Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bengaluru, India.
J Exp Med. 2021 Nov 1;218(11). doi: 10.1084/jem.20210479. Epub 2021 Sep 21.
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.
受体鸟苷酸环化酶 C（GC-C）的激活突变，该酶是胃肠道肽激素鸟苷素和尿鸟苷素以及细菌热稳定肠毒素的靶标，可导致早发性腹泻和慢性炎症性肠病（IBD）。GC-C 通过 cGMP 产生和激活 cGMP 依赖性蛋白激酶 II 来调节肠道中的离子和液体分泌。我们描述了一种新型小鼠模型，该模型携带 GC-C 中的激活突变，与受影响的挪威家族中的突变相同。突变小鼠表现出升高的肠道 cGMP 水平以及增加的粪便水分和钠含量。突变小鼠的基础和利那洛肽介导的小肠转运速度更高，并且它们对 DSS 诱导的结肠炎更敏感。结肠组织的粪便微生物组和基因表达分析显示菌群失调，IFN 刺激基因上调，以及与人类 IBD 和结肠炎动物模型相关的基因失调。因此，这种新型小鼠模型为肠道上皮细胞 cGMP 的多种作用提供了分子见解，这些作用最终导致肠道中的菌群失调和炎症的发生。
