Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohnʼs Disease

Tronstad, Rune Rose; Kummen, Martin; Holm, Kristian; Volkmann, Hilde Løland von; Anmarkrud, Jarl Andreas; Høivik, Marte Lie; Moum, Bjørn; Gilja, Odd Helge; Hausken, Trygve; Baines, John F.; Karlsen, Tom H.; Fiskerstrand, Torunn; Hov, Johannes R.

doi:10.1097/mib.0000000000001264

Cited by 15 publications

(12 citation statements)

References 225 publications

(277 reference statements)

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“…We suggest that this early life susceptibility to STa-secreting ETEC is counter balanced by the critical role of GC-C in protecting the mucosa from non-STa producing, invasive bacterial pathogens, such as Salmonella . Concomitant with robust GC-C activity in the infant intestine is the colonization and expansion of commensal microflora and we suggest that additional studies will be necessary to determine if GC-C-regulated microflora complexity impacts susceptibility to invasive pathogen infection 20 , 25 , 30 .…”

Section: Discussionmentioning

confidence: 99%

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Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens

Amarachintha

Harmel‐Laws

Steinbrecher

2018

Sci Rep

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The guanylate cyclase C (GC-C) receptor regulates electrolyte and water secretion into the gut following activation by the E. coli enterotoxin STa, or by weaker endogenous agonists guanylin and uroguanylin. Our previous work has demonstrated that GC-C plays an important role in controlling initial infection as well as carrying load of non-invasive bacterial pathogens in the gut. Here, we use Salmonella enterica serovar Typhimurium to determine whether GC-C signaling is important in host defense against pathogens that actively invade enterocytes. In vitro studies indicated that GC-C signaling significantly reduces Salmonella invasion into Caco2-BBE monolayers. Relative to controls, GC-C knockout mice develop severe systemic illness following oral Salmonella infection, characterized by disrupted intestinal mucus layer, elevated cytokines and organ CFUs, and reduced animal survival. In Salmonella-infected wildtype mice, oral gavage of GC-C agonist peptide reduced host/pathogen physical interaction and diminished bacterial translocation to mesenteric lymph nodes. These studies suggest that early life susceptibility to STa-secreting enterotoxigenic E. coli may be counter-balanced by a critical role of GC-C in protecting the mucosa from non-STa producing, invasive bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

“…S2 ). Although therapeutic GC-C agonists have been extensively studied in the treatment of irritable bowel syndrome and chronic constipation, additional studies focusing on the impact of GC-C agonists on the bacterial microflora of the bowel, pathogenic or otherwise, is warranted 20 .…”

Section: Discussionmentioning

confidence: 99%

Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens

Amarachintha

Harmel‐Laws

Steinbrecher

2018

Sci Rep

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“…This is supported by a recent report that genetic GC-C activation influences the intestinal microbiota in patients with familial diarrhoea and increased susceptibility for Crohn’s disease, including increases in Enterobacteriaceae and loss of Bifidobacterium and Faecalibacterium prausnitzii ; the latter change is frequently associated with Crohn’s disease. 64 …”

Section: Biology Of the Gc-c Signalling Axismentioning

confidence: 99%

Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders

Waldman

Camilleri

2018

Gut

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Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome–constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs.

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“…Ion transport across IECs may play an important role in the establishment and maintenance of the gut microbiota . Indeed, prominent depletion of Faecalibacterium and Bifidobacterium and an increase in Enterobacteriaceae have been described in patients with an activating mutation in GC‐C that is characterized by dysregulated intestinal ion transport, secretory diarrhea, and chronic mucosal inflammation . Independent studies have also reported alterations in the gut microbiota composition in GC‐C‐null mice and a decrease in the relative abundance of Lactobacillus spp., members of which have been implicated in inflammasome activation through caspase‐1‐dependent processing and release of IL‐1β by macrophages .…”

Section: Discussionmentioning

confidence: 99%

“…These findings support an alternate model in which cyclic nucleotide signaling in enterocytes could regulate inflammasome activation by shaping the gut microbiota and modulating host–microbe cross talk. Thus, prolonged inflammasome activation may explain why chronic inflammation is seen in patients with activating mutations in GC‐C, with a considerable number of them diagnosed with Crohn's disease .…”

Section: Discussionmentioning

confidence: 99%

Cyclic nucleotides, gut physiology and inflammation

2020

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Misregulation of gut function and homeostasis impinges on the overall wellbeing of the entire organism. Diarrheal disease is the second leading cause of death in children under 5 years of age, and globally, 1.7 billion cases of childhood diarrhea are reported every year. Accompanying diarrheal episodes are a number of secondary effects in gut physiology and structure, such as erosion of the mucosal barrier that lines the gut, facilitating further inflammation of the gut in response to the normal microbiome. Here, we focus on pathogenic bacteria-mediated diarrhea, emphasizing the role of cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3 0 ,5 0 -monophosphate in driving signaling outputs that result in the secretion of water and ions from the epithelial cells of the gut. We also speculate on how this aberrant efflux and influx of ions could modulate inflammasome signaling, and therefore cell survival and maintenance of gut architecture and function.

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Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohnʼs Disease

Abstract: The findings support that the activating mutation in GUCY2C creates an intestinal environment with a major influence on the microbiota, which could contribute to the increased susceptibility to IBD in patients with FGDS.

Cited by 15 publications

References 225 publications

Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens

Guanylate cyclase C reduces invasion of intestinal epithelial cells by bacterial pathogens

Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders

Cyclic nucleotides, gut physiology and inflammation

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