ArticleToxicological sciences : an official journal of the Society of Toxicology2019
Human 3D Gastrointestinal Microtissue Barrier Function As a Predictor of Drug-Induced Diarrhea.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The trial behind it
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Who cites it
27 citing papers in PubMed, 61 citations in OpenAlex.
- Intestinal Organoid-Based Mathematical Modeling Predicts Clinical Gastrointestinal Toxicity of Oral Oncology Drugs.CPT: pharmacometrics & systems pharmacology · 2026Article
- Integrating Human Intestinal Organoids into FDA's New Approach Methodologies for Drug Discovery.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Drug-induced gastrointestinal toxicity and barrier integrity: cytoskeleton-mediated impairment in a clinically relevant human intestinal epithelium model.Experimental & molecular medicine · 2026Article
- Quantitative systems toxicology: modelling to mechanistically understand and predict drug safety.Nature reviews. Drug discovery · 2026Review
- 25 years of applying the 3Rs principles in safety pharmacology: success stories and future perspectives.Frontiers in physiology · 2026Review
- Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy.Pharmacology & therapeutics · 2025Review
- The application of organoids in treatment decision-making for digestive system cancers: progress and challenges.Molecular cancer · 2025Review
- Human Small Intestinal Tissue Models to Assess Barrier Permeability: Comparative Analysis of Caco-2 Cells, Jejunal and Duodenal Enteroid-Derived Cells, and EpiIntestinalBioengineering (Basel, Switzerland) · 2025Article
- High-throughput assay for predicting diarrhea risk using a 2D human intestinal stem cell-derived model.Toxicology in vitro : an international journal published in association with BIBRA · 2025Article
- Comparative analysis of Caco-2 cells and human jejunal and duodenal enteroid-derived cells in gel- and membrane-based barrier models of intestinal permeability.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The differentiation state of small intestinal organoid models influences prediction of drug-induced toxicity.Frontiers in cell and developmental biology · 2025Article
- Qualification of the human Reconstructed Intestine Micronuclei Cytome assay for site-of-contact genotoxic hazard identification.NAM journal · 2025Article
- Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.NPJ precision oncology · 2024Article
- High-Throughput Assay for Predicting Diarrhea Risk Using a 2D Human Intestinal Stem Cell-Derived Model.bioRxiv : the preprint server for biology · 2024Article
- Towards Full Thickness Small Intestinal Models: Incorporation of Stromal Cells.Tissue engineering and regenerative medicine · 2024Review
- iPSC-derived and Patient-Derived Organoids: Applications and challenges in scalability and reproducibility as pre-clinical models.Current research in toxicology · 2024Article
- Characterization and optimization of variability in a human colonic epithelium culture model.ALTEX · 2024Article
- 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
- Progress and promise of alternative animal and non-animal methods in biomedical research.Archives of toxicology · 2023Review
- Biological effects of polystyrene micro- and nano-plastics on human intestinal organoid-derived epithelial tissue models without and with M cells.Nanomedicine : nanotechnology, biology, and medicine · 2023Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
Drug-induced gastrointestinal toxicities (GITs) rank among the most common clinical side effects. Preclinical efforts to reduce incidence are limited by inadequate predictivity of in vitro assays. Recent breakthroughs in in vitro culture methods support intestinal stem cell maintenance and continual differentiation into the epithelial cell types resident in the intestine. These diverse cells self-assemble into microtissues with in vivo-like architecture. Here, we evaluate human GI microtissues grown in transwell plates that allow apical and/or basolateral drug treatment and 96-well throughput. Evaluation of assay utility focused on predictivity for diarrhea because this adverse effect correlates with intestinal barrier dysfunction which can be measured in GI microtissues using transepithelial electrical resistance (TEER). A validation set of widely prescribed drugs was assembled and tested for effects on TEER. When the resulting TEER inhibition potencies were adjusted for clinical exposure, a threshold was identified that distinguished drugs that induced clinical diarrhea from those that lack this liability. Microtissue TEER assay predictivity was further challenged with a smaller set of drugs whose clinical development was limited by diarrhea that was unexpected based on 1-month animal studies. Microtissue TEER accurately predicted diarrhea for each of these drugs. The label-free nature of TEER enabled repeated quantitation with sufficient precision to develop a mathematical model describing the temporal dynamics of barrier damage and recovery. This human 3D GI microtissue is the first in vitro assay with validated predictivity for diarrhea-inducing drugs. It should provide a platform for lead optimization and offers potential for dose schedule exploration.
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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.