BETA-GLUCURONIDASE ACTIVITY OF GUT MICROBIOME AND ENTEROHEPATIC RECIRCULATION OF MYCOPHENOLIC ACID IN KIDNEY TRANSPLANT RECIPIENTS

Introduction:

Bacterial b-glucuronidase (BGUS) converts mycophenolic acid glucuronide back to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil. This conversion occurs through enterohepatic recirculation (EHR), likely enhancing immunosuppression and toxicity in kidney transplant recipients (KTRs). The objective of this project was to determine if inactivation of bacteria in stool eliminates BGUS activity.

Methods:

Adult KTRs (n=84, 37 prospective and 47 cross-sectional) underwent simultaneous pharmacokinetic (PK) study and stool collection. We defined MPA %EHR as MPA AUC 5-12hr /AUC 0-12hrx100. We then assessed BGUS activity using a fluorometric assay (ABCAM kit ab234625) in the stool samples of these participants. This activity was then reassessed after autoclaving one aliquot of the same stool samples.

Results:

The characteristics of the participants were as follows: 61  (70%) male, 59 (70%) White, 6 (9%) Hispanic.  There was significant variation in EHR among KTRs. (Figure 1).

Figure 1: Enterohepatic recirculation variability among KTRs. Enterohepatic recirculation (EHR) was assessed by calculating the ratio of the area under the concentration-time curve (AUC) of MPA during the 5-12 hour interval to the total AUC over the 0-12 hour post-dose period.

The in-vitro BGUS activity decreased in stool samples that were auto-claved compared to the aliquot that was not auto-claved. (Figure 2)

Figure 2: In-vitro BGUS activity for active and inactive gut bacteria. BGUS activity is decreased in bacterially inactive (red) stool samples compared to active (blue) samples. Participants underwent a pharmacokinetic (PK) study and microbiome stool collection between 30-60 days post-kidney-transplant, N = stool samples from 3 KTRs.

Conclusions:

Our findings show variation in MPA % EHR in KTRs. BGUS activity was reduced with autoclaving, suggesting that inactivating bacteria decreases BGUS activity. Better understanding of factors associated with EHR may provide opportunities to optomize MMF dosing based on the stool microbiome.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.