Absence of VIP-Receptor Signaling in the Gut Confers Increased GvHD Susceptibility and Contributes to Microbiome with Anti-Leukemic Properties
Year: 2025
Type: article
Abstract: Introduction Graft-versus-host disease (GvHD) is a major complication following allogeneic transplants , characterized by donor T cell-mediated damage to host tissues and alterations in the gut microbiome . Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide that promotes Th2 T cell responses while inhibiting pro-inflammatory cytokine production . VIP-producing enteric neurons are crucial for maintaining mucosal barrier integrity and gut microbiome homeostasis . Our previous research has focused on the role of VIP from donor plasmacytoid dendritic cells in reducing GvHD. The impact of host-derived VIP on GvHD progression needs to be better understood. Objective We hypothesized that VIP signaling modulates gut microbiome diversity, decreases GvHD, and improves survival in wild-type (WT) transplant recipients compared to VIP knockout (KO) transplant recipients. Methods and Results We investigated the role of endogenous VIP signaling in GvHD using murine models of allogeneic bone marrow transplantation (allo-BMT). VIP-KO mice had increased GvHD severity, with enhanced activation and proliferation of Th1 and Th17 T cells, resulting in higher mortality. Using radiation chimeras with VIP gene knockout in either hematopoietic or non-hematopoietic cells, we found that VIP from non-hematopoietic tissues mitigates GvHD induced by donor T cells. Immunofluorescence confirmed VIP expression in the enteric neurons of allo-BMT recipients (Figure 1), suggesting localized modulation of T cell activity and the gut microbiome . Stool analysis from VIP-KO mice revealed a lower pH and a microbiome enriched with proinflammatory species, such as Ruminococcus gnavus and Lactobacillus murinus , known to promote TNFα secretion and Th1/Th17 polarization, respectively. Cohousing WT and VIP-KO mice did not reduce GvHD in VIP-KO mice undergoing allo-BMT (data not shown); instead, co-housing WT and VIP-KO mice transferred the gut microbiome (Figure 2A, 2C) and anti-leukemic response (Figure 2B) of VIP-KO mice to WT mice. Treatment of wild-type mice undergoing allo-BMT with daily injections of a VIP-receptor antagonist led to an increased frequency of Lactobacillus murinus and increased GvHD severity. These results underscore the importance of VIP signaling in the gut. Conclusion Our findings demonstrate that the absence of VIP-receptor signaling increases susceptibility to GvHD following allo-BMT, leading to heightened donor T cell alloreactivity and the development of a microbiome with anti-leukemic properties.
Institutions: Emory University, Winship Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W4407976199