Abstract: TH-PO0993
Mechanistic Insights into Mycophenolic-Acid Induced Diarrhea and Intestinal Barrier Dysfunction in Kidney Transplantation
Session Information
- Transplantation: Basic - Immune Biology, Tissue Injury, and Emerging Technologies
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 2001 Transplantation: Basic
Authors
- Gupta, Kajal, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Vo, Duy, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Onyeaghala, Guillaume Chinedu, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Mohamed, Moataz, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Saqr, Abdelrahman, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Dorr, Casey R., University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Staley, Christopher, University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Jacobson, Pamala A., University of Minnesota Medical School, Minneapolis, Minnesota, United States
- Israni, Ajay K., The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
Background
Diarrhea is a common, dose-limiting adverse effect of mycophenolic acid (MPA) in kidney transplant recipients (KTRs) and contributes to dose reduction and poor clinical outcomes. While intestinal epithelial injury is implicated, the contribution of the gut microbiome, particularly β-glucuronidase (β-GUS)-mediated enterohepatic recirculation (EHR) to barrier dysfunction, remains poorly defined (Fig 1A).
Methods
We developed a translational Transwell-based intestinal epithelial model using Caco-2 monolayers and Caco-2/HT-29 co-culture to better recapitulate mucus-producing epithelium. Polarized monolayers were exposed to clinically relevant concentrations of MPA and its primary metabolite, mycophenolic acid glucuronide (MPAG). Barrier integrity was assessed longitudinally using transepithelial electrical resistance (TEER).
Results
Monolayers matured to peak TEER at day 20-21 days (500–510 Ωcm2). MPA exposure induced a sustained decline in barrier function, with TEER decreasing to ~280 Ωcm2 by day 24 (25–30% reduction vs. control 550–560 Ωcm2). MPAG demonstrated a modest effect (410–420 Ωcm2). The Caco-2/HT-29 co-culture exhibited greater sensitivity to MPA-induced injury compared to Caco-2 monolayers (Fig 1B). Lower TEER values reflected increased epithelial permeability following MPA exposure.
Conclusion
MPA induces quantifiable intestinal epithelial barrier dysfunction, providing a mechanistic basis for Transplant-associated diarrhea. Given the role of microbial βGUS in deconjugating MPAG and driving EHR, microbiome-mediated MPA reactivation may amplify epithelial injury and contribute to inter-individual variability in gastrointestinal toxicity. These findings establish a translational platform for mechanistic interrogation of drug–microbiome interactions and support development of microbiome-informed strategies to mitigate MPA associated gastrointestinal complications in transplant recipients.
Funding
- Other NIH Support