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Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier
  1. Cristina Martínez1,
  2. Beatriz Lobo1,
  3. Marc Pigrau1,
  4. Laura Ramos1,
  5. Ana Maria González-Castro1,
  6. Carmen Alonso1,4,
  7. Mar Guilarte1,2,
  8. Meritxell Guilá1,
  9. Ines de Torres3,
  10. Fernando Azpiroz1,4,
  11. Javier Santos1,4,
  12. María Vicario1,4
  1. 1Department of Gastroenterology, Digestive System Research Unit, Hospital Universitari Vall d'Hebron and Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (Departmento de Medicina), Barcelona, Spain
  2. 2Allergy Unit, Hospital Universitari Vall d'Hebron and Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (Departmento de Medicina), Barcelona, Spain
  3. 3Pathology Department, Hospital Universitari Vall d'Hebron and Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona (Departmento de Medicina), Barcelona, Spain
  4. 4Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
  1. Correspondence to Dr María Vicario, Digestive System Research Unit, Laboratory of Neuro-Immuno-Gastroenterology, Department of Gastroenterology, Vall d'Hebron Institut de Recerca, Paseo Vall d'Hebron 119-129, 08035, Barcelona, Spain; maria.vicario{at}vhir.org

Abstract

Objective Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations.

Design A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117+ cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy.

Results Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms.

Conclusion The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

  • IBS-D
  • intestinal permeability
  • tight junction signalling
  • mucosal mast cells
  • brain–gut interaction
  • intestinal mast cells
  • gene expression
  • gut inflammation
  • intestinal barrier function
  • stress
  • small bowel disease
  • serotonin
  • neurogastroenterology
  • neural–immune interactions
  • motility disorders
  • anorectal function
  • visceral sensitivity
  • gastrointestinal motility
  • gas physiology
  • functional bowel disorder
  • antibacterial mucosal immunity
  • enteric bacterial microflora
  • gut immunology

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Footnotes

  • Funding Supported in part by the Fondo de Investigación Sanitaria and CIBERehd, Instituto Carlos III, Subdirección General de Investigación Sanitaria, Ministerio de Ciencia e Innovación: CM08/00229 (B Lobo); CM05/00055 (L Ramos); CM10/00155 (M Pigrau); CM04/00019 (C Alonso); PI05/1423, EC07/90148 & PI/080940 (J Santos); CP10/00502 (M Vicario); Ministerio de Educación, Dirección General de Investigación: SAF 2009-07416 (F Azpiroz); Agència de Gestió d'Ajuts Universitaris i de Recerca, de la Generalitat de Catalunya: 2009 SGR 219 (F Azpiroz and J Santos); the International Foundation for Functional Gastrointestinal Disorders (2008 IFFGD) and the 2010 Rome Foundation Award (J Santos); and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas: CB06/04/0021 (F Azpiroz and J Santos). CIBERehd is funded by the Instituto de Salud Carlos III.

  • Competing interests None.

  • Ethics approval Approval provided by the Ethics Committee of the Hospital Vall d'Hebron.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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