Mechanisms of Mycophenolic Acid-Induced Gastrointestinal Toxicity and Potential Therapeutic Interventions in Primary Mouse Colonic Organoids
Date
2024-09-17
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Abstract
Mycophenolate Mofetil (MMF) is a commonly prescribed immunosuppressant that demonstrates important clinical relevance. However, MMF therapy is linked to frequent gastrointestinal (GI) side effects that limit its use. Little is known about the mechanisms underlying MMF-induced GI injury. Using a primary mouse colon organoid model, we have found that mycophenolic acid (MPA), the pharmacologically active metabolite of MMF, significantly alters intestinal barrier function and permeability through modulation of tight junctions. RNA sequencing revealed that MPA significantly disrupted pathways related to cell cycle regulation, DNA replication, cytoskeleton dynamics, and suppression of senescence. MPA was observed to significantly reduce cellular proliferation, which was ameliorated through guanosine supplementation. Addition of exogenous guanosine was also observed to significantly restore barrier function back to control levels. The guanosine studies presented in this thesis suggest MPA’s inhibition of nucleotide metabolism is not selective for lymphocytes but is broader than originally described. This work represents one of the first investigations of MPA using a colon organoid model, providing critical insights into the intracellular mechanisms of MPA-induced GI toxicity.
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Keywords
Mycophenolate mofetil, Mycophenolic acid, Immunosuppressive therapy, Cell culture, Organoids, Gastrointestinal toxicity, Colonoid culture, Intestinal barrier function, Transepithelial resistance, FITC-dextran permeability, Total RNA-sequencing, Guanosine supplementation, Ingenuity Pathway Analysis, Colonoid monolayer culture
Citation
Mack-Bowles, B. (2024). Mechanisms of mycophenolic acid-induced gastrointestinal toxicity and potential therapeutic interventions in primary mouse colonic organoids (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.