Table 1.

Expanding pathophysiological roles of the GC-C signalling axis in intestine based on animal models of human diseases

Animal model	Target	Observations	Conclusion	Reference
Mice: GI function in the absence of GC-C expression	GC-C receptor	No diarrhoeal symptoms on exposure to STa Interestingly, no changes were found in the intestinal fluidity of GC-C knockout mice	GC-C is a necessary component of maintaining the intestinal barrier. However, further research is needed to determine the effects of guanylin peptides in knockout mice	90
Mice: colorectal transformation induced by high-fat diet	Guanylin–GUCY2C signalling axis	Caloric suppression led to decreased guanylin–GUCY2C activity and tumourigenesis	There is potential for using GC-C agonists in the prevention of colorectal cancer in obese patients	16
Mice: visceral hypersensitivity	Colorectal GC-C receptors	Downstream cGMP activation and exposure to stretch receptive endings decreased pain and hypersensitivity	GC-C agonists can relieve visceral hypersensitivity	4 12 60
Mice: visceral hypersensitivity	Colorectal GC-C receptors	Direct uroguanylin exposure to stretch receptive endings decreased pain and hypersensitivity	GC-C agonists can relieve visceral hypersensitivity	12
Mice: spontaneous colitis	GC-C receptors	On exposure to lipopolysaccharide, GC-C knockout mice experienced severe inflammation, possibly due to systemic cytokine burst of loss of mucosal immune cell immunosuppression	GC-C signalling plays an important role in intestinal inflammation and damage	62
Mice: microbiota	GC-C receptors	GC-C knock out mice had higher faecal bacterial loads. Decreased guanylin expression was noted in both knockout and control mice, with greater difference in knockout mice	GC-C signalling pathway contributes to host immune defence by reducing bacterial load and decreasing risk of systemic infection	91
Rats: zinc deficiency–induced diarrhoea	Uroguanylin	Zinc deficiency has been associated with increased mRNA expression of preprouroguanylin in the small intestine, colon, stomach, kidney, thymus and testis	Zinc deficiency could cause diarrhoea via the upregulation of uroguanylin	92
Mice: colon adenocarcinoma	Uroguanylin	Oral uroguanylin replacement therapy resulted in decreased intestinal polyp formation in the Min/+ mouse model for colorectal cancer	GC-C agonists are potential new targets in the prevention of intestinal polyps and cancers	11

GC-C, guanylate cyclase-C.