Background Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible. Methods VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non‐inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated. Key Results VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP‐CD than with SUP‐UC. Furthermore, in CD but not UC, SUP‐I reduced VIP expression in the ENS as compared to SUP‐NI. Next, IL‐6 but not IL‐5, IL‐10, IL‐17, IFN‐γ or TNF‐α reduced VIP expression in the ENS. Finally, in CD, SUP‐I incubated with anti‐IL‐6 antibody increased VIP expression as compared to SUP‐I alone. Conclusions & Inferences Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL‐6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD. Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL‐6 is a putative soluble factor responsible in part for changes in VIP expression in CD.