Establishment of an evaluation system for gastrointestinal toxicity using human intestinal organoids

Abstract

Gastrointestinal toxicity (GI-tox) is a common clinical adverse event. It is very important to clarify GI-tox concerns in the nonclinical stage, because GI-tox significantly reduces patients' QOL.

Up to now, the main in vitro evaluation system for GI-tox has been monolayer culture of single cell line. Intestinal organoids contain undifferentiated cells and have a three-dimensional structure, thus GI-tox can be evaluated in a closer environment to the body. Previous studies revealed that GI-tox inducible compounds caused a decrease in cell viability. In addition, since the size of organoids is also reduced, it was considered that GI-tox could be evaluated by organoid size quantification.

Therefore, we aimed to establish an image analysis method for evaluating GI-tox using images of organoids. Then, we developed an application that can recognize organoids from bright-field images and extract feature values such as area and color. Next, the application was used to evaluate the GI-tox of clinical compounds. The result showed that the combination of the IC50 value for organoids area reduction and the maximum clinical blood concentration of each compound allowed the development of an evaluation system to identify compounds with potential GI-tox. Based on the above, this evaluation system was useful for distinguishing GI-tox at the nonclinical stage and for safety evaluation strategies.