ArticleArchives of toxicology2021
New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids.
Article in Archives of toxicology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 2 of them syntheses that pooled it.
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The trial behind it
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Who cites it
24 citing papers in PubMed, 2 syntheses or guidelines pooled it, 50 citations in OpenAlex.
- Multi-omics time-series analysis in microbiome research: a systematic review.Briefings in bioinformatics · 2025Pooled it
- S-1 and 5-Fluorouracil-related adverse events in patients with advanced gastric cancer: A meta-analysis.PloS one · 2023Pooled it
- Antimetabolites synergize with non-genotoxic antibody drug conjugate conditioning in hematopoietic stem cell lentiviral gene therapy.Molecular therapy. Advances · 2026Article
- The Gut Microbiome Dependency Continuum in Drug Discovery: A Unified Pharmacology Framework Linking Clinical Drugs, Natural Products, and Engineered Microbial Therapeutics.Biotech (Basel (Switzerland)) · 2026Review
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- Article
- Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.Cell reports. Medicine · 2026Article
- Drug-induced gastrointestinal toxicity and barrier integrity: cytoskeleton-mediated impairment in a clinically relevant human intestinal epithelium model.Experimental & molecular medicine · 2026Article
- Screening of Fecal Bacteroides Strains and Discovery of Bacteroides eggerthii S13-F8 with Protective Effects Against Chemotherapy-Induced Diarrhea.Probiotics and antimicrobial proteins · 2026Article
- Genome-Scale Metabolic Modeling Identifies Synergistic Metabolites that Enhance 5-Fluorouracil Efficacy in Colon Cancer.Iranian biomedical journal · 2025Article
- Network pharmacology and experimental validation reveal that betulin alleviates 5-fluorouracil-induced intestinal injury by inhibiting intestinal senescence and enhances antitumor efficacy.The Journal of pharmacology and experimental therapeutics · 2025Article
- Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy.Pharmacology & therapeutics · 2025Review
- Role of Human Microbiome in Development and Management of Head and Neck Squamous Cell Carcinoma.Cancers · 2025Review
- Disturbance of bile acids profile aggravates the diarrhea induced by capecitabine through inhibiting the Wnt/β-catenin pathway.Journal of advanced research · 2025Article
- Ribosome Quality Control mitigates the cytotoxicity of ribosome collisions induced by 5-Fluorouracil.Nucleic acids research · 2024Article
- Applications of 3D organoids in toxicological studies: a comprehensive analysis based on bibliometrics and advances in toxicological mechanisms.Archives of toxicology · 2024Review
- Finding a Direct Method for a Dynamic Process: The DD (Direct and Dynamic) Cell-Tox Method.International journal of molecular sciences · 2024Article
- Article
- A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity.CPT: pharmacometrics & systems pharmacology · 2023Article
- Mito-TEMPO mitigates 5-fluorouracil-induced intestinal injury via attenuating mitochondrial oxidative stress, inflammation, and apoptosis: an in vivo study.Inflammopharmacology · 2023Article
Corrections and comments
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Authors and funding
16 authors at 5 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
5-Fluorouracil (5-FU) is a widely used chemotherapeutical that induces acute toxicity in the small and large intestine of patients. Symptoms can be severe and lead to the interruption of cancer treatments. However, there is limited understanding of the molecular mechanisms underlying 5-FU-induced intestinal toxicity. In this study, well-established 3D organoid models of human colon and small intestine (SI) were used to characterize 5-FU transcriptomic and metabolomic responses. Clinically relevant 5-FU concentrations for in vitro testing in organoids were established using physiologically based pharmacokinetic simulation of dosing regimens recommended for cancer patients, resulting in exposures to 10, 100 and 1000 µM. After treatment, different measurements were performed: cell viability and apoptosis; image analysis of cell morphological changes; RNA sequencing; and metabolome analysis of supernatant from organoids cultures. Based on analysis of the differentially expressed genes, the most prominent molecular pathways affected by 5-FU included cell cycle, p53 signalling, mitochondrial ATP synthesis and apoptosis. Short time-series expression miner demonstrated tissue-specific mechanisms affected by 5-FU, namely biosynthesis and transport of small molecules, and mRNA translation for colon; cell signalling mediated by Rho GTPases and fork-head box transcription factors for SI. Metabolomic analysis showed that in addition to the effects on TCA cycle and oxidative stress in both organoids, tissue-specific metabolic alterations were also induced by 5-FU. Multi-omics integration identified transcription factor E2F1, a regulator of cell cycle and apoptosis, as the best key node across all samples. These results provide new insights into 5-FU toxicity mechanisms and underline the relevance of human organoid models in the safety assessment in drug development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.