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

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Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for many hematological malignancies. However, its success is frequently compromised by acute graft-versus-host disease (aGVHD), a severe complication driven by allogeneic T cell-mediated organ damage. While lower gastrointestinal involvement is well recognized, gastric aGVHD remains poorly understood due to diagnostic challenges and symptom overlap with treatment-related toxicity. Using a murine major-histocompatibility-mismatch model, we identified aGVHD-associated gastric pathology characterized by T cell infiltration, elevated expression of the inflammatory cytokines TNF, IFN-γ, and IL-6, as well as loss of parietal cells with subsequent basification. Furthermore, gastrin-producing G-cells were lost. Given gastrin´s established roles in tissue regeneration and acid secretion by parietal cells, we investigated whether treatment with a gastrin analogue, pentagastrin could reduce stomach aGVHD. Pentagastrin has an increased stability and a longer half-life compared to endogenous gastrin and is successfully used for routine examination of gastric acid secretion. Pentagastrin treatment in murine aGVHD models restored parietal cell populations, normalized gastric pH, and increased both stomach stem cell marker expression and the abundance of LGR5+ cells. Pentagastrin also increased the expression of tight junction genes (Cldn2, Ocln), which are surrogate markers for barrier integrity. Furthermore, pentagastrin improved survival and reduced clinical and histological aGVHD scores throughout the gastrointestinal tract in multiple mouse models while maintaining the GVL effect. While microbiome analysis by 16s sequencing revealed changes with pentagastrin treatment, the protective effect appeared largely microbiome independent. Supporting these findings, gastrin increased the viability of organoids in vitro and maintained organoid numbers in multiple aGVHD organoid models. We could show that gastrin increased the expression of the same stem cell and cell adhesion markers (Olfm4, Cldn2, Ocln) in organoids as pentagastrin in vivo. Gast-/- mice experienced more severe aGVHD in intestine and liver and lost parietal cells in the aGVHD model. Clinical relevance was underscored by histopathological evaluation of biopsies from different patient cohorts with aGVHD. Reduced gastrin scores were connected to reduced survival. Specifically, patients with gastric aGVHD had reduced gastrin scores compared to allo-HCT recipients without gastric GVHD. Patients with aGVHD grade 3-4 had lower gastrin scores than those with grade 1-2. To validate these findings, we analyzed serum and plasma samples and found a decline in gastrin levels upon allo-HCT. Additionally, aGVHD patients had significantly lower gastrin levels compared to healthy individuals. Together with our prior work on glucagon-like peptide 2 (GLP-2), where we showed the therapeutic potential of GLP-2 for lower gastrointestinal aGVHD in mice and patients, these findings suggest that targeting enteroendocrine hormones may represent a broader therapeutic strategy for restoring gastrointestinal homeostasis in aGVHD.This study delineates the protective role of gastrin in aGVHD of the stomach in mice and patients and provides a rationale for the therapeutic use of pentagastrin in a clinical trial for patients with aGVHD.

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