PROJECT SUMMARY/ABSTRACT In this application, we are applying for renewal of our consortium between Baylor College of Medicine in Houston TX and Children’s National Hospital in Washington DC as a Core Clinical Center in the BMT CTN Network. Our consortium performs over 350 transplants per year (over 150 pediatric and over 200 adult procedures) and also infuses over 150 immune effector cell products (Investigational and commercial products) per year. We also have strong programs in non-malignant disorders performing over 300 allogeneic transplants for non-malignant hematologic, metabolic and immunologic disorders in the last 5 years. Furthermore, our centers have extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and have successfully sponsored and implemented over 140 cell and gene therapy studies under more than 70 investigator initiated INDs, including multiple Phase II multicenter studies. We have also been strong contributors to BMT CTN with 161 patients enrolled in the last funding period. Importantly we have been highly successful in matching CTN clinical trial accrual to the diverse populations of our two catchment areas including 27.8% Hispanic, 19.6% African American and 3.5% Asian subjects. Although both centers have strengths in cell therapies we selected a research proposal based on the laboratory work of Dr. Pavan Reddy a physician scientist who directs the NCI-designated comprehensive cancer center at Baylor College of Medicine because we hypothesize that this is a highly feasible strategy with strong potential to appreciably impact the incidence of graft versus host disease (GVHD) which remains a significant cause of morbidity and mortality in patients post hematopoietic cell transplant. (HCT) In preclinical studies, Dr Reddy discovered that butyrate was significantly decreased in intestinal epithelial cells of mice experiencing GVHD, and that increasing intestinal butyrate- producing bacteria reduced the severity of experimental acute gastrointestinal GVHD. Administration of resistant potato starch (RPS), as a prebiotic, promoted an increase in butyrogenic bacteria and intestinal levels of butyrate. In a pilot study testing this intervention in the clinic, administration of RPS to allogeneic transplant recipients was feasible and was associated with significant alterations in intestinal and plasma metabolites. A phase II trial examining the effect of RPS on GVHD in allo-HCT recipients is underway and, in this application, we propose a randomized Phase III trial to evaluate the effects of modulating the microbiome to reduce GVHD in a larger multicenter cohort. We assert that this approach requires multicenter testing to confirm whether the microbiome modulation is reproducible in diverse populations in different geographic locations and to determine if there is a significant reduction in the incidence of GVHD.