Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators
- T Piche1,2,3,4,
- G Barbara5,6,
- P Aubert1,2,3,
- S Bruley des Varannes1,2,3,
- R Dainese4,
- J L Nano4,
- C Cremon5,6,
- V Stanghellini5,6,
- R De Giorgio5,6,
- J P Galmiche1,2,3,
- M Neunlist1,2,3
- 1INSERM, U913, Nantes, France
- 2Université de Nantes, Faculté de Médecine, Nantes, France
- 3CHU Nantes, Hôtel Dieu, Institut des Maladies de l’Appareil Digestif, Nantes, France
- 4Service de Gastroentérologie & Inserm U895, Pôle digestif médicochirurgical, Hôpital de l’Archet II, Nice, France
- 5Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy
- 6CRBA, Centro Unificato di Ricerca BioMedica Applicata, St. Orsola Hospital, Bologna, Italy
- Dr M Neunlist, INSERM U 913, Hôpital Hôtel Dieu 1, place Alexis Ricordeau, 44035 Nantes, France;
- Revised 12 August 2008
- Accepted 19 August 2008
- Published Online First 29 September 2008
Background: Growing evidence suggests that patients with irritable bowel syndrome (IBS) have increased intestinal permeability. In addition, mucosal soluble mediators are involved in the pathophysiology of pain in IBS. We aimed to investigate (1) paracellular permeability in colonic biopsies of patients with IBS; and (2) the ability of soluble factors from colonic biopsies to reproduce these alterations in vitro.
Methods: Paracellular permeability in colonic biopsies of healthy subjects and patients with IBS was measured by mounting the biopsies in Ussing chambers. Cleared supernatant (SUP) of the culture from colonic biopsies was collected and applied to Caco-2 cells for 48 h. Paracellular permeability and transepithelial resistance (TER) were evaluated. mRNA expression of the tight junction proteins, zonula occludens (ZO)-1 and occludin, was assessed in colonic biopsies. Abdominal pain was assessed using a validated questionnaire.
Results: Permeability of colonic biopsies was significantly higher in patients with IBS compared to healthy subjects. These changes were associated with significantly lower expression of ZO-1 mRNA in biopsies of IBS as compared to healthy subjects. Compared to healthy subjects, SUP of IBS markedly reduced TER and significantly increased permeability in Caco-2 cells. SUP of IBS patients induced a significant decrease of ZO-1 mRNA in Caco-2 as compared to healthy subjects. SUP-induced increased paracellular permeability correlated with the severity of abdominal pain.
Conclusions: Our study shows that colonic soluble mediators are able to reproduce functional (permeability) and molecular (ZO-1 mRNA expression) alterations observed in IBS patients. These findings might pave the way both to identify novel biomarkers as well as new therapeutic targets in IBS.
See Commentary, p 161
Funding: This study was supported by a grant from Sanofi–Aventis and a “Programme Hospitalier de Recherche Clinique 2007–2008” of the CHU of Nice. The study was also supported by the Italian Ministry of Education, University and Research (No. 2002052573, to GB, VS and RDeG), and R.F.O. from the University of Bologna (to GB, RDeG and VS).
Competing interests: None.
Ethics approval: The study was approved by the two local ethics committees (Bologna and Nice) on 8 June 2005, and conducted in accordance with the Declaration of Helsinki.