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.

中文翻译：

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肠道相关 cGMP 介导 GUCY2C 激活突变小鼠模型中的结肠炎和生态失调

受体鸟苷酸环化酶 C (GC-C)、胃肠肽激素鸟苷和尿鸟苷的靶标以及细菌热稳定性肠毒素的激活突变会导致早发性腹泻和慢性炎症性肠病 (IBD)。GC-C 通过 cGMP 的产生和 cGMP 依赖性蛋白激酶 II 的激活来调节肠道中的离子和液体分泌。我们描述了一种在Gucy2c中具有激活突变的新型小鼠模型相当于在受影响的挪威家庭中看到的情况。突变小鼠表现出肠道cGMP水平升高和粪便水和钠含量增加。基础和利那洛肽介导的小肠转运在突变小鼠中更高，并且它们更容易患 DSS 诱导的结肠炎。结肠组织的粪便微生物组和基因表达分析揭示了生态失调、干扰素刺激基因的上调以及与人类 IBD 和结肠炎动物模型相关的基因的错误调节。因此，这种新型小鼠模型为肠上皮细胞 cGMP 的多种作用提供了分子见解，最终导致肠道菌群失调和炎症的诱导。