Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index

Ulcerative colitis (UC) belongs to a group of chronic idiopathic inflammatory disorders that primarily affects the colon and is a major type of inflammatory bowel disease (IBD). Common clinical symptoms in UC are diarrhea, rectal bleeding and abdominal pain. Non-specific manifestations include, among others, fever, loss of appetite and weight loss1,2. This disease significantly impacts patient quality of life due to its repeated remissions and relapses. There is an increasing incidence rate of IBD in China, particularly of UC3,4. Although treatment outcome for UC has improved with the use of anti-TNFα agents such as infliximab, the risk of opportunistic infections is increased with such treatments and a certain proportion of patients have severe side effects. Therefore, a continuous search for more specific etiological factors and the identification of novel pharmacological targets are needed. Recent studies have suggested that the aberrant of guanylate cyclase-C (GC-C) signaling is involved in diarrhea, constipation, abdominal pain, dysfunctional epithelial barrier function, intestinal polypsand tumor growth5. GC-C is a transmembrane receptor that is expressed primarily on intestinal epithelial cells (IECs). The peptides guanylin(Gn) and uroguanylin(Ugn) are the endogenous ligands for GC-C, and are highly expressed in the gastrointestinal (GI) epithelium6. The binding of these ligands to GC-C results in the conversion of guanosine triphosphate(GTP) to cyclic-guanosine-3′, 5′-monophosphate (cGMP). Increased levels of cGMP activate the cGMP-dependent protein kinaseII (PKGII), which phosphorylates the cystic fibrosis transmembrane conductance regulator(CFTR), increasing chloride (Cl−) secretion into the lumen. Bicarbonate (HCO3−) secretion, through an as yet unidentified channel, also occurs in a CFTR-dependent manner. cGMP also inhibits the sodium-hydrogen exchanger NHE3, thereby decreasing sodium (Na+) absorption. Therefore, this physiological activation of GC-C regulates intestinal fluid and electrolyte homeostasis, preventing dehydration and intestinal obstruction7,8,9. A study by Brenna O et al. revealed that GC-C, Gn and Ugn, as well as several downstream mediators of the GC-C signaling pathway, were all significantly downregulated in both the inflamed colonic mucosa of IBD patients and in rats with 2,4,6- trinitrobenzenesulfonic acid (TNBS) colitis10. However, the association between GC-C signaling and the clinical severity of UC has not been previously reported. Therefore, in this study, we investigated the expression of GC-C and its endogenous ligands, Gn and Ugn, in the colonic mucosa of UC patients with different disease activity indexes (DAIs) to evaluate the relationship of the GC-C signaling pathway and UC with different clinical assessments.