Vasoactive Intestinal Polypeptide in the Enteric Neural Plexus Promotes Microbiome Diversity and Resistance to GvHD

Abstract Graft-versus-host disease (GvHD) in allo-transplant recipients is characterized by donor T cell- mediated damage to recipient organs and changes in the gut microbiome. Vasoactive intestinal peptide (VIP), an immunosuppressive neuropeptide, directs T cell responses towards a Th2 phenotype while inhibiting proinflammatory cytokine production. VIP-producing enteric neurons contribute to the mucosal barrier and maintain gut microbiome homeostasis. The impact of VIP production by host cells on GvHD remains unclear. We examined the effect of endogenous VIP synthesis in modulating GvHD in multiple murine allo-BMT models. VIP knock-out mice were exquisitely sensitive to GvHD, experiencing activation and expansion of Th1- and Th17-polarized T cells and early death. Transplanting radiation chimeric mice in which the VIP gene was knocked out in either hematopoietic or non-hematopoietic cells demonstrated that VIP production by non-hematopoietic tissues limited the GvHD activity of donor T cells. Immunofluorescence staining demonstrated VIP expression in enteric neurons in allo-BMT recipients, consistent with local effects of VIP on T cells and the gut microbiome. VIP- KO mice had lower gut pH, higher frequencies of Bacillota species, and less microbiome diversity post-transplantation. These data support the crucial role of VIP in maintaining the diversity of the gut microbiome with beneficial commensal species and in modulating the alloreactivity of donor T cells after allo-BMT.