title: The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis.
abstract: BACKGROUND
  GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation.
  
  
  OBJECTIVE
  To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis.
  
  
  METHODS
  Colitis was induced in wild type and GP-BAR1(-/-) mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies.
  
  
  RESULTS
  GP-BAR1(-/-) mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1.
  
  
  CONCLUSIONS
  GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.
authors: Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy.
authors: Sabrina
authors: S
authors: Cipriani
authors: Andrea
authors: A
authors: Mencarelli
authors: Maria Giovanna
authors: MG
authors: Chini
authors: Eleonora
authors: E
authors: Distrutti
authors: Barbara
authors: B
authors: Renga
authors: Giuseppe
authors: G
authors: Bifulco
authors: Franco
authors: F
authors: Baldelli
authors: Annibale
authors: A
authors: Donini
authors: Stefano
authors: S
authors: Fiorucci
mesh_terms: D000818:Animals; D002772:Cholera Toxin; D002939:Ciprofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D006242:Haptoglobins; D007109:Immunity; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D010539:Permeability; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D019108:Tight Junctions
chemical_list: C513561:Gpbar1 protein, mouse; D006242:Haptoglobins; D008024:Ligands; D011498:Protein Precursors; D043562:Receptors, G-Protein-Coupled; C408043:zonulin; D002939:Ciprofloxacin; D002772:Cholera Toxin