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

Autor:	Mishra V; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Bose A; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Kiran S; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Banerjee S; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Shah IA; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Chaukimath P; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Reshi MM; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Srinivas S; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Barman A; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India., Visweswariah SS; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2021 Nov 01; Vol. 218 (11). Date of Electronic Publication: 2021 Sep 21.
DOI:	10.1084/jem.20210479
Abstrakt:	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. Competing Interests: Disclosures: The authors declare no competing interests exist. (© 2021 Mishra et al.)
Databáze:	MEDLINE
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