Sangya Chatterjee

Acute graft-versus-host disease (aGVHD) is a major cause of death after allogeneic hematopoietic cell transplantation, and patients with steroid-refractory aGVHD have a dismal prognosis. We have previously shown that the enteroendocrine hormone glucagon-like peptide-2 has tissue regenerative activity in the lower gastrointestinal tract 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 in pH in the stomach, and allogeneic T cells had 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. Gastrin also increased the viability of stomach and small intestine organoids in vitro. Compared with wild-type mice, Gast−/− mice experienced more severe aGVHD in the intestine and liver, 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 the therapeutic use of pentagastrin in a clinical trial of patients with aGVHD.

Acute graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). Most patients who have undergone allo-HCT receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglial morphology shifted toward a highly branched phenotype. Consistent with a proinflammatory phenotype, the microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived aryl hydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of the primary microglia with the AhR ligand 6-formylindolo(3,2-b)carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR ligand FICZ treatment. Moreover, the AhR ligand indole-3-acetate was also reduced in the CNS of patients who developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR ligands resulted in increased microglial activation in CNS GVHD. FICZ treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS GVHD in vivo.