The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease

<b><i>Objective.</i></b> Activation of membrane receptor guanylate cyclase-C (GC-C) is implicated in gastrointestinal fluid and electrolyte balance, preservation of intestinal barrier integrity, anti-trophic effects and inhibition of pain sensation. To evaluate GC-C signaling, we examined the regulation of GC-C (<i>GUCY2C</i>/<i>Gucy2c</i>) and its endogenous ligands guanylin (GN/<i>GUCA2A</i>/<i>Guca2a</i>) and uroguanylin (UGN/<i>GUCA2B</i>/<i>Guca2b</i>) in colonic Crohn’s disease (CD), ulcerative colitis (UC) and in rats with 2,4,6-Trinitrobenzene sulphonic acid (TNBS) colitis. Correlation analyses between expression of <i>GUCA2A</i> and <i>GUCY2C</i> and expression of inflammatory cytokines (<i>IL1A,</i> <i>IL1B,</i> <i>TNFA</i> and <i>IFNG</i>) were conducted. Additionally, expression of transcription factors for <i>GUCA2A</i> and <i>GUCY2C,</i> and the GC-C signaling pathway, were examined. <b><i>Material and methods.</i></b> Biopsies from active UC/CD, un-inflamed UC/CD and healthy controls, and inflamed and healthy rat colon were investigated with gene expression microarray, immunohistochemistry (IHC) and <i>in situ</i> hybridization (ISH). <b><i>Results.</i></b> <i>GUCA2A</i>/<i>Guca2a,</i> <i>GUCA2B,</i> <i>GUCY2C</i>/<i>Gucy2c,</i> transcription factors, as well as several cyclic guanosine-3′,5′-monophosphate downstream mediators were all significantly down-regulated in both inflamed colonic inflammatory bowel disease (IBD) mucosa and TNBS colitis. Expression of <i>GUCA2A</i> and <i>GUCY2C</i> negatively correlated to expression of inflammatory cytokines. IHC and ISH confirmed microarray results for <i>GUCA2A</i>/<i>Guca2a</i> and <i>GUCY2C</i>/<i>Gucy2c</i> in inflamed samples. We identified a highly significant positive correlation between the expression of the transcription factor caudal type homeobox 2 (<i>CDX2</i>) and the expression of the downstream target gene <i>GUCY2C.</i> <b><i>Conclusions.</i> GUCA2A,</b> <i>GUCA2B</i> and <i>GUCY2C</i> as well as several steps of the GC-C signaling pathway are down-regulated in IBD. This may have implications in IBD pathogenesis.