title: The effects of a TGR5 agonist and a dipeptidyl peptidase IV inhibitor on dextran sulfate sodium-induced colitis in mice.
abstract: OBJECTIVE
  Luminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon-like peptide-2 (GLP-2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase-IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP-2 release, which is enhanced by DPPIV inhibition.
  
  
  METHODS
  Intestinal injury was induced in mice by administration of dextran sulfate sodium (DSS) in drinking water (free access to water containing 5% DSS for 7 days). The selective TGR5 agonist betulinic acid (BTA) and the DPPIV inhibitor sitagliptin phosphate monohydrate (STG) were administered orally for 7 days. Male C57BL/6 mice (6-7 weeks old) were divided into five groups: normal control group, disease control group, BTA low group (drinking water containing 15 mg/L BTA), BTA high group (50 mg/L BTA), and BTA high + STG (3 mg/kg, i.g.) group.
  
  
  RESULTS
  The selective TGR5 agonist BTA dose-dependently suppressed disease activity index and mRNA expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the colon. Nevertheless, STG administration had little additive effect on BTA-induced protection. Fibroblast activation protein mRNA expression, but not expression of other DPP family members, was increased in the colon of DSS-treated mice with increased mucosal DPPIV. Co-administration of the selective GLP-2 antagonist GLP-2 (3-33) reversed the effect of BTA.
  
  
  CONCLUSIONS
  The selective TGR5 agonist BTA ameliorated DSS-induced colitis in mice via the GLP-2 pathway with no effect of DPPIV inhibition, suggesting that other DPP enzymatic activity is involved in GLP-2 degradation.
authors.affiliation: Second Department of Internal Medicine, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Sakanaka
authors.forename: Takuya
authors.initials: T
authors.lastname: Inoue
authors.forename: Naoki
authors.initials: N
authors.lastname: Yorifuji
authors.forename: Munetaka
authors.initials: M
authors.lastname: Iguchi
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Ken
authors.initials: K
authors.lastname: Narabayashi
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kakimoto
authors.forename: Sadaharu
authors.initials: S
authors.lastname: Nouda
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Okada
authors.forename: Takanori
authors.initials: T
authors.lastname: Kuramoto
authors.forename: Kumi
authors.initials: K
authors.lastname: Ishida
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Abe
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Umegaki
authors.forename: Yasutada
authors.initials: Y
authors.lastname: Akiba
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kaunitz
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Higuchi
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D053767:Glucagon-Like Peptide 2 / Q000378:metabolism / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D053978:Pentacyclic Triterpenes; D010446:Peptide Fragments / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage* / Q000494:pharmacology*; D014315:Triterpenes / Q000008:administration & dosage* / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D053767:Glucagon-Like Peptide 2; C513561:Gpbar1 protein, mouse; D018836:Inflammation Mediators; D053978:Pentacyclic Triterpenes; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D014315:Triterpenes; C451520:glucagon-like peptide-2 (3-33); D016264:Dextran Sulfate; D000068900:Sitagliptin Phosphate; D000094062:Betulinic Acid
keywords: DPPIV; GLP-2; TGR5; dextran sulfate sodium; sitagliptin
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