Inflammation may trigger protective cell shift in ulcerative colitis, study finds
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Paneth cell metaplasia (PCM), long viewed as a consequence of chronic inflammation in ulcerative colitis, may also help protect and repair the intestine, according to researchers at Science Tokyo. The study found that inflammation increases IL-22 signaling, which promotes PCM and the production of REG3A, a protein that helps heal the intestinal lining. The findings suggest PCM may be a protective response but should be monitored because persistent PCM could increase cancer risk.
Chronic inflammation can trigger a process called metaplasia, in which cells not normally found in a tissue begin to appear as the body adapts to ongoing damage. In the colon, one such change is called Paneth cell metaplasia (PCM), where Paneth cells, which are normally found in the small intestine, begin to appear in the colon. PCM has been observed in patients with ulcerative colitis (UC), a type of inflammatory bowel disease that causes inflammation and ulcers in the inner lining of the colon and rectum. However, its exact role in UC and the reasons why it develops have remained unclear.
Now, researchers from the Institute of Science Tokyo (Science Tokyo), Japan, have discovered that PCM may function as part of a protective repair response in the inflamed intestine. The study, published in the journal Nature Communications on March 28, 2026, was led by Assistant Professor Go Ito, together with graduate student Tomohiro Muto from the Department of Gastroenterology and Hepatology at Science Tokyo.
The study was performed as part of an international collaboration between Science Tokyo and the Institute of Molecular Biology, Kiel University (Christian-Albrechts-University), Germany, with contributions from Professor Stefan Schreiber and Professor Philip Rosenstiel. Analysis of endoscopic biopsy samples further showed that PCM was associated with ongoing microscopic inflammation and became more common in the left colon as disease duration increased.
To investigate how PCM develops, the researchers analyzed gene activity in metaplastic Paneth cells from patients with UC. Compared with normal Paneth cells, the metaplastic cells produced lower levels of some antimicrobial proteins, but strongly expressed an antimicrobial protein called REG3A and a gene activated by interleukin-22 (IL-22), a signaling molecule produced by immune cells.
The team found that inflammatory IL-22 signaling promotes PCM formation and REG3A production. Beyond its antimicrobial role, REG3A also stimulated regeneration of the intestinal lining through pathways involved in cell growth and tissue repair, suggesting that PCM contributes to mucosal healing in UC.
Additional mouse experiments supported these findings, showing that mice lacking Reg3a in intestinal epithelial cells healed more slowly from intestinal injury in both acute and chronic colitis models, highlighting the role of Reg3a in tissue repair during inflammation. Although mouse models did not fully reproduce human PCM, they confirmed the important role of Reg3a in intestinal repair during inflammation.
Despite its protective role, the researchers caution that PCM should be carefully monitored. Because PCM promotes epithelial cell growth, persistent metaplastic changes may increase the risk of inflammation-associated cancer. "When PCM is detected, clinicians should consider more frequent surveillance and intensified treatment, even in patients who appear to be in endoscopic remission, to mitigate potential risks of underlying pathological activity and cancer development," Ito says.
The findings also have implications for the treatment of UC. Since PCM appears to increase alongside active inflammation in UC, the researchers suggest that it can be used as a biomarker to monitor disease activity. At the same time, the beneficial effects of REG3A could be a therapeutic strategy for repairing damaged intestinal tissue.
Publication details
Tomohiro Muto et al, IL-22 induces Paneth cell metaplasia in the colonic epithelium of ulcerative colitis, promoting wound healing via REG3A, Nature Communications (2026). DOI: 10.1038/s41467-026-71136-1
Journal information: Nature Communications
Key medical concepts
Ulcerative ColitisInterleukin-22
Clinical categories
GastroenterologyCommon illnesses & Prevention Provided by Institute of Science Tokyo Who's behind this story?
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