Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C.

Vishwas Mishra,Mudasir M Reshi,Anaxee Barman,Avipsa Bose,Pooja Chaukimath,Shashi Kiran,Sanghita Banerjee,Swarna Srinivas,Idrees A Shah,Sandhya S Visweswariah

doi:10.1084/jem.20210479

Vishwas Mishra, Mudasir M Reshi + Show 8 more

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https://doi.org/10.1084/jem.20210479

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Abstract

Activating mutations in receptor guanylyl cyclase C (GC-C), the target of gastrointestinal peptide hormones guanylin and uroguanylin, and bacterial heat-stable enterotoxins cause early-onset diarrhea and chronic inflammatory bowel disease (IBD). GC-C regulates ion and fluid secretion in the gut via cGMP production and activation of cGMP-dependent protein kinase II. We characterize a novel mouse model harboring an activating mutation in Gucy2c equivalent to that seen in an affected Norwegian family. Mutant mice demonstrated elevated intestinal cGMP levels and enhanced fecal water and sodium content. Basal and linaclotide-mediated small intestinal transit was higher in mutant mice, and they were more susceptible to DSS-induced colitis. Fecal microbiome and gene expression analyses of colonic tissue revealed dysbiosis, up-regulation of IFN-stimulated genes, and misregulation of genes associated with human IBD and animal models of colitis. This novel mouse model thus provides molecular insights into the multiple roles of intestinal epithelial cell cGMP, which culminate in dysbiosis and the induction of inflammation in the gut.

Highlights

Monogenic intestinal epithelium defects contributing to pediatric inflammatory bowel disease (IBD) have been described and are not readily amenable to current treatment regimens (Leung and Muise, 2018; Nambu and Muise, 2021)
Biochemical characterization of the S839I mutation in mouse guanylyl cyclase C (GC-C) The S840 residue in human geometric center (GC)-C is equivalent to S839 in mouse GC-C due to the absence of M701 in mouse GC-C (Fiskerstrand et al, 2012)
Our results show that S839I mice harboring an activating mutation in Gucy2c reveal roles of cyclic guanosine monophosphate (cGMP) in regulating gut function and enhanced colonic susceptibility to damage in a colitis model

Summary

Introduction

Monogenic intestinal epithelium defects contributing to pediatric inflammatory bowel disease (IBD) have been described and are not readily amenable to current treatment regimens (Leung and Muise, 2018; Nambu and Muise, 2021). Among the genes associated with very early–onset IBD are mutations in the receptor guanylyl cyclase C gene (GUCY2C; Bose et al, 2020; Crowley et al, 2020). The receptor encoded by this gene, guanylyl cyclase C (GC-C), is the target of the gastrointestinal hormones guanylin (encoded by GUCA2A) and uroguanylin (encoded by GUCA2B; Arshad and Visweswariah, 2012; Basu et al, 2010). PKGII phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR) and the sodiumhydrogen exchanger, NHE3 (Chen et al, 2015; Golin-Bisello et al, 2005). Phosphorylation of CFTR increases secretion of chloride and bicarbonate ions, while phosphorylation of NHE3 inhibits sodium uptake by the intestinal epithelial cell (IEC; Chen et al, 2015). The ensuing osmotic imbalance across the IEC causes efflux of water from the cell required for mucus hydration and passage of the bolus of food along the gut (Arshad and Visweswariah, 2013)

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