Abstract Background Vasoactive Intestinal Peptide (VIP) is a neuropeptide widely expressed by neurons of the enteric nervous system. Effects of VIP on intestinal motility, mucosal vasodilation and gastric secretion are well-studied 1. Further, VIP is discussed to play a pivotal role in intestinal injury. It was shown that VIP can modulate immune responses and ameliorate inflammation in murine colitis models 1. Previously, we were able to show that VIP can modulate the small intestinal epithelium directly, by enhancing proliferation and secretory differentiation 2. In view of this promising data and previous promising evidence we here aimed to elucidate potential pro-regenerative effects of VIP on colonic mucosa in the context of inflammation in detail. Methods First, we employed colonic organoids derived from murine colonic crypts as a model to study the effects of VIP on the colonic epithelium in a state of homeostasis. To investigate potential pro-regenerative effects of VIP in the context of inflammatory injury, we established an in vitro inflammation model by exposing organoids to a chemokine cocktail (20 ng/mL TNF-α, 20 ng/mL IL-1β, 100 ng/mL LPS). To complement our in vitro data, Lgr5-EGFP-IRES-CreERT mice were treated intraperitoneally with VIP, both in a homeostatic state and following onset of dextran sulfate sodium (DSS)-provoked inflammation. Results Treatment of murine colonic organoids with VIP enhanced the differentiation towards the secretory lineage, inducing the gene expression Atoh1 and Spdef. In line with this, we observed an increase in MUC2+ cells and an increase of REG4 protein levels after VIP treatment. The expansion of secretory cell types by VIP coincided with the prominent upregulation of the Unfolded Protein Response, with an activation of the PERK/ATF4 pathway. Inflammation induced by the chemokine cocktail was ameliorated by VIP treatment. Specifically, VIP-treated colonic organoids exhibited decreased expression of several pro-inflammatory markers such as Tnfsf10, Nf-κB and Isg15 on mRNA level. Finally, in the murine DSS-inflammation model, VIP injections reduced colonic TNF-α level and limited immune-cell infiltration. Conclusion Our findings suggest that VIP promotes secretory differentiation and activates protective stress response pathways in the colonic epithelium, thereby reinforcing mucosal barrier and modulating epithelial inflammation. These results highlight VIP as a potential therapeutic modulator of mucosal repair in inflammatory colonic injury. References: 1.Iwasaki M, Akiba Y, Kaunitz J. Recent advances in vasoactive intestinal peptide physiology and pathophysiology: focus on the gastrointestinal system. F1000Research. 2019. 2.Agibalova T, Hempel A, Maurer HC, Ragab M, Ermolova A, Wieland J, et al. Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury. Stem Cell Res Ther. 2024. Conflict of interest: Ms. Hempel, Anneke: No conflict of interest Ragab, Mohab: No conflict of interest Agibalova, Tatiana: No conflict of interest Durner, Niklas: No conflict of interest Heindl, Fabian: No conflict of interest Stumpp, Patricia Maria: No conflict of interest Janssen, Klaus-Peter: No conflict of interest Reichert, Maximilian: No conflict of interest Schmid, Roland: No conflict of interest Middelhoff, Moritz: No conflict of interest
Hempel et al. (2026) studied this question.