Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

Duan, Tianying; Çil, Onur; Tse, Chung Ming; Sarker, Rafiquel; Lin, Rongheng; Donowitz, Mark

doi:10.1096/fj.201901166r

Cited by 11 publications

(5 citation statements)

References 48 publications

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“…Although somatostatin analogs such as octreotide and/or surgical resection are the standard of care for VIPoma ( 28 ), cinacalcet may offer an alternative option for patients who do not tolerate or respond to these treatments. Other potential indications for cinacalcet include medullary thyroid cancer–associated diarrhea ( 29 ), bile acid diarrhea ( 30 ), and tyrosine kinase inhibitor diarrhea ( 19 ), in which increased CFTR-mediated Cl – secretion is a major cause of diarrhea. Cinacalcet may also be effective in some congenital diarrheas such as gain-of-function mutations in GUCY2C , which is associated with excessive cyclic nucleotide-mediated CFTR activation in enterocytes ( 31 ), as well as microvillus inclusion disease, which may involve impaired intestinal absorption and unbalanced CFTR-mediated Cl – secretion ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Oak¹,

Chhetri²,

Rivera³

et al. 2021

JCI Insight

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Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures, such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca 2+ . The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl – secretion by greater than 80%. Cinacalcet also reduced Cl – secretion induced by cholera toxin, heat-stable E . coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) Cl – secretion following activation of CaSR and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed loop models of cholera and traveler’s diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3–mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas, including cholera, traveler’s diarrhea, and VIPoma.

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Section: Discussionmentioning

confidence: 99%

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Oak¹,

Chhetri²,

Rivera³

et al. 2021

JCI Insight

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“…In vivo studies have reported both CFTR and FXR to have potential as therapeutic targets for diarrheal disease. A recently published study has implicated CFTR in CDCA-induced Clsecretion in a rat model of bile acid diarrhoea (BAD), with inhibition of CFTR reducing stool water content (Duan et al 2019). Furthermore, previously published data from our laboratory have shown that FXR activation prevents secretory diarrhoea in in vivo models (Mroz et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Nutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease

et al. 2022

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Introduction Bile acids classically known for their roles in dietary fat absorption are now recognized as hormones critical to regulating intestinal and metabolic function, including mucosal immune responses, epithelial proliferation/apoptosis, and transepithelial transport and barrier function. Downregulation of the nuclear bile acid receptor, farnesoid X receptor (FXR), in intestinal epithelium occurs in inflammatory bowel disease and colorectal cancer, whereas FXR activation prevents disease progression in pre‐clinical models. Thus strategies to upregulate epithelial FXR expression have been proposed to treat such conditions. Previous studies suggest that some plant‐derived phytochemicals have the capacity to modulate FXR activity. Plant sources have been reported to contain such phytochemicals, which are proposed to modulate FXR. Aim The aim of the current study was to investigate the potential for developing plant extracts, rich in FXR‐modulating phytochemicals, as a novel nutraceutical‐based approach to treat and prevent intestinal diseases. Methods T84 human colonic epithelial cells and primary cultures of murine colonic epithelial enteroids were employed to examine the effects of a common‐dietary phytochemical, denoted here as KFS1, and a KFS1‐rich plant extract on FXR expression and signaling in vitro. Ex vivo studies were carried out on human colonic tissue obtained during endoscopy with ethical approval from Beaumont Hospital. In vivo studies in C57BL/6 mice were carried out and proximal colonic tissue were examined with ethical approval from the HPRA. Expression of FXR and FGF19/15, an established marker of FXR activation, was assessed by qRT‐PCR, ELISA and immunoblotting. Data are expressed as mean ± SEM for a series of n experiments. Results KFS1 treatment (5 µM; 24hrs) increased FXR mRNA and protein expression in T84 cells by 4.2 ± 0.4 (p<0.05; n = 4) and 1.7 ± 0.1 fold (p<0.05; n = 7) respectively. KFS1 also enhanced FGF19 protein expression in response to the FXR agonist GW4064 (5 µM), by 4.1 ± 0.5 fold (p<0.001; n = 7). Similarly KFS1 upregulated FXR expression by 2.1 ± 0.4 fold in human biopsies (p<0.05; n = 6). Oral KFS1 administration to mice had a tendency to upregulate colonic epithelial FXR signaling in vivo and increased FXR expression and GW4064‐induced FGF15 by 2.3 ± 0.2 (p<0.01; n = 4) and 2.2 ± 0.1 fold (p<0.01; n = 4) in murine colonic enteroids. Finally a methanolic KFS1‐rich plant extract, denoted QE1, verified by LC/MS to contain KFS1, increased FXR protein expression in vitro by 1.8 ± 0.2 fold (p<0.05; n = 5) and enhanced GW4064‐induced FGF19 protein by 1.9 ± 0.1 fold (p<0.01; n = 9). Conclusion Our data demonstrate that KFS1‐containing plant extracts modulate expression and activity of FXR in the intestinal epithelium. Given the critical role of FXR in maintenance of gut health and metabolic function, such extracts have significant therapeutic and commercial potential to be developed as a novel first‐in‐class “FXR‐targeted nutraceutical” for treatment and prevention of common in...

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“…Bile acid-induced diarrhea is usually caused by an excess of bile acids in the colon due to bile acid malabsorption ( Yde et al, 2016 ), which is very common in patients with inflammatory diseases, such as ileal resection, Crohn’s disease, and diarrhea-predominant irritable bowel syndrome ( Duan et al, 2019 ). An earlier study indicated that the mechanism of bile acid-induced diarrhea might be associated with an increase in mucosal permeability to ion and water and mucosal damage ( Argenzio and Whipp, 1983 ).…”

Section: Role and Regulation Of Aqp3 Expression In Diarrheamentioning

confidence: 99%

Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review

Zhu,

Nie,

et al. 2023

Front. Physiol.

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Aquaporin-3 (AQP3) is a predominant water channel protein expressed in the intestine, and plays important roles in the gut physiology and pathophysiology due to its permeability to water, glycerol and hydrogen peroxide. In this review, we systematically summarized the current understanding of the expression of AQP3 in the intestine of different species, and focused on the potential roles of AQP3 in water transport, different types of diarrhea and constipation, intestinal inflammation, intestinal barrier function, oxidative stress, and autophagy. These updated findings have supported that AQP3 may function as an important target in maintaining gut health of human and animals.

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Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

Cited by 11 publications

References 48 publications

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Repurposing calcium sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas

Nutraceutical targeting of the bile acid receptor, farnesoid X receptor, for intestinal disease

Roles and regulation of Aquaporin-3 in maintaining the gut health: an updated review

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