GUCA2A encodes guanylin, an endogenous activator of intestinal guanylate cyclase-C (GC-C) that functions as a gut hormone regulating intestinal homeostasis 1. The protein stimulates GC-C through the same receptor binding region as heat-stable enterotoxins, activating downstream cGMP signaling pathways that control fluid and electrolyte balance, intestinal barrier integrity, and anti-trophic effects 1. GUCA2A is specifically expressed in BEST4+ intestinal epithelial cells, suggesting specialized roles in pH regulation and electrolyte transport 2. In disease contexts, GUCA2A expression is significantly downregulated in inflammatory bowel disease, correlating negatively with inflammatory cytokine expression 1. The gene serves as a tumor suppressor in colorectal cancer, with silencing of the GUCA2A-GUCY2C axis occurring across multiple colorectal cancer pathways including chr1 instability, serrated, and microsatellite instability tumors 3. GUCA2A shows promise as a diagnostic and prognostic biomarker, with reduced expression associated with poor patient survival 45. Additionally, GUCA2A levels increase after bariatric surgery and may contribute to metabolic improvements in obesity-associated conditions 6.