Diarrhoea and inflammatory bowel disease (IBD) are the most common gastrointestinal disorders worldwide. Even though the treatments for acute diarrhoea are widely available, chronic diarrhoea due to infection by enterotoxigenic and enteropathogenic E. coli leads to malnutrition and stunted development in children below five years. However, therapeutic strategies for dealing with chronic and moderate-to-severe diarrhoea are unclear due to the lack of well-defined preclinical models.

Receptor guanylyl cyclase C (GC-C), encoded by GUCY2C, is activated by gastrointestinal hormones guanylin and uroguanylin to produce cyclic guanosine 5’-monophosphate (cGMP) in intestinal epithelial cells. Guanylin/uroguanylin activate GC-C to maintain fluid-ion homeostasis in the gut, while heat-stable enterotoxins produced by enterotoxigenic E. coli are super-agonists of GC-C.  Gain-of-function mutations in GUCY2C lead to chronic diarrhoea associated with gut inflammation, and such mutations in GUCY2C are recognised as one of the monogenic causes of paediatric inflammatory bowel disease. We have generated a transgenic mouse expressing a gain-of-function mutation seen in a Norwegian Family with Familial GUCY2C Diarrhoea Syndrome.  This mouse would serve as a model for chronic diarrhoeal diseases caused by elevated cGMP levels in the gut, either due to mutation or frequent and persistent infection with E. coli producing ST. The mice exhibited increased frequency of bowel movements, enhanced faecal water and sodium content, and small intestinal barrier permeability. Mice showed an altered faecal microbiome and intestinal gene expression changes seen in human IBD patients. We observed an up-regulation of interferon-stimulated genes in the gut and changes in immune cell types homing to the gut. Many of these phenotypes could be reversed by the administration of zinc.  Therefore, elevated cGMP in the intestine results in altered gut physiology, leading not only to diarrhoea but also gastrointestinal inflammation.  This mouse model can be used to enhance the molecular understanding of changes in the gut that result from chronic diarrhoea and allow the testing of clinical regimes for the treatment of diarrhoea-associated gut inflammation.