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

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...

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Autores principales: Mishra, Vishwas, Bose, Avipsa, Kiran, Shashi, Banerjee, Sanghita, Shah, Idrees A., Chaukimath, Pooja, Reshi, Mudasir M., Srinivas, Swarna, Barman, Anaxee, Visweswariah, Sandhya S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480670/
https://www.ncbi.nlm.nih.gov/pubmed/34546338
http://dx.doi.org/10.1084/jem.20210479
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author Mishra, Vishwas
Bose, Avipsa
Kiran, Shashi
Banerjee, Sanghita
Shah, Idrees A.
Chaukimath, Pooja
Reshi, Mudasir M.
Srinivas, Swarna
Barman, Anaxee
Visweswariah, Sandhya S.
author_facet Mishra, Vishwas
Bose, Avipsa
Kiran, Shashi
Banerjee, Sanghita
Shah, Idrees A.
Chaukimath, Pooja
Reshi, Mudasir M.
Srinivas, Swarna
Barman, Anaxee
Visweswariah, Sandhya S.
author_sort Mishra, Vishwas
collection PubMed
description 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.
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spelling pubmed-84806702021-10-26 Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C Mishra, Vishwas Bose, Avipsa Kiran, Shashi Banerjee, Sanghita Shah, Idrees A. Chaukimath, Pooja Reshi, Mudasir M. Srinivas, Swarna Barman, Anaxee Visweswariah, Sandhya S. J Exp Med Article 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. Rockefeller University Press 2021-09-21 /pmc/articles/PMC8480670/ /pubmed/34546338 http://dx.doi.org/10.1084/jem.20210479 Text en © 2021 Mishra et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mishra, Vishwas
Bose, Avipsa
Kiran, Shashi
Banerjee, Sanghita
Shah, Idrees A.
Chaukimath, Pooja
Reshi, Mudasir M.
Srinivas, Swarna
Barman, Anaxee
Visweswariah, Sandhya S.
Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title_full Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title_fullStr Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title_full_unstemmed Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title_short Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C
title_sort gut-associated cgmp mediates colitis and dysbiosis in a mouse model of an activating mutation in gucy2c
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480670/
https://www.ncbi.nlm.nih.gov/pubmed/34546338
http://dx.doi.org/10.1084/jem.20210479
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