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.
