Stiff Gut Tissue, Not Inflammation, May Drive IBD Pain

"They sit touching the nerve endings," Xu said.

Piezo1 sits in the immune cell's membrane, where it acts like a pressure-sensitive button. In immune cells, the protein plays a role in inflammation; in neurons, it helps generate pain signals.

Here's the chain the researchers mapped:

• Stiffened tissue pulls or squeezes the immune cell, pressing the Piezo1 "button" and opening a channel.
• Calcium ions rush into the cell.
• That surge pushes a protein called NF-kB from the cell's interior fluid into the nucleus, the DNA control center.
• NF-kB switches on a gene ordering the cell to manufacture nerve growth factor (NGF).
• NGF exits the immune cell and makes nearby pain-sensing nerve endings grow denser and become hypersensitive — so ordinary gut activity hurts.

In mice with colitis, the researchers used a probe to press on gut tissue and measure its hardness. The gut was stiffer than in healthy mice in two disease models: one with visible inflammation and one with almost none. In that second group, "the pain was still there, which is why a colonoscopy can look normal while the patient hurts," Xu said.

Can the pain be switched off?

The team used chemicals as on-off switches for Piezo1 in immune cells, tracking calcium signals and NGF production. Both rose and fell in step with the switch — meaning Piezo1 activity is both necessary for the response and sufficient to trigger it.

Blocking the chain abolished pain hypersensitivity in both sets of mice. Deleting the Piezo1 gene entirely from gut immune cells eliminated the pain, and caused no problems in healthy mice.

The study was "well controlled," said Hongzhen Hu, scientific director of the Mark Lebwohl Center for Neuroinflammation and Sensation at the Icahn School of Medicine at Mount Sinai, who wasn't involved in the research. He cautioned that future work should examine cytokines — the chemical messengers that coordinate inflammation — and confirm the same chain reaction in human cells.

What are the limitations?

The mouse experiments may not reflect long-term chronic disease, Xu noted, since the mice experienced symptoms only transiently. And translating the findings into a treatment will take time.

Xu's team is now developing a drug that targets Piezo1 to switch off gut pain locally without suppressing the entire immune system — a more targeted approach than current options such as immunosuppressants or opioids.

Anti-NGF treatments have been explored for other chronic pain conditions but not for ulcerative colitis. Fully blocking NGF carries downsides, Xu said, because the protein also helps maintain nerves.

For now, the study shows how immune cells can detect a physical change — tissue stiffening — and convert it into a pain signal. "For the pain field, that's a conceptual shift," Xu said.