Loss of GLP-2R signaling in Glp2r−/− mice increases the long-term severity of graft versus host disease

Background

Glucagon-like peptide-2 (GLP-2) reduces systemic and gut inflammation while preserving mucosal integrity. Preclinical and clinical reports implicate GLP-2 receptor (GLP-2R) agonism as a potential therapy for graft vs. host disease (GvHD).

Methods

Here we assessed whether enhanced vs. loss of GLP-2R signaling modifies gut injury and inflammation in experimental murine acute GvHD (aGvHD). Allogeneic hematopoietic cell transplantation (HCT) was performed using bone marrow and splenocytes from BALB/cJ donor mice to induce aGvHD in C57BL/6J recipients. Chimerism was determined by flow cytometry of immune cell compartments. Inflammation was assessed by measuring circulating cytokines and histological scoring of gut mucosal damage. GLP-2 responsivity was assessed using histology and gene expression analyses. The gut microbiome was assessed by 16S rRNA sequencing.

Results

Allogeneic chimerism was >90% in peripheral blood and in the gut epithelial compartment. Gut GLP-2R signaling was preserved following allogeneic bone marrow transplantation. Surprisingly, GLP-2R agonism using teduglutide did not reduce circulating cytokines, gut injury, immune cell infiltration or the severity of aGvHD. In contrast, transplant recipient Glp2r^−/− mice exhibited reduced survival, associated with increased bacteremia. Shifts in microbial species abundance with gain or loss of GLP-2R signaling were not correlated with aGvHD clinical outcomes.

Conclusions

Activation of GLP-2R signaling did not reduce the severity of experimental aGvHD, failing to replicate a previous study using an identical aGvHD protocol. Nevertheless, loss of GLP-2R signaling in transplant recipients decreased survival and increased bacteremia, implicating an essential role for endogenous GLP-2R signaling in maintaining barrier function in the context of immune-mediated gut epithelial injury.