids.
Other scientists are investigating anti-NGF treatments for chronic pain conditions other than ulcerative colitis, Xu said. Completely blocking NGF could have drawbacks because the protein also helps maintain nerves.
Further research is therefore needed before the findings can be translated into a treatment. For now, the study offers new insight into how immune cells detect physical changes such as tissue stiffening and convert them into pain signals.
“For the pain field, this is a conceptual shift,” Xu said.
This article is for informational purposes only and does not provide medical advice.
Wu, L., Shen, T., Wang, Z., Wang, T., Hu, X., Sun, M., Zhang, L., Cheng, Y., Hao, Y., Zhou, L., Lin, M., Bian, J., Feng, J., and Xu, H. (2026). Autonomous mechanosensory relay of macrophages and nociceptors causes chronic visceral pain. Science Immunology, 11(124).
Source: www.livescience.com