Gastrin for the treatment of acute graft-versus-host disease of the stomach

Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT) and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 (GLP-2) has tissue regenerative activity in the lower GI in mice and patients with steroid-refractory aGVHD. Here we explored the tissue protective effect of the enteroendocrine hormone gastrin for aGVHD of the stomach. We observed that aGVHD caused a loss of gastrin-producing G-cells and parietal cells (PCs) and an increase of pH in the stomach, while allogeneic T cells infiltrated the stomach wall. Pentagastrin treatment of aGVHD mice rescued the loss of PCs, normalized the pH in the stomach, increased stomach stem cell marker expression and abundance of LGR5+ cells, and changes in the stomach microbiome. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Gast-/- mice experienced more severe aGVHD in the intestine and liver compared to WT mice, which was rescued by pentagastrin-treatment. In patients developing aGVHD, low gastrin levels in stomach biopsies were connected to reduced survival. Moreover, gastrin expression in the stomach correlated with aGVHD severity and tissue damage scores in independent patient cohorts. This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.