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1 Faculte de Medecine, INSERM U539, NANTES, 44035, France
2 Pole Digestif, CHU Hotel Dieu, NANTES, 44035, France
3 Faculte de Medecine, INSERM U539, NANTES, 44035, France; Service d' Anatomie Pathologique, CHU Hotel Dieu, NANTES, 44035, France
4 Faculte de Medecine, INSERM U539, NANTES, 44035, France; Pole Digestif, CHU Hotel Dieu, NANTES, 44035, France
* To whom correspondence should be addressed. E-mail: michel.neunlist{at}sante.univ-nantes.fr.
Although the enteric nervous system (ENS) has been shown to regulate various mucosal functions, its role in the physiological control of the human intestinal epithelial barrier is unknown. The aim of this study was to investigate whether the ENS is able to modulate epithelial barrier permeability and a key tight junction-associated protein, ZO-1. Therefore, we developed a co-culture model, consisting of human submucosa containing the submucosal neuronal network and human polarized colonic epithelial monolayers (HT29-Cl.16E or Caco-2). Submucosal neurons were activated by electrical field stimulation (EFS). Permeability was assessed by measuring the flux of paracellular permeability markers (FITC-dextran or FITC-inulin) across epithelial monolayers. Expression of ZO-1 was determined by immunofluorescence, quantitative immunoblot analysis and real time RT-PCR. Using the coculture model, we showed that EFS of submucosal neurons resulted in a reduction in FITC-dextran or FITC-inulin fluxes, which was blocked by tetrodotoxin (TTX). In HT29-Cl.16E, the effect of submucosal neurons activation was blocked by a vasoactive intestinal peptide receptor antagonist (VIPra) and reproduced by VIP. Furthermore, ZO-1 expression (mRNA, protein) assessed in HT29-Cl.16E, was significantly increased following submucosal neurons activation by EFS. These effects on ZO-1 expression were blocked by TTX and VIPra and reproduced by VIP. In conclusion, our results strongly suggest a modulatory role of VIPergic submucosal neuronal pathways on intestinal epithelial barrier permeability and ZO-1 expression.
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