Insights Into Gut Barrier Dysfunction and Metabolic Alterations in Mycophenolate-Induced Enteropathy

Area of Science:

• Gastroenterology
• Pharmacology
• Cell Biology

Background:

• Mycophenolic acid (MPA) is a crucial immunosuppressant.
• Gastrointestinal toxicity limits MPA's clinical use.
• Gut bacterial metabolism of MPA glucuronides increases local MPA exposure, potentially harming epithelial barrier function and metabolism.

Purpose of the Study:

• To investigate MPA's impact on gut barrier integrity.
• To explore MPA's effects on metabolic pathways in gut epithelial cells.

Main Methods:

• Caco-2 cells were exposed to MPA (10 or 100 μM).
• Barrier function was assessed using transepithelial electrical resistance (TEER) and lucifer yellow (LY) permeability.
• Intracellular metabolic changes were analyzed via targeted LC-MS/MS metabolomics.

Main Results:

• MPA exposure during early monolayer formation reduced TEER and increased LY permeability, with effects lasting post-withdrawal.
• Differentiated monolayers showed no significant changes in barrier function.
• Metabolomic analysis revealed distinct metabolic profiles in MPA-exposed cells, with significant alterations in nucleotide synthesis pathways.

Conclusions:

• MPA can disrupt gut epithelial barrier integrity and alter cellular metabolism, especially during critical early development stages.
• The observed metabolic perturbations, particularly in nucleotide synthesis, highlight potential mechanisms underlying MPA's gastrointestinal toxicity.
• These findings underscore the importance of considering MPA's impact on gut health beyond its immunosuppressive effects.