title: Pharmacological activation of the bile acid nuclear farnesoid X receptor is feasible in patients with quiescent Crohn's colitis.
abstract: BACKGROUND
  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. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC.
  
  
  METHODS
  Nine 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.
  
  
  RESULTS
  At 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.
  
  
  CONCLUSIONS
  Pharmacological 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.
  
  
  BACKGROUND
  TrialRegister.nl NTR2009.
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands. f.d.m.vanschaik@umcutrecht.nl
authors.forename: Fiona D M
authors.initials: FD
authors.lastname: van Schaik
authors.forename: Raffaella M
authors.initials: RM
authors.lastname: Gadaleta
authors.forename: Frank G
authors.initials: FG
authors.lastname: Schaap
authors.forename: Saskia W C
authors.initials: SW
authors.lastname: van Mil
authors.forename: Peter D
authors.initials: PD
authors.lastname: Siersema
authors.forename: Bas
authors.initials: B
authors.lastname: Oldenburg
authors.forename: Karel J
authors.initials: KJ
authors.lastname: van Erpecum
mesh_terms: D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000378:metabolism*; D016022:Case-Control Studies; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D005346:Fibroblast Growth Factors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human