Tauroursodeoxycholic acid protects bile acid homeostasis under inflammatory conditions and dampens Crohn's disease-like ileitis.
Bile acids regulate the expression of intestinal bile acid transporters and are natural ligands for nuclear receptors controlling inflammation. Accumulating evidence suggests that signaling through these receptors is impaired in inflammatory bowel disease. We investigated whether tauroursodeoxycholic acid (TUDCA), a secondary bile acid with cytoprotective properties, regulates ileal nuclear receptor and bile acid transporter expression and assessed its therapeutic potential in an experimental model of Crohn's disease (CD). Gene expression of the nuclear receptors farnesoid X receptor, pregnane X receptor and vitamin D receptor and the bile acid transporters apical sodium-dependent bile acid transporter and organic solute transporter α and β was analyzed in Caco-2 cell monolayers exposed to tumor necrosis factor (TNF)α, in ileal tissue of TNFΔARE/WTmice and in inflamed ileal biopsies from CD patients by quantitative real-time polymerase chain reaction. TNFΔARE/WTmice and wild-type littermates were treated with TUDCA or placebo for 11 weeks and ileal histopathology and expression of the aforementioned genes were determined. Exposing Caco-2 cell monolayers to TNFα impaired the mRNA expression of nuclear receptors and bile acid transporters, whereas co-incubation with TUDCA antagonized their downregulation. TNFΔARE/WTmice displayed altered ileal bile acid homeostasis that mimicked the situation in human CD ileitis. Administration of TUDCA attenuated ileitis and alleviated the downregulation of nuclear receptors and bile acid transporters in these mice. These results show that TUDCA protects bile acid homeostasis under inflammatory conditions and suppresses CD-like ileitis. Together with previous observations showing similar efficacy in experimental colitis, we conclude that TUDCA could be a promising therapeutic agent for inflammatory bowel disease, warranting a clinical trial.
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Lien
L
Van den Bossche
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Daniel
D
Borsboom
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Sarah
S
Devriese
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Sophie
S
Van Welden
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Tom
T
Holvoet
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Lindsey
L
Devisscher
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Pieter
P
Hindryckx
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Martine
M
De Vos
Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium.
Debby
D
Laukens
D000328:Adult; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D003424:Crohn Disease / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007079:Ileitis / Q000378:metabolism*; D007082:Ileum / Q000187:drug effects / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D055815:Young Adult
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C037643:bile acid binding proteins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine