Abstract：
The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.
摘要：
肠道菌群与巯基嘌呤（6-MP）之间的相互作用，一种用于小儿急性淋巴细胞白血病（ALL）治疗的关键药物，尚未被广泛研究。在这里，我们揭示了在比格犬和小鼠中2周6-MP治疗后肠道微生物群的显着扰动，随后的功能预测显示SCFA产生受损和氨基酸合成改变。并且血浆中的靶向代谢组学也显示了氨基酸的变化。此外,粪便的靶向代谢组学分析显示氨基酸和SCFA发生变化。此外，广谱抗生素消融肠道微生物群加剧了氨基酸的失衡，特别是导致S-腺苷甲硫氨酸（SAM）浓度的显着降低。重要的是,肠道微生物群的消耗加重了由6-MP引起的小肠损伤，导致肠道通透性增加。考虑到毒性和6-MP代谢物之间的关系，我们在假无菌大鼠中进行了一项药代动力学研究,以证实肠道微生物群耗竭改变了6-MP的甲基化代谢物.具体来说,MeTIN的浓度，次级甲基化代谢物，与SAM呈负相关，关键的甲基供体。此外,我们观察到粪便和血浆中Alistipes和SAM水平之间存在很强的相关性。总之,我们的研究表明，6-MP会破坏肠道微生物群，和耗尽肠道微生物群加剧6-MP诱导的肠道毒性。此外，来自微生物群的SAM在影响血浆SAM和6-MP甲基化中起着至关重要的作用。这些发现强调了理解肠道微生物群在6-MP代谢和毒性中的作用的重要性。
