PROJECT SUMMARY/ABSTRACT The program project grant’s (PPG’s) overarching goal is to make allogeneic hematopoietic cell transplantation (allo-HCT) safer and more efficacious for patients with non-malignant and malignant blood diseases. Towards this end, it will address importance of microbiome in mitigating the severity of graft- versus-host disease (GVHD), the most significant complication of allo-HCT and improving outcomes after allo-HCT. The proposal has a unifying central theme, specifically to understand the role of intestinal microbial metabolite interactions with host metabolism and impact on intestinal GVHD. The proposed projects in the PPG are independent and yet synergistic. It will integrate big data (cutting edge technologies high throughput sequencing of genomes of microbial communities complemented by metabolomes), mechanistic studies of fundamental microbial and mammalian biology in well-defined HCT model systems and in humans, and, also importantly an IRB approved bench to bedside translation of these into proof of concept prospective human clinical trial under an IND from FDA. The PPG brings together investigators who are leaders from diverse fields into a cohesive group that has worked, published together and bring their varied expertise to improve outcomes of allo-HCT for blood diseases. The PPG being proposed will have four projects and four cores. All projects germinated from the common unified preliminary datasets that were generated by project leaders over last several years. Project 1 will explore the role of crosstalk between host intestinal epithelial cell (IEC) mitochondria and microbial metabolites, specifically the short chain fatty acid (butyrate) in murine models of GVHD. In synergistic, yet distinct line if investigation, project 2 will explore the role of host-microbiome interaction dependent metabolites, secondary bile acids (SBAs), on IEC homeostasis and GVHD in murine models. Project 3 will delineate the critical microbes and the mechanisms employed by them in breaking down specific host diet (resistant starch) to generate butyrate and SBAs. The role of dietary resistant starch on host microbiome and metabolome and its impact on clinical GVHD will be explored in a proof of concept clinical trial in project 4. These projects will be facilitated by state of the art Cores that include Metabolomics, Gnotobiotics mice and bacterial phenotyping, Bioinformatics, Biostatistics and supported by the Administrative Core. All of the investigators are from University of Michigan (a single institution).