IL-22 Drives Protective Paneth Cell Metaplasia in Ulcerative Colitis via REG3A

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by recurrent mucosal injury and impaired healing of the colonic epithelium. A long-recognized but poorly understood histological feature of UC is Paneth cell metaplasia (PCM)—the aberrant appearance of Paneth cells, normally restricted to the small intestine, within the colonic mucosa. This study provides the first comprehensive mechanistic and functional characterization of PCM in UC, linking it to IL-22 signaling and the wound-healing peptide REG3A.

The authors analyzed colonoscopic biopsy samples from 222 UC patients and 78 non-IBD controls at a single center (Institute of Science Tokyo). PCM was essentially absent from the left colon of healthy individuals but significantly elevated across all left-sided colonic regions in UC patients, and similarly elevated in colonic Crohn's disease. Critically, PCM frequency increased with disease duration, rising sharply after 10 years, and correlated strongly with histologically active inflammation and higher Mayo endoscopic subscores. These clinical findings establish PCM as a marker of disease chronicity and ongoing mucosal injury.

Mechanistically, the team demonstrated that IL-22—a cytokine upregulated in inflamed intestinal epithelium—induces PCM formation in colonic organoids by suppressing Notch signaling, thereby redirecting epithelial progenitor differentiation toward a Paneth cell fate. Single-cell transcriptomic analyses and immunostaining confirmed that metaplastic Paneth cells within these niches express REG3A, a secretory lectin with antimicrobial properties. Notably, REG3A expression in the normal colon is negligible but is robustly induced within PCM niches under inflammatory conditions.

Functional studies in mouse colonic organoids showed that Reg3a directly enhanced epithelial cell proliferation and accelerated wound closure in scratch assays. In vivo, intestinal epithelium-specific Reg3a knockout mice (Reg3a^ΔIEC) demonstrated significantly delayed mucosal wound healing in both acute and chronic DSS-induced colitis models, confirming a non-redundant protective role. Importantly, experiments with patient-derived human colonic organoids validated translational relevance: exogenous REG3A administration stimulated proliferation and wound healing in human epithelial cells, suggesting a conserved mechanism.

Together, these findings reframe PCM from a passive histological curiosity into an active, IL-22-driven adaptive response that locally generates REG3A to promote epithelial repair. This has implications for how mucosal healing is assessed and potentially augmented in UC patients, particularly those with long-standing disease. Caveats include the single-center clinical cohort, reliance on DSS colitis as an animal model (which does not fully recapitulate human UC), and the need for future studies to assess whether PCM-associated REG3A influences microbiome composition or colorectal cancer risk in chronic UC.