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 ofMarvinbryantia,Lactobacillus,Ruminococcus, and [Eubacterium]nodatumgroup. FOLFOX-treated mice showed increasedMarvinbryantia,Bacteroides, andCandidatus Arthromitus, and decreasedAkkermansia. 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.
背景：共生肠道菌群可增强癌症治疗效果，而治疗诱导的菌群失调可能降低疗效或增加毒性。我们的临床前研究比较了两种水溶性SN-38衍生物（BN-MePPR和BN-MOA）与伊立替康及FOLFOX方案在携带患者来源结肠腺癌异种移植瘤（CRC PDX）的NOD scid gamma小鼠中的抗肿瘤效果，以及对粪便菌群和代谢产物的影响。方法：使用八种CRC PDX模型进行了五项伊立替康及其衍生物的独立实验和八项FOLFOX的独立实验。化疗药物通过腹腔注射给药4-5次，间隔5天。在治疗前后收集粪便样本。通过16S rRNA基因（V3-V4区）测序分析菌群组成。采用质谱法对短链脂肪酸（SCFAs）和氨基酸（AAs）进行定量。结果：与对照组相比，所有治疗均显著抑制肿瘤生长。然而，治疗组与未治疗组之间肠道菌群的α和β多样性未观察到显著变化。对照组的肿瘤进展与Marvinbryantia、乳杆菌属、瘤胃球菌属和[真杆菌属]结节菌群的丰度增加相关。FOLFOX治疗组小鼠显示Marvinbryantia、拟杆菌属和Candidatus Arthromitus增加，而阿克曼菌属减少。伊立替康及其衍生物组未发现明显的分类群变化。各组SCFA水平保持稳定，而BN-MePPR、BN-MOA和伊立替康均增加了AA浓度。结论：与早期的毒理学数据相反，这些发现表明所测试的化疗药物对肠道微生物组和代谢组的影响相对有限，强调了临床前研究中研究方法选择的重要性。
肿瘤(癌症)患者之家