title: Sacral nerve stimulation enhances early intestinal mucosal repair following mucosal injury in a pig model.
abstract: Reducing intestinal epithelial barrier (IEB) dysfunctions is recognized as being of major therapeutic interest for various intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability. Here, we report in a pig model that SNS enhances morphological and functional recovery of IEB following mucosal injury induced via 2,4,6-trinitrobenzenesulfonic acid. These effects are associated with an increased expression of tight junction proteins such as ZO-1 and FAK. These results establish that SNS enhances intestinal barrier repair in acute mucosal injury. They further set the scientific basis for future use of SNS as a complementary or alternative therapeutic option for the treatment of gut disorders with IEB dysfunctions such as inflammatory bowel diseases or irritable bowel syndrome.
  
  
  
  Intestinal epithelial barrier (IEB) dysfunctions, such as increased permeability or altered healing, are central to intestinal disorders. Sacral nerve stimulation (SNS) is known to reduce IEB permeability, but its ability to modulate IEB repair remains unknown. This study aimed to characterize the impact of SNS on mucosal repair following 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced lesions. Six pigs were stimulated by SNS 3 h prior to and 3 h after TNBS enema, while sham animals (n = 8) were not stimulated. The impact of SNS on mucosal changes was evaluated by combining in vivo imaging, histological and functional methods. Biochemical and transcriptomic approaches were used to analyse the IEB and mucosal inflammatory response. We observed that SNS enhanced the recovery from TNBS-induced increase in transcellular permeability. At 24 h, TNBS-induced alterations of mucosal morphology were significantly less in SNS compared with sham animals. SNS reduced TNBS-induced changes in ZO-1 expression and its epithelial pericellular distribution, and also increased pFAK/FAK expression compared with sham. Interestingly, SNS increased the mucosal density of neutrophils, which was correlated with an increase in trypsin and TGF-β1 levels compared with sham. Finally, SNS prevented the TNBS-induced increases in IL-1β and IL-4 over time that were observed with sham treatment. In conclusion, our results show that SNS enhances mucosal repair following injury. This study highlights novel mechanisms of action of SNS and identifies SNS as a new therapy for diseases with IEB repair disorders.
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Brégeon
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Coron
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Anna Christina Cordeiro
authors.initials: AC
authors.lastname: Da Silva
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Jaulin
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Aubert
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Chevalier
authors.affiliation: Inserm U563, CHU Purpan, Toulouse Cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurette
authors.affiliation: INSERM, U913, Nantes, F-44093, France.|Université Nantes, Nantes, F-44093, France.|CHU Nantes, Hôtel Dieu, Institut des Maladies de l'Appareil Digestif, F-44093, France.
authors.forename: Michel
authors.identifier: 0000-0003-1892-5071
authors.initials: M
authors.lastname: Neunlist
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D004558:Electric Stimulation; D004599:Electric Stimulation Therapy; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D012007:Rectum / Q000294:innervation; D012447:Sacrum / Q000294:innervation*; D013552:Swine; D014302:Trinitrobenzenesulfonic Acid; D014945:Wound Healing
chemical_list: D016207:Cytokines; D014302:Trinitrobenzenesulfonic Acid