The Gut Microbiome and Development of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation in Children - ABSTRACT This Mentored Patient-Oriented Research Career Development Award (K23) proposal will provide an excellent research environment, expert mentorship, and advanced didactic and practical training that will facilitate Dr. Sarah Heston’s transition into an independent clinician-scientist. Dr. Heston’s long-term career goal is to utilize the gut microbiome to improve the health of immunocompromised children. The proposed research will reveal the role of the gut microbiome in the development of acute gastrointestinal graft-versus-host disease (GI- GHVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in children. Allo-HCT is a life-saving treatment for a growing number of children with otherwise incurable oncologic, hematologic, and metabolic disorders; however, GI-GVHD limits survival in these patients. Mortality from severe GI-GVHD can approach 50%, and effective prediction and prevention strategies are limited. Dr. Heston’s proposal will address both the influence of the gut microbiome on developing GI-GVHD and the interactions between the gut microbiome and the host immune response that precede GI-GVHD. Dr. Heston will utilize three robust patient cohorts: 1) 198 pediatric allo-HCT recipients from Duke University and the Children’s Hospital of Philadelphia; 2) 75 prospectively enrolled pediatric allo-HCT recipients; and 3) 50 adult allo-HCT recipients enrolled in a phase I clinical trial of tributyrin, a prodrug of the microbial metabolite butyrate. Dr. Heston will determine the utility of gut microbial gene expression data for predicting GI-GVHD after allo-HCT, identify gut microbial-host interactions that contribute to GI-GVHD after allo-HCT, and evaluate host immune responses among HCT recipients receiving a short chain fatty acid supplement. The proposed studies will support Dr. Heston’s professional development by providing experience with 1) longitudinal microbiome analyses, 2) prospective clinical study design and execution, 3) the host immune response, and 4) multi-omic analyses. Dr. Heston’s mentorship team has extensive experience in these areas and will oversee her successful completion of the proposal’s objectives. Drs. John Rawls and Matthew Kelly are experts in the microbiome and will serve as co-primary mentors. Drs. Chao, Shinohara, and Li are world-renown investigators of allo-HCT and GI-GVHD, the crosstalk between innate and adaptive immunity, and computational modeling of high-dimensional data, respectively. The mentorship team will provide Dr. Heston with expert guidance in completing her research aims and achieving her career development goals. Dr. Heston’s external advisors, Drs. Fisher, Seed, and Wolf, add complementary expertise in clinical research with immunocompromised children and the microbiome. The proposed research will identify specific mechanisms by which the gut microbiome modifies the risk of GI-GVHD that can be leveraged for future rationally designed biotherapeutics to prevent GI-GVHD. Upon completion of the planned career development and research activities, Dr. Heston will be equipped to lead impactful research in pediatric infectious diseases and utilize the microbiome to improve clinical outcomes in immunocompromised children.
