Objective To predict the gastrointestinal side effects of chemotherapeutic drugs using healthy murine colon organoids. It aimed to identify safer alternative treatments for patients intolerant to certain chemotherapy regimens and demonstrate the potential clinical applications of organoids in predicting gastrointestinal side effects.

Methods Healthy mouse colonic crypt cells were cultured in 3D. Paraffin sections of colon tissues and organoids were subsequently prepared, followed by haematoxylin and eosinand immunohistochemical staining (CDX2, Ki67, and CK19). The colonic organoids were treated with five chemotherapeutic drugs, and cell activity was assessed to determine their intestinal toxicity. The consistency of the incidence of gastrointestinal side effects observed in this study and in clinical practice were analyzed by comparing the results to the published literature.

Results The histological characteristics of the colon organoids were highly consistent with those of the original colon tissues. The tolerance of normal colon organoids to different chemotherapeutic drugs was variable. Capecitabine had the least cytotoxic effect on mouse colon organoids, whereas paclitaxel liposomes showed the strongest cytotoxic effect when IC₅₀ was the only consideration. Considering clinical drug concentrations, a significant difference was observed in the organoid inhibition rates between albumin paclitaxel and liposomal paclitaxel. Statistical analysis of clinical trial data showed that the incidence of grade Ⅲ/Ⅳ diarrhea caused by albumin paclitaxel, epirubicin, capecitabine, and cyclophosphamide was consistent with the corresponding organoid inhibition rates.

Conclusions Combining clinical drug doses, we recommend prioritizing albumin paclitaxel and avoiding the use of liposomal paclitaxel to improve chemotherapy tolerance. This study demonstrates that normal colon organoids can effectively predict the occurrence of severe diarrhea associated with most chemotherapeutic drugs.