Gut immune cells sustain pain even without inflammation through newly identified signaling pathway

by Sanjukta Mondal, Medical Xpress

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People with inflammatory bowel conditions such as ulcerative colitis often suffer from severe, long-lasting gut pain that lingers even after signs of inflammation are gone. Such abdominal pain can significantly affect one's quality of life, but unfortunately there are few treatment options. Uncertainty about the underlying mechanisms that drive this type of pain is responsible for the lack of effective treatments.

To clarify these mechanisms, researchers investigated how chronic gut pain is triggered and sustained in conditions like ulcerative colitis, focusing on the behavior of immune cells. They wanted to see if immune cells could directly feel physical pressure and trigger pain via nerve sensitization.

With the help of genetically engineered mice with ulcerative colitis-like inflammation, the researchers examined whether gut-wall immune cells called tissue-resident CX3CR1⁺ macrophages carry the mechanosensitive channel Piezo1. They then traced how tissue stiffness sets off a molecular chain reaction through this channel and the role it plays in pain pathways.

The resident CX3CR1⁺ macrophages turned out to be the major actors. They use Piezo1 to sense harmful mechanical changes in inflamed tissue, which activates a protein that switches on nerve growth factor (NGF) production. NGF carries the pain message from the immune cell to the pain-sensing nerve. Disrupting any part of this process by genetically knocking it out eliminated visceral pain sensitivity in both inflammatory and noninflammatory models.

The findings are published in Science Immunology.

In search of the mystery component

Doctors have noticed that, in clinical practice, anti-inflammatory drugs can heal the gut lining, clear active ulcers and calm the immune system in people with inflammatory bowel conditions such as ulcerative colitis. Yet many patients continue to suffer from severe, debilitating abdominal pain long after their inflammation appears completely resolved.

Current understanding of chronic gut pain usually hinges on chemical pathways in which inflamed immune cells release inflammatory molecules such as cytokines, which irritate nearby nerves. However, if this were true, anti-inflammatory medications should have resolved the pain, but in many cases they don't, so there must be an additional component involved.

Since immune cells are part of the pathway responsible for pain sensitization, the researchers wanted to know if they had a role beyond sensing chemical cues and whether they reacted to direct physical pressure or tissue stiffness.

For the experiments, the team gave mice drinking water containing 2.5% dextran sulfate sodium for seven days to mimic active ulcerative colitis, triggering severe chemical inflammation and damage to colon tissue. To induce tissue stiffening and visceral pain without inflammation, they administered zymosan, a yeast derivative, directly into the rectum.

The researchers also selectively deleted three genes: the mechanical sensor Piezo1 and Ngf from resident Cx3cr1 macrophages, and Ntrk1, which encodes the NGF receptor TrkA, from pain-sensing Trpv1 nerves. To gauge the mice's gut pain, the researchers inflated a tiny balloon inside the colon in gradually increasing steps, from 20 to 80 µl, while recording the electrical activity of abdominal wall muscles using electromyography (EMG).

Immune cells at play

They found that as the intestinal wall stiffens during colitis and after injury, Piezo1 on tissue-resident CX3CR1⁺ macrophages opens, allowing calcium to flood into the cells. This calcium surge activates the NF-κB signaling pathway, which enters the nucleus and binds directly to the nerve growth factor gene promoter, driving NGF production.

The released NGF binds to TrkA receptors on nearby TRPV1⁺ pain-sensing nerves, prompting them to grow and send out extra branches throughout the gut wall. This lowers the pain threshold, causing even normal movements like intestinal stretching to trigger severe visceral pain.

The researchers observed the same pathway in mice without inflammation, showing that mechanical forces alone can drive chronic pain, independently of inflammatory signals. However, Piezo1 in newly arriving macrophages did not have the same effect. This indicated that having the pressure sensor is not enough to cause chronic gut pain; an immune cell must be parked directly next to a pain nerve to deliver the message.

Blocking this signaling circuit at any point, either genetically or with drugs, eliminated chronic pain in the mouse model. This held true for deletion of Piezo1 or Ngf from resident macrophages, as well as removing or blocking Ntrk1 from TRPV1⁺ nerves. Future studies could investigate different ways these elements can be targeted using drugs to reduce the pain of those living with chronic gut pain due to ulcerative colitis.

Written for you by our author Sanjukta Mondal, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Liyan Wu et al., An autonomous macrophage-nociceptor mechanosensory relay drives chronic visceral pain, Science Immunology (2026). DOI: 10.1126/sciimmunol.aeb3809

Journal information: Science Immunology

Key medical concepts

PIEZO1 GeneNerve Growth Factor

Clinical categories

GastroenterologyDigestive healthAllergy and immunology Who's behind this story?

Sanjukta Mondal

Master's in Chemistry. Freelance science journalist and communicator. Published in Chemistry World, BioSpace, and The Hindu. Full profile →

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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