Comparative Analysis of Gut Microbiota Responses to New SN-38 Derivatives, Irinotecan, and FOLFOX in Mice Bearing Colorectal Cancer Patient-Derived Xenografts

Abstract

Background: Symbiotic gut microbiota can enhance cancer therapy efficacy, while treatment-induced dysbiosis may reduce effectiveness or increase toxicity. Our preclinical study compared the anticancer effects and impact on fecal microbiota and metabolites of two water-soluble SN-38 derivatives (BN-MePPR and BN-MOA), with those observed after treatment with Irinotecan, and the FOLFOX regimen in NOD scid gamma mice bearing patient-derived colon adenocarcinoma xenografts (CRC PDX). Methods: Five individual experiments with Irinotecan and its derivatives and eight individual experiments with FOLFOX were conducted using eight CRC PDX models. Chemotherapeutics were administered intraperitoneally 4–5 times at 5-day intervals. Fecal samples were collected before and after treatment. Microbiota composition was analyzed by 16S rRNA gene (V3–V4 regions) sequencing. Mass spectrometry was used to quantify short-chain fatty acids (SCFAs) and amino acids (AAs). Results: All treatments significantly inhibited tumor growth versus controls. However, no significant changes were observed in gut microbiota α- and β-diversity between treated and untreated groups. Tumor progression in controls was associated with increased abundance of Marvinbryantia, Lactobacillus, Ruminococcus, and [Eubacterium] nodatum group. FOLFOX-treated mice showed increased Marvinbryantia, Bacteroides, and Candidatus Arthromitus, and decreased Akkermansia. No distinct taxa changes were found in the Irinotecan or derivative groups. SCFA levels remained unchanged across groups, while BN-MePPR, BN-MOA, and Irinotecan all increased AA concentrations. Conclusions: Contrary to earlier toxicological data, these findings indicate a relatively limited impact of the tested chemotherapeutics on the gut microbiome and metabolome, emphasizing the importance of research method selection in preclinical studies.