Bile acid – farnesoid X receptor – fibroblast growth factor 19 axis in patients with short bowel syndrome: the randomized glepaglutide phase 2 trial

2021 ◽  
Author(s):  
Mark Krogh Hvistendahl ◽  
Rahim Mohammad Naimi ◽  
Svend Høime Hansen ◽  
Jens Frederik Rehfeld ◽  
Hannelouise Kissow ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Short Bowel Syndrome ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth ◽  
Phase 2 ◽  
Short Bowel ◽  
Phase 2 Trial ◽  
Fibroblast Growth Factor 19

scholarly journals Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids

2013 ◽  
Vol 304 (10) ◽  
pp. G940-G948 ◽  
Author(s):  
Justine H. Zhang ◽  
Jonathan D. Nolan ◽  
Sarah L. Kennie ◽  
Ian M. Johnston ◽  
Tracy Dew ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Culture Fluid ◽  
Farnesoid X Receptor ◽  
Transcript Expression ◽  
Fibroblast Growth ◽  
Primary Explants ◽  
Fgf19 Expression ◽  
Fibroblast Growth Factor 19

Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes was determined. FGF19 transcripts were detected in ileum but were unquantifiable in colon. No loss of FGF19 mRNA occurred as a consequence of the explant system. Ileal FGF19 transcript expression was induced 350-fold by 50 μM chenodeoxycholate (CDCA, n = 24, P < 0.0001) and 161-fold by 50 μM glycochenodeoxycholate (GCDCA, n = 12, P = 0.0005). The responses of other genes to CDCA or GCDCA (50 μM) were smaller: median increases of ileal bile acid binding protein, organic solute transporter-α and -β, and short heterodimer partner were 2.4- to 4.0-fold; apical membrane sodium bile acid transporter and farnesoid X receptor (FXR) showed little change. The EC50 for FGF19 transcript induction by CDCA was 20 μM. FGF19 protein concentrations were significantly higher in the culture fluid from BA-stimulated explants. FGF19 induction with cholate was 81% of that found with CDCA, but deoxycholate (40%) and lithocholate (4%) were significantly less potent. The synthetic FXR agonist obeticholic acid was much more potent than CDCA with a 70-fold FGF19 stimulation at 1 μM. We concluded that FGF19 expression in human ileum is very highly responsive to BA. Changes in FGF19 induction are a potential mechanism involved in disorders of BA homeostasis.

S2058 Reduced Fibroblast Growth Factor 19 in Patients with Short Bowel Syndrome.

2009 ◽  
Vol 136 (5) ◽  
pp. A-322
Author(s):  
Sanjeev Pattni ◽  
Katharina Wallis ◽  
Tracy Dew ◽  
Alastair Forbes ◽  
Simon M. Gabe ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Short Bowel Syndrome ◽  
Fibroblast Growth ◽  
Short Bowel ◽  
Fibroblast Growth Factor 19

MON-PP011: Fibroblast Growth Factor 19 in Patients with Short Bowel Syndrome on Long-Term Home Parenteral Nutrition

2015 ◽  
Vol 34 ◽  
pp. S131
Author(s):  
M. Montagnani ◽  
M. Guidetti ◽  
F. Agostini ◽  
P. Simoni ◽  
S. Demurtas ◽  
...  
Keyword(s):  
Growth Factor ◽  
Parenteral Nutrition ◽  
Fibroblast Growth Factor ◽  
Short Bowel Syndrome ◽  
Home Parenteral Nutrition ◽  
Fibroblast Growth ◽  
Short Bowel ◽  
Fibroblast Growth Factor 19

scholarly journals OC-036 Stimulated expression of ileal fibroblast growth factor 19 by bile acids is impaired in patients with primary and secondary bile acid diarrhoea

