Abstract
BackgroundThe bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.MethodsNine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined.ResultsAt baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups.ConclusionsPharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients.Trial RegistrationTrialRegister.nl NTR2009
Highlights
The bile acid nuclear Farnesoid X Receptor (FXR) is the master regulator of bile acid homeostasis
In two murine models for colitis, we recently showed that the administration of a semi-synthetic FXR agonist ameliorates intestinal inflammation, with improvement of colitis symptoms, preservation of intestinal barrier function, reduced goblet cell loss and inhibition of proinflammatory cytokine expression [11]
In the short study period compliance with chenodeoxycholic acid (CDCA) ingestion was 100% in all patients, except one who had by accident been taking one pill less for one day
Summary
The bile acid nuclear Farnesoid X Receptor (FXR) is the master regulator of bile acid homeostasis. Phospholipid concentration and composition in the colonic mucus layer (pivotal in intestinal barrier function) are dependent on bile acid-induced phospholipid secretion in the ileum with subsequent spread to the distal colon by propulsory motility, and these are deficient in patients with Inflammatory Bowel Disease (IBD) [7,8]. In two murine models for colitis, we recently showed that the administration of a semi-synthetic FXR agonist ameliorates intestinal inflammation, with improvement of colitis symptoms, preservation of intestinal barrier function, reduced goblet cell loss and inhibition of proinflammatory cytokine expression [11]. We recently found reduced FXR target gene expression in the ileum of patients with clinically quiescent CC [13]. The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn’s colitis (CC) exhibit reduced ileal FXR target gene expression. We here explore the feasibility of pharmacological FXR activation in CC
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