title: Psychological stress-induced colonic barrier dysfunction: Role of immune-mediated mechanisms.
abstract: BACKGROUND
  Evidence suggests that patients with irritable bowel syndrome (IBS) exhibit increases in gut permeability and alterations in tight junction (TJ) protein expression. Although psychological stress worsens IBS symptoms, the mechanisms by which stress enhances gut permeability and affects TJ protein expression remain to be determined. Here, we test the hypothesis that chronic intermittent psychological stress activates the release of proinflammatory cytokines to alter TJ proteins and promotes increased gut permeability.
  
  
  METHODS
  Male Fischer-344 rats were subjected to 1 hour of water avoidance stress (WAS) or SHAM stress per day for 7 days. Following the stress protocol, colonic permeability was measured via transepithelial electrical resistance (TEER) and macromolecular flux of horseradish peroxidase (HRP). In tissue isolated from rats exposed to the WAS or SHAM stress, TJ proteins claudin-2, junctional adhesion molecule-A (JAM-A) and zonula occluden-1 (ZO-1) were measured via Western blotting, histological appearance of the colonic segments was assessed via hematoxylin and eosin staining, and an inflammatory cytokine panel was quantified via quantitative reverse transcription-polymerase chain reaction.
  
  
  RESULTS
  Repetitive daily exposure to WAS decreased the TEER, increased the macromolecular flux of HRP, and altered the expression of claudin-2, JAM-A and ZO-1 proteins within colonic tissue compared to SHAM controls. In the absence of a histologically defined inflammation, the cytokine profiles of WAS-treated animals revealed an increase in interleukin-1β and tumor necrosis factor (TNF)-α. Subsequent analysis revealed a significant positive correlation between TNF-α and expression of TJ protein claudin-2.
  
  
  CONCLUSIONS
  Our findings suggest that chronic stress increases colonic permeability via sub-inflammatory cytokine-mediated remodeling of TJ protein expression.
authors.affiliation: Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hattay
authors.affiliation: Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Prusator
authors.affiliation: Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tran
authors.affiliation: Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.|VA Medical Center, Oklahoma City, OK, USA.|Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: B
authors.identifier: http://orcid.org/0000-0002-2647-1316
authors.initials: B
authors.lastname: Greenwood-Van Meerveld
mesh_terms: D000818:Animals; D003106:Colon / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D007111:Immunity, Cellular / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013315:Stress, Psychological / Q000276:immunology* / Q000378:metabolism / Q000523:psychology*
chemical_list: D016207:Cytokines
keywords: immune; inflammation; permeability; rat; stress; tight junction proteins