Mechanisms of Mycophenolic Acid-Induced Gastrointestinal Toxicity and Potential Therapeutic Interventions in Primary Mouse Colonic Organoids
Bibliographic record
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".