title: The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations.
abstract: OBJECTIVE
  Diarrhea-predominant irritable bowel syndrome (IBS-D) patients show altered epithelial permeability and mucosal micro-inflammation in both proximal and distal regions of the intestine. The objective of this study was to determine the molecular events and mechanisms and the clinical role of upper small intestinal alterations.
  
  
  METHODS
  Clinical assessment and a jejunal biopsy was obtained in IBS-D patients and healthy subjects. Routine histology and immunohistochemistry was performed in all participants to assess the number of mast cells (MCs) and intraepithelial lymphocytes. RNA in tissue samples was isolated to identify genes showing consistent differential expression by microarray analysis followed by pathway and network analysis in order to identify the biological functions of the differentially expressed genes in IBS-D. Gene and protein expression of tight junction (TJ) components was also assessed by quantitative real-time polymerase chain reaction and confocal microscopy to evaluate the pathways identified by gene expression analysis.
  
  
  RESULTS
  The analysis reveals a strong association between the transcript signature of the jejunal mucosa of IBS-D and intestinal permeability, MC biology, and TJ signaling. The expression of zonula occludens 1 (ZO-1) was reduced in IBS-D at both gene and protein level, with protein redistribution from the TJ to the cytoplasm. Remarkably, our analysis disclosed significant correlation between ZO proteins, MC activation, and clinical symptoms.
  
  
  CONCLUSIONS
  IBS-D manifestations are linked to molecular alterations involving MC-related dysregulation of TJ functioning in the jejunal mucosa.
authors.affiliation: Department of Gastroenterology, Digestive System Research Unit, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona-Departmento de Medicina, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Martínez
authors.forename: María
authors.initials: M
authors.lastname: Vicario
authors.forename: Laura
authors.initials: L
authors.lastname: Ramos
authors.forename: Beatriz
authors.initials: B
authors.lastname: Lobo
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Mosquera
authors.forename: Carmen
authors.initials: C
authors.lastname: Alonso
authors.forename: Alex
authors.initials: A
authors.lastname: Sánchez
authors.forename: Mar
authors.initials: M
authors.lastname: Guilarte
authors.forename: María
authors.initials: M
authors.lastname: Antolín
authors.forename: Inés
authors.initials: I
authors.lastname: de Torres
authors.forename: Ana M
authors.initials: AM
authors.lastname: González-Castro
authors.forename: Marc
authors.initials: M
authors.lastname: Pigrau
authors.forename: Esteban
authors.initials: E
authors.lastname: Saperas
authors.forename: Fernando
authors.initials: F
authors.lastname: Azpiroz
authors.forename: Javier
authors.initials: J
authors.lastname: Santos
mesh_terms: D000328:Adult; D003967:Diarrhea / Q000150:complications*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007583:Jejunum / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000473:pathology; D046228:Microarray Analysis; D008875:Middle Aged; D010539:Permeability; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism*; D055815:Young Adult