Pressure-Sensitive Protein PIEZO1 Found Key to Gut Movement

A study by scientists at Harvard Medical School and the Icahn School of Medicine at Mount Sinai has revealed how a pressure-sensitive protein, PIEZO1, helps regulate intestinal motility and control inflammation. The research, based on mouse models and published in Cell, explains how mechanical forces in the gut trigger peristalsis and may also modulate immune responses.

Enteric neurons use pressure to regulate motion

The intestines rely on rhythmic contractions called peristalsis to move food. While previous research established the role of enteric neurons – nerve cells embedded within the gut wall – in controlling these movements, the mechanism behind pressure sensing remained unclear.

The team found that PIEZO1, a protein known to detect mechanical pressure, is highly active in excitatory enteric neurons that release acetylcholine. By genetically modifying mice to glow green in PIEZO1-expressing neurons, researchers confirmed the protein’s presence in the cells responsible for initiating muscle contractions.

Further tests showed that when PIEZO1 was absent, intestinal tissues failed to contract in response to pressure, confirming its role as a pressure sensor in regulating gut motility.

Modulating PIEZO1 alters bowel movements

Using light-activated and chemically modified mouse models, the researchers demonstrated that activating PIEZO1 neurons accelerated waste passage, while disabling them slowed it down. This supports the protein’s essential role in normal digestive function.

Exercise, which increases pressure in the abdomen, also enhanced gut motility in normal mice. In contrast, mice lacking functional PIEZO1 genes showed no such increase, suggesting that PIEZO1 translates physical pressure into intestinal responses.

PIEZO1 affects immune response in IBD models

To understand PIEZO1's role in inflammation, the researchers used mouse models of inflammatory bowel disease (IBD). Mice with PIEZO1 showed typical increases in motility during inflammation, while those lacking it experienced more severe symptoms, including weight loss and loss of mucus-producing cells.

The worsening of inflammation was linked to a decrease in acetylcholine, a neurotransmitter known to support both muscle contraction and anti-inflammatory signaling. This indicates that PIEZO1 not only controls movement but also helps reduce gut inflammation by promoting acetylcholine release.

Potential target for IBD treatment

The findings suggest that PIEZO1 could be a therapeutic target for treating disorders like IBD, diarrhea or constipation. Stimulating or blocking PIEZO1 activity may help control gut motility or inflammation without suppressing the immune system more broadly.

“Eventually, we might stimulate PIEZO1 to speed up excretion, block it to treat diarrhea, or use it as a novel target to treat intestinal inflammation in IBD patients."

Dr. Ruaidhri Jackson.

Future studies by the team aim to explore drugs that selectively influence PIEZO1 in the gut, offering a new pathway for precision treatment of gastrointestinal disorders.

Reference: Xie Z, Rose L, Feng J, et al. Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force. Cell. doi: 10.1016/j.cell.2025.02.031

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