title: Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation.
abstract: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models.
  
  
  
  Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice. Serum Fgf15 levels were analyzed by ELISA. Biliary and fecal BA composition was differentiated by HPLC-MS/MS.
  
  
  
  Dextran sulfate sodium-treated mice with ileum-sparing colitis showed higher Fgf15 serum levels. In contrast, IL10 mice with ileitis had a trend toward decreased Fgf15 serum levels compared with controls and increased expression of Asbt as a negative Fxr-target gene. In hepatic tissue of both models, no histological changes, but higher interleukin 6 (IL-6) mRNA expression and down-regulation of Fxr and Cytochrom P450 7a1 mRNA expression were observed. Fibroblast growth factor receptor 4 up-regulation was in line with higher Fgf15 serum levels in dextran sulfate sodium-treated mice. A distinct fecal BA profile was observed in both models with significantly higher levels of taurine-conjugated BA in particular tauro-β-muricholic acid in IL10 mice.
  
  
  
  Ileum-sparing colitis is characterized by activation of Fxr-Fgf15 signaling with higher expression of Fxr-target gene Fgf15, whereas ileal inflammation showed no signs of Fxr-Fgf15 activation. Abundance of BA such as T-β-MCA may be important for intestinal Fxr activation in mice.
authors: *Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany; †Department of Clinical Pharmacology and Toxicology, USZ, Zurich, Switzerland; ‡Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, CIBERehd, University of Salamanca, Salamanca, Spain; and §Division of Gastroenterology and Hepatology, USZ, Zurich, Switzerland.
authors: Monika
authors: M
authors: Rau
authors: Bruno
authors: B
authors: Stieger
authors: Maria J
authors: MJ
authors: Monte
authors: Johannes
authors: J
authors: Schmitt
authors: Daniel
authors: D
authors: Jahn
authors: Isabelle
authors: I
authors: Frey-Wagner
authors: Tina
authors: T
authors: Raselli
authors: Jose J G
authors: JJ
authors: Marin
authors: Beat
authors: B
authors: Müllhaupt
authors: Gerhard
authors: G
authors: Rogler
authors: Andreas
authors: A
authors: Geier
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003577:Cytochrome P-450 Enzyme System; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood / Q000378:metabolism*; D007082:Ileum / Q000503:physiopathology; D007422:Intestines / Q000503:physiopathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D016264:Dextran Sulfate; D005346:Fibroblast Growth Factors; D051499:Receptor, Fibroblast Growth Factor, Type 4; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse