Therapeutic zinc targets dysregulated GC-C signaling and restores ileal defects in a preclinical model of familial diarrheal disease.

Hyperactivating mutations in guanylyl cyclase C (GC-C) are monogenic causes of early-onset inflammatory bowel disease, familial diarrheal syndrome, and congenital secretory diarrhea. The mechanisms linking elevated cGMP levels to immune imbalance remain poorly defined. Here, using a preclinical model of a disease-associated GC-C mutation, we observe pleiotropic alterations in the small intestinal epithelium. Transcriptomic and functional analyses revealed impaired Paneth and goblet cell differentiation, compromised barrier integrity, heightened epithelial permeability, and increased proinflammatory cytokine levels. Intestinal organoids from mutant mice exhibited amplified cGMP responses to GC-C ligands and defects in secretory lineage specification, confirming cell-autonomous mechanisms. Strikingly, oral zinc administration suppressed aberrant GC-C activity, normalized cGMP levels, and restored barrier function. These findings highlight the central role of epithelial cGMP signaling in coordinating barrier integrity and immune-epithelial interactions and identify zinc as a tractable therapeutic strategy for GC-C-mediated intestinal disorders.