title: The PepT1-NOD2 signaling pathway aggravates induced colitis in mice.
abstract: OBJECTIVE
  The human di/tripeptide transporter human intestinal H-coupled oligonucleotide transporter (hPepT1) is abnormally expressed in colons of patients with inflammatory bowel disease, although its exact role in pathogenesis is unclear. We investigated the contribution of PepT1 to intestinal inflammation in mouse models of colitis and the involvement of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway in the pathogenic activity of colonic epithelial hPepT1.
  
  
  METHODS
  Transgenic mice were generated in which hPepT1 expression was regulated by the β-actin or villin promoters; colitis was induced using 2,4,6-trinitrobenzene sulfonic acid (TNBS) or dextran sodium sulfate (DSS) and the inflammatory responses were assessed. The effects of NOD2 deletion in the hPepT1 transgenic mice also was studied to determine the involvement of the PepT1-NOD2 signaling pathway.
  
  
  RESULTS
  TNBS and DSS induced more severe levels of inflammation in β-actin-hPepT1 transgenic mice than wild-type littermates. Intestinal epithelial cell-specific hPepT1 overexpression in villin-hPepT1 transgenic mice increased the severity of inflammation induced by DSS, but not TNBS. Bone marrow transplantation studies showed that hPepT1 expression in intestinal epithelial cells and immune cells has an important role in the proinflammatory response. Antibiotics abolished the effect of hPepT1 overexpression on the inflammatory response in DSS-induced colitis in β-actin-hPepT1 and villin-hPepT1 transgenic mice, indicating that commensal bacteria are required to aggravate intestinal inflammation. Nod2-/-, β-actin-hPepT1 transgenic/Nod2-/-, and villin-hPepT1 transgenic/Nod2-/- littermates had similar levels of susceptibility to DSS-induced colitis, indicating that hPepT1 overexpression increased intestinal inflammation in a NOD2-dependent manner.
  
  
  CONCLUSIONS
  The PepT1-NOD2 signaling pathway is involved in aggravation of DSS-induced colitis in mice.
authors.affiliation: Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.forename: Hang Thi Thu
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Ingersoll
authors.forename: Saravanan
authors.initials: S
authors.lastname: Ayyadurai
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.forename: Moiz A
authors.initials: MA
authors.lastname: Charania
authors.forename: Yutao
authors.initials: Y
authors.lastname: Yan
authors.forename: Shanthi V
authors.initials: SV
authors.lastname: Sitaraman
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D000199:Actins; D000900:Anti-Bacterial Agents; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters; C026615:villin; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate