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.

Nontyphoidal disease contributes toward significant morbidity and mortality across the world. Host factors, including gamma interferon, tumor necrosis factor alpha, and gut microbiota, significantly influence the outcome of pathogenesis. However, the entire repertoire of host protective mechanisms contributing to pathogenicity is not completely appreciated. Here, we investigated the roles of receptor guanylyl cyclase C (GC-C), which is predominantly expressed in the intestine and regulates intestinal cell proliferation and fluid-ion homeostasis. Mice deficient in GC-C () displayed accelerated mortality compared with that for wild-type mice following infection via the oral route, even though both groups possessed comparable systemic infection burdens. Survival following intraperitoneal infection remained similar in both groups, indicating that GC-C offered protection via a gut-mediated response. The serum cortisol level was higher in mice than wild-type () mice, and an increase in infection-induced thymic atrophy with a loss of immature CD4 CD8 double-positive thymocytes was observed. Accelerated and enhanced damage in the ileum, including submucosal edema, epithelial cell damage, focal tufting, and distortion of the villus architecture, was seen in mice concomitantly with a larger number of ileal tissue-associated bacteria. Transcription of key mediators of-induced inflammation (interleukin-22/Reg3β) was altered in mice in comparison to that in mice. A reduction in fecal lactobacilli, which are protective against infection, was observed in mice. mice cohoused with wild-type mice continued to show reduced amounts of lactobacilli and increased susceptibility to infection. Our study, therefore, suggests that the receptor GC-C confers a survival advantage during gut-mediated serovar Typhimurium pathogenesis, presumably by regulating effector mechanisms and maintaining a beneficial microbiome.

The availability of genome sequence information and a large number of protein structures has allowed the cataloging of genes into various families, based on their function and predicted biochemical activity. Intriguingly, a number of proteins harbor changes in the amino acid sequence at residues, that from structural elucidation, are critical for catalytic activity. Such proteins have been categorized as ‘pseudoenzymes’. Here, we review the role of the pseudokinase (or kinase-homology) domain in receptor guanylyl cyclases. These are multidomain single-pass, transmembrane proteins harboring an extracellular ligand-binding domain, and an intracellular domain composed of a kinase-homology domain that regulates the activity of the associated guanylyl cyclase domain. Mutations that lie in the kinase-homology domain of these receptors are associated with human disease, and either abolish or enhance cGMP production by these receptors to alter downstream signaling events. This raises the interesting possibility that one could identify molecules that bind to the pseudokinase domain and regulate the activities of these receptors, in order to alleviate symptoms in patients harboring these mutations.

The current work is enlightened about a cost effective bioprocess using one factor at a time approach for the production of bio-surfactant through solid state fermentation. A fungal strain Penicillium chrysogenum SNP5 isolated from grease contaminated soil was reconnoitered for the production of bio-surfactant. Various physiochemical parameters i.e., substrate composition, nitrogen supplements, extraction media and pH were optimized in order to optimized the production in terms of emulsification index and oil displacement assay. Maximum oil displacement area produced using grease waste and wheat bran (1:1 w/w), waste cooking oil and wheat bran (1:1 v/w) as a substrate were 3.5 cm and 5 cm, respectively. Whereas, considered values for emulsification activity with oil and diesel were 43% and 22% during optimization of substrate composition. Variable ratios of grease waste and wheat bran were capable to enhance the emulsification activity with oil and diesel up to 45% and 24% in presence of grease and wheat bran (1.5:1). The strain also showed enhancement of emulsification activity 45% and 23% with oil and diesel respectively to utilized yeast extract as a nitrogen source and the highest emulsification activity 38% in diesel, 47% in oil and oil displacement 5.5 cm was found at pH 8 with grease and wheat bran as a substrate. Preliminary characterizations by thin layer chromatography showed that the bio-surfactant was lipopeptide in nature and was also confirmed through FTIR analysis. Metabolization of industrial grease waste through solid state fermentation has never been reported before for the production of biosurfactants therefore would be applicable in petroleum and biodiesel industry. The partially purified biosurfactants was further investigated for antimicrobial activity and enhanced oil recovery. It displayed effective zones of inhibition against both gram +ve (1.67 cm) and gram-ve (1.93 cm) as well as 16.5% enhanced recovery of oil. Both results also give a positive support to its role in pharmaceuticals as well as in petroleum and oil industry.

Visweswariah SS. 2019. Correction for Majumdar et al., "Absence of receptor guanylyl cyclase C enhances ileal damage and reduces cytokine and antimicrobial peptide production during oral Salmonella enterica serovar Typhimurium infection." Infect Immun 87:e00495-19.