Gut ◽  
2015 ◽  
Vol 64 (Suppl 1) ◽  
pp. A19.1-A19
Author(s):  
JD Nolan ◽  
RN Appleby ◽  
GK Madhan ◽  
IM Johnston ◽  
K Sarah ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Bile Acids ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Secondary Bile Acid ◽  
Fibroblast Growth Factor 19

scholarly journals 770 Evaluation of Fibroblast Growth Factor 19 and 7α-Hydroxy-4-Cholesten-3-One in the Diagnosis of Bile Acid Diarrhea

2010 ◽  
Vol 138 (5) ◽  
pp. S-107
Author(s):  
Sanjeev S. Pattni ◽  
Gordon Brydon ◽  
Tracy Dew ◽  
Julian R. Walters
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor 19

scholarly journals Defective FXR-FGF15 signaling and bile acid homeostasis in cystic fibrosis mice can be restored by the laxative polyethylene glycol

2019 ◽  
Vol 316 (3) ◽  
pp. G404-G411 ◽  
Author(s):  
Anna Bertolini ◽  
Ivo P. van de Peppel ◽  
Marcela Doktorova-Demmin ◽  
Frank A. J. A. Bodewes ◽  
Hugo de Jonge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Polyethylene Glycol ◽  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth ◽  
Gastrointestinal Complications ◽  
Osmotic Laxative

The gastrointestinal phenotype of cystic fibrosis (CF) features intestinal bile acid (BA) malabsorption, impaired intestinal farnesoid X receptor (FXR) activation, and consequently reduced fibroblast growth factor 19 (FGF19, FGF15 in mice) production. The osmotic laxative polyethylene glycol (PEG) has been shown to decrease intestinal mucus accumulation in CF mice and could, by doing so, improve BA reabsorption. Here we determined the effect of PEG on BA excretion and FXR-FGF15 signaling in CF mice. Male Cftr−/−tm1Unc (CF) and wild-type (WT) littermates were administered PEG 4000 in drinking water and fed either chow or a semisynthetic diet. PEG was withdrawn for 3 days before termination. Fecal BA excretion was measured at PEG dosages of 37 g/l (100%) and 0 g/l (0%). Ileal FXR activation was assessed by gene expression of its downstream targets Fgf15 and small heterodimer partner ( Shp). In CF mice, PEG withdrawal increased fecal BA excretion on either diet compared with full PEG dosage (chow, 2-fold, P = 0.06; semisynthetic, 4.4-fold, P = 0.007). PEG withdrawal did not affect fecal BA excretion in WT mice on either diet. After PEG withdrawal, gene expression levels of intestinal FXR target genes Fgf15 and Shp were decreased in CF mice but unaffected in WT littermates. PEG did not affect the gene expression of the main intestinal BA transporter apical sodium-dependent bile acid transporter (ASBT). PEG treatment ameliorates intestinal BA malabsorption in CF mice and restores intestinal FXR-FGF15 signaling, independent from Asbt gene expression. These findings highlight the potential of PEG in the prevention and treatment of the gastrointestinal phenotype of CF. NEW & NOTEWORTHY A gastrointestinal feature of cystic fibrosis is bile acid malabsorption and consequent impairment of farnesoid X receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling. FXR-FGF15 signaling regulates various metabolic processes and could be implicated in metabolic and gastrointestinal complications of cystic fibrosis, such as diabetes and liver disease. In cystic fibrosis mice, treatment with the osmotic laxative polyethylene glycol is associated with decreased fecal bile acid loss and restoration of FXR-FGF15 signaling.

Chenodeoxycholic acid stimulated fibroblast growth factor 19 response - a potential biochemical test for bile acid diarrhoea.

2017 ◽  
Vol 45 (11) ◽  
pp. 1433-1442 ◽  
Author(s):  
C. Borup ◽  
S. Wildt ◽  
J. J. Rumessen ◽  
P. N. Bouchelouche ◽  
J. Graff ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Chenodeoxycholic Acid ◽  
Biochemical Test ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor 19

scholarly journals Commentary: fibroblast growth factor 19 in patients with bile acid diarrhoea

2013 ◽  
Vol 38 (10) ◽  
pp. 1320-1321 ◽  
Author(s):  
M. Camilleri ◽  
A. Acosta
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor 19
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