Exploring the Interplay of Microbiome, Bile Acids, Immune Reconstitution, and Clinical Outcomes Following Allogeneic Hematopoietic Transplantation in Pediatrics
The gut microbiome plays a critical role in modulating the immune response, influencing outcomes of allogeneic transplantation, a life-saving treatment for relapsed/refractory leukemia and lymphoma. However, this treatment comes with significant complications that can limit is efficacy. Understanding and leveraging the immunomodulatory potential of the microbiome is crucial for optimizing cancer therapy outcomes. However, the mechanisms underlying the microbiome's influence on outcomes post-transplant, especially in pediatric patients, remain insufficiently understood. Early recovery of key immune cells post-transplant is a predictor of superior overall survival and low risk of graft versus host disease and mortality. Microbiota and microbe-derived bile acids have been identified as regulators of the immune system, suggesting a mechanism through which the microbiome affects hematopoietic transplant outcomes.
The proposed project aims to unravel the intricate relationship between the microbiome, bile acids, and allo-HCT outcomes in pediatric recipients. My long-term goal is to identify therapeutic interventions that optimize the microbiota composition, facilitating superior immune function and improve treatment tolerance for enhanced clinical outcomes. The project will leverage a substantial sample size from three large centers (411 patients), ensuring statistical and clinical significance.
Project Goal:
Aim1: Determine the microbiota community and bile acids linked to immune reconstitution.
1.1 Elucidate the relationship between microbiome, bile acids, and T cell immune reconstitution in pediatric patients.
1.2 Identify therapeutic strategies to improve immune reconstitution in preclinical models by harnessing the microbiome and bile acids.
Aim 2: Determine the microbiota composition and bile acids associated with graft versus host disease and mortality.
2.1. Identify the microbiome composition and bile acid profile that protect against graft versus host disease and mortality in pediatric patients.
2.2. Identify therapies aiming to improve graft versus host disease in preclinical models by altering microbiota and bile acids.
Our goal involves the identification of microbiome compositions and bile acid profiles linked to optimal immune recovery post-HCT, with lower risk of toxicities. This study also aims to uncover profiles associated with higher risks of graft versus host disease and mortality. Insights gained will pave the way for future projects aimed at improving outcomes in pediatric HCT recipients by optimizing gut microbial communities. The overarching goal is to elucidate microbiota-host interactions in pediatric patients undergoing allo-HCT, leading to improved outcomes and quality of life, ultimately marking a significant advancement in the field.
