Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat

Prasad, Hari; Visweswariah, Sandhya S.

doi:10.1016/j.jcmgh.2021.03.005

Cited by 15 publications

(17 citation statements)

References 96 publications

(179 reference statements)

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“…Therefore, reduced NHE3 activity in the gut of patients with hyperactive GUCY2C mutations could contribute to the incidence of Crohn’s-like symptoms and colitis. We recently speculated that impaired intestinal sodium transport and its effects on the microbiome could serve as a major upstream mediator of downstream pathophysiology ( Prasad and Visweswariah, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, pathways not directly regulated by cGMP could also be misregulated in these mice, which, in turn, could feed back into the regulation of GC-C and its ligands. Since mice lacking Nhe3 display a susceptibility to DSS-induced colitis ( Kiela et al, 2009 ), electrolyte flux and imbalance in the intestine, coupled with alterations in the microbiome, may be the distal drivers of increased susceptibility to chemical-induced colitis ( Prasad and Visweswariah, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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

Mishra

Bose

Kiran

et al. 2021

Journal of Experimental Medicine

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Mishra

Bose

Kiran

et al. 2021

Journal of Experimental Medicine

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“…There is emerging evidence that the ionic milieu in the intestine plays a critical role in inducing gut inflammation and colitis (Prasad and Visweswariah, 2021). Impaired Na + and water transport, which occurs as a result of NHE3 deficiency, may mediate pathogenesis in gastrointestinal disorders such as CSD and IBD.…”

Section: Discussionmentioning

confidence: 99%

Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis

Xue

Rieg

Thomas

et al. 2022

Front. Cell. Infect. Microbiol.

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In the intestine, the Na+/H+ exchanger 3 (NHE3) plays a critical role for Na+ and fluid absorption. NHE3 deficiency predisposes patients to inflammatory bowel disease (IBD). In mice, selective deletion of intestinal NHE3 causes various local and systemic pathologies due to dramatic changes in the intestinal environment, which can influence microbiota colonization. By using metagenome shotgun sequencing, we determined the effect of inducible intestinal epithelial cell-specific deletion of NHE3 (NHE3IEC-KO) in adulthood on the gut microbiome in mice. Compared with control mice, NHE3IEC-KO mice show a significantly different gut microbiome signature, with an unexpected greater diversity. At the phylum level, NHE3IEC-KO mice showed a significant expansion in Proteobacteria and a tendency for lower Firmicutes/Bacteroidetes (F/B) ratio, an indicator of dysbiosis. At the family level, NHE3IEC-KO mice showed significant expansions in Bacteroidaceae, Rikenellaceae, Tannerellaceae, Flavobacteriaceae and Erysipelotrichaceae, but had contractions in Lachnospiraceae, Prevotellaceae and Eubacteriaceae. At the species level, after removing those with lowest occurrence and abundance, we identified 23 species that were significantly expanded (several of which are established pro-inflammatory pathobionts); whereas another 23 species were found to be contracted (some of which are potential anti-inflammatory probiotics) in NHE3IEC-KO mice. These results reveal that intestinal NHE3 deletion creates an intestinal environment favoring the competitive advantage of inflammophilic over anti-inflammatory species, which is commonly featured in conventional NHE3 knockout mice and patients with IBD. In conclusion, our study emphasizes the importance of intestinal NHE3 for gut microbiota homeostasis, and provides a deeper understanding regarding interactions between NHE3, dysbiosis, and IBD.

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“…Loss of function of NHE3, a well-known effector, negatively regulated by GC-C, has also been linked to IBD-like pathologies in humans and mice models (57,114,115), indicating that the impairment of Na + absorption shared by both activating GC-C and inactivating NHE3 mutations could be a pathogenic driver in IBD. In line with this hypothesis, impaired sodium absorption is a long-recognized pathological feature in IBD and microscopic colitis, a poorly understood type of IBD that is nearly as common as CD and UC (16). Several studies have shown reduced NHE3 expression/activity in IBD patients and after exposure to proinflammatory cytokines and Clostridium difficile toxin B; however, it has been uncertain until recently whether the downregulation of NHE3 plays a causal role rather than simply reflecting the disease (116)(117)(118).…”

Section: Emerging Gc-c-directed Colorectal Cancer Therapiesmentioning

confidence: 98%

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

2022

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Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.

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Impaired Intestinal Sodium Transport in Inflammatory Bowel Disease: From the Passenger to the Driver's Seat

Abstract: We synthesize genetic and cellular evidence to construct a model proposing that impaired intestinal sodium transport can act as an upstream pathogenic factor in IBD. The model predicts that strategies designed to correct disturbed electrolyte homeostasis carry high therapeutic potential.

Cited by 15 publications

References 96 publications

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

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

Intestine-Specific NHE3 Deletion in Adulthood Causes Microbial Dysbiosis

Receptor Guanylyl Cyclase C and Cyclic GMP in Health and Disease: Perspectives and Therapeutic Opportunities

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