Gut microbial beta-glucuronidases as a biomarker for mycophenolic acid enterohepatic recirculation and associated toxicities

PROJECT SUMMARY Mycophenolic acid (MPA) is a crucial immunosuppressive medication that prevents kidney transplant rejection and prolongs the survival of the transplanted organ. MPA, however, is associated with dose-limiting side effects of diarrhea and leukopenia. Recent animal studies have shown that MPA-related toxicities are dependent on the gut microbiota, but our understanding of MPA reactivation in the gut and its contribution to associated toxicities is incomplete. Understanding the impact of gut-mediated MPA reactivation is critical because transplant physicians frequently encounter MPA-associated toxicities in clinical practice. Transplant physicians routinely decrease the dosage of MPA during episodes of post-transplant diarrhea and leukopenia, but large studies have shown that such actions are associated with acute organ rejection. Thus, it is imperative that we define the roles played by gut bacterial beta-glucuronidase (GUS) enzymes in MPA reactivation, enterohepatic recirculation, and associated toxicities. The overall goals of this proposal are to identify the microbial GUS enzymes involved in reactivation of MPA and to define the relationship between fecal GUS activity, MPA enterohepatic recirculation, and MPA-associated toxicities in kidney transplant recipients. We hypothesize that specific microbial GUS enzymes drive the reactivation and enterohepatic recirculation of MPA, and that quantitative fecal GUS enzyme assays will serve as a biomarker for MPA-associated toxicities. Here we will study a cohort of 210 kidney transplant recipients with and without MPA-associated toxicities. Our center at Weill Cornell routinely performs approximately 250 kidney transplant recipients per year, supporting the feasibility of recruiting this number of patients that will sufficiently power the study to successfully test our hypothesis. In Aim 1, we will define the gut microbial GUS enzymes that reactivate MPA and the drugs that may disrupt them. In Aim 2, we will define the relationship among quantitative fecal GUS activities, MPA enterohepatic recirculation, and MPA-associated toxicities. This project will reveal fundamental data about the gut microbiota's ability to reactivate MPA, influence enterohepatic recirculation, and impact therapeutic tolerance. Importantly, it will assess fecal GUS enzyme activity as a novel biomarker for MPA-associated toxicities, allowing for the development of more personalized approaches to optimize MPA efficacy and minimize MPA-associated toxicities in kidney transplant recipients.