Drug-induced gastrointestinal toxicities (GITs) are among the most common clinical side effects that can limit the application of drugs.

To better predict these side effects, MatTek has developed a model of the human gastrointestinal tract (GI tract) in microformat. Intestinal stem cells can be kept in culture for longer periods continously differentiating living epithelial cell types, which are then aggregates to form a microtissue similar to the situation in the human intestine. Thereafter, the pharmaceutical ist added to the cells apical and/or basolateral. The transepithelial resistance is measured (a measure of the density of the cells or the permeability of substances). The greater the permeability, the greater the diarrhoea would be, could simply be formulated. The microtissue is grown in transwell plates for 96-well throughput.

A large number of drugs have been tested, for which the GI toxicity could be correctly predicted. Additionally, a threshold value could be determined above which diarrhoea induction can be considered. The scientists were also able to develop a mathematical model that can determine the temporal dynamics of barrier damage and its restoration.

The model can predict diarrhoea better than animal experiments with rats and dogs.

A validation study carried out jointly with the pharmaceutical manufacturer AstraZeneca was published in the journal Toxicological Sciences.

Peters, MF, Landry, T, Pin, C, Maratea, K, Dick, C, Wagoner, MP, Choy, AL, Barthlow, H, Snow, D, Stevens, Z, Armento, A, Scott, CW & Ayehunie, S (2018). Human 3D Gastrointestinal Microtissue Barrier Function as a Predictor of Drug-Induced Diarrhea. Toxicol Sci. 2018 Oct 26. doi: 10,1093/toxsci/kfy268.

Further information:
https://www.ncbi.nlm.nih.gov/pubmed/30364994