Human 3D Gastrointestinal Microtissue Barrier Function As a Predictor of Drug-Induced Diarrhea

Area of Science:

• Biomedical Engineering
• Toxicology
• Stem Cell Biology

Background:

• Drug-induced gastrointestinal toxicities (GITs) are common clinical side effects.
• Current in vitro assays lack predictive accuracy for GITs.
• Advancements in stem cell culture enable the creation of in vivo-like intestinal microtissues.

Purpose of the Study:

• To evaluate human GI microtissues for predicting drug-induced diarrhea.
• To assess the utility of transepithelial electrical resistance (TEER) as a measure of intestinal barrier function in microtissues.
• To establish a validated in vitro assay for preclinical drug safety screening.

Main Methods:

• Human GI microtissues were cultured in transwell plates for drug treatment.
• Transepithelial electrical resistance (TEER) was measured to assess intestinal barrier integrity.
• A validation set of drugs was tested, and TEER inhibition was correlated with clinical diarrhea incidence.

Main Results:

• The GI microtissue TEER assay accurately predicted diarrhea for a set of known drugs.
• The assay demonstrated high predictive power for drugs with unexpected diarrhea liabilities in animal studies.
• A mathematical model was developed to describe barrier damage and recovery dynamics.

Conclusions:

• Human 3D GI microtissues with TEER measurement represent the first validated in vitro assay for predicting diarrhea-inducing drugs.
• This assay can enhance preclinical drug development by improving lead optimization and dose schedule exploration.
• The model provides a valuable tool for identifying potential GITs early in the drug discovery process.