title: Bile acid malabsorption deactivates pregnane X receptor in patients with Crohn's disease.
abstract: BACKGROUND
  Recent studies have suggested that the downregulation of pregnane X receptor (PXR) may contribute to the susceptibility and exacerbation of Crohn's disease (CD). Because bile acid malabsorption is one of the features of CD and bile acids are potential activators of PXR, we explored the relationship between bile acid malabsorption and PXR activities in patients with CD.
  
  
  METHODS
  Twenty-one patients with CD (4 ileal-resected and 17 nonresected), 10 with ulcerative colitis (UC), and 26 healthy controls were studied. Serum biomarkers for the activity of CYP3A4, a target gene of PXR, and for cholesterol and bile acid metabolism were quantified by liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay.
  
  
  RESULTS
  The concentrations of 4β-hydroxycholesterol (4β-HC), a known marker for CYP3A4 activity, and those of 25-hydroxycholesterol (25-HC), another metabolite by CYP3A4, were significantly reduced in all patients with CD, especially in those with the history of ileal resection. The concentration of 7α-hydroxy-4-cholesten-3-one (C4), a marker for hepatic bile acid biosynthesis, was significantly elevated, whereas the levels of fibroblast growth factor 19 (FGF19), a marker for intestinal bile acid flux, were reduced in patients with CD compared with patients with UC and controls. A significant negative correlation was observed between 4β-HC or 25-HC and C4 concentrations in all patients with CD.
  
  
  CONCLUSIONS
  The degree of bile acid malabsorption was closely associated with the deactivation of PXR in CD. Enterohepatic circulation of bile acids is a key factor for preservation of baseline activity of hepatointestinal PXR.
authors.affiliation: Department of Gastroenterology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan. junnki@dg.mbn.or.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Iwamoto
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Saito
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.forename: Teruo
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ikegami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuzaki
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002784:Cholesterol / Q000378:metabolism; D002853:Chromatography, Liquid; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D051544:Cytochrome P-450 CYP3A / Q000097:blood; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D011379:Prognosis; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; C117476:FGF19 protein, human; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human