DEVELOPMENT OF MICROBIOME-BASED THERAPY FOR TREATMENT-REFRACTORY GRAFT-VERSUS-HOST DISEASE

About This Grant

PROJECT SUMMARY/ABSTRACT Title: Development of microbiome-based therapy for treatment-refractory graft-versus-host disease Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for high-risk hematological malignancies. However, complications, such as graft-versus-host disease (GVHD), continue to limit the success of allo-HSCT. The intestinal microbiome can affect the pathophysiology of acute intestinal GVHD. Recent studies suggest ileal microbiota could affect GVHD severity based on a murine model of GVHD and a clinical study showing that histological GVHD damage of the ileum rather than the colon is associated with refractoriness to treatment. However, no analyses of the small intestinal microbiome have been performed in allo-HSCT patients. Thus, we urgently need to understand the role of the ileal microbiota in epithelial regeneration to prevent treatment-refractory GVHD (TR-GVHD). In this application, we focus on two major processes of TR-GVHD: 1) insufficient suppression of alloreactive immune cells and 2) impaired tissue regeneration. We hypothesize that disrupted ileal microbiota 1) impair epithelial regeneration following GVHD damage and 2) modulate GVHD severity by influencing alloreactive immune cells. To investigate these hypotheses, we established a novel murine model of GVHD using in vivo splenic T cell depletion (SpTCD) in which GVHD is induced by bone-marrow-graft–derived T cells after SpTCD and mediated by microbiome disruption. In this model, we found that administration of Lachnospiraceae species (Lachno spp.) significantly promoted epithelial regeneration in the ileum due to luminal secondary bile acids (SBAs). We hypothesize that Lachno spp. play a key role in promoting epithelial regeneration by producing SBAs and thereby suppressing severe GVHD. Our long-term goal is to develop treatment strategies for preventing TR-GVHD induced by microbiota disruption. In Aim 1, we focus on the ileal epithelium. We propose to identify specific SBAs and SBA-mediated signaling pathways that promote epithelial regeneration after GVHD damage. In Aim 2, we will investigate the mucosal immune compartment of the ileum to uncover the mechanisms by which Lachno spp. or Lachno spp.- derived SBAs mitigate the activation of alloreactive immune cells. As a translational step, in Aim 3, we will evaluate if Lachno spp.-derived SBAs enhance the efficacy of GVHD prophylaxis with post-transplant cyclophosphamide and improve the effectiveness of corticosteroid therapy to treat GVHD. Across all Aims, our goal is to uncover novel microbiome-based strategies to prevent TR-GVHD driven by microbiome disruption.