PROJECT SUMMARY/ABSTRACT – PROJECT 4 Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potent form of cellular therapy that has the potential to cure malignant and benign hematological conditions. However, its utility is limited by the development of graft-versus-host disease (GVHD). GI GVHD is the principal cause of non- relapse mortality (NRM) after allo-HCT. Recent evidence has brought into focus the role played by the metabolites derived from host-microbiota interactions in the severity of GI GVHD. However, the biological mechanisms, clinical feasibility, and the impact of altering the GI microbial metabolites on GI GVHD remain unknown. Project 4 will focus on dietary manipulation of the microbiome-metabolomic axis via dietary supplementation with resistant potato starch (RPS) for mitigating GVHD in allo-HCT patients. This project encompasses an investigator initiated proof-of-concept clinical trial that has been developed to translate the preliminary data generated from Projects 1 and 3. This trial is being performed under an IND from the FDA. It includes serial biosample (stool and plasma) collection and analyses for the microbiota and metabolite alterations, informed by mechanistic studies from projects 1, 2, and 3. We will also combine these data with longitudinal measurement of molecules reflecting intestinal epithelial injury, collectively comprising discovery approaches to more comprehensively study the effects of RPS on the microbiome, its dependent metabolites and host in allo-HCT patients.