Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
Department of Pharmacy, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China; Department of Pharmacy, Children's Hospital of Soochow University, Suzhou, Jiangsu, 215025, China.
Int Immunopharmacol. 2023 Oct;123:110782. doi: 10.1016/j.intimp.2023.110782. Epub 2023 Aug 11.
Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute lymphoblastic leukemia (ALL), the anti-inflammatory effect of mercaptopurine (6-MP) and the impact of gut microbiome changes caused by 6-MP on anti-inflammasome remain unclear.
We aimed to explore the association between 6-MP therapeutic effects and microbiome-involved inflammatory responses in ALL mice models.
ALL murine model was built by i.v. injecting murine L1210 cells into DBA/2 mice (model group). Two weeks after cell injections, 6-MP was orally administrated for 14 days (6-MP group). Fecal samples of mice were collected at different time points. Cecum short-chain fatty acids (SCFAs) concentrations were determined by LC-MS/MS method. Serum cytokines were measured using a cytometric bead array. Gut microbiota composition in mice was explored using 16S rRNA gene sequencing.
The anti-tumor effect of 6-MP was proved in ALL mice models. The levels of pro-inflammatory factors IL-6 and TNFα significantly decreased after the administration of 6-MP. Cecum contents' acetate, propionate, and butyrate levels were negatively correlated with IL-6 (correlation coefficient: acetate, -0.24; propionate, -0.26; butyrate, -0.17) and TNFα (correlation coefficient: acetate, -0.45; propionate, -0.42; butyrate, -0.31) changes. Relative abundance changes of f_Lachnospiraceae.g_ASF356 and f_Peptococcaceae.g_uncultured were in accordance with the changes of butyrate levels and opposite to the changes of pro-inflammatory levels.
The anti-inflammatory response of 6-MP influenced by intestinal microbiota and its metabolites SCFAs, especially butyrate, played an essential role in improving ALL progression.
炎症小体在血液系统恶性肿瘤的发病机制和进展中起着重要作用。巯嘌呤（6-MP）作为治疗急性淋巴细胞白血病（ALL）的骨干药物之一，其抗炎作用以及 6-MP 引起的肠道微生物组变化对炎症小体的影响尚不清楚。
本研究旨在探讨 ALL 小鼠模型中 6-MP 治疗效果与微生物组相关炎症反应之间的关系。
通过静脉注射 L1210 细胞构建 ALL 小鼠模型（模型组）。细胞注射 2 周后，给予小鼠 6-MP 口服治疗 14 天（6-MP 组）。收集不同时间点的小鼠粪便样本。采用 LC-MS/MS 方法测定粪便短链脂肪酸（SCFAs）浓度。采用流式细胞术检测试剂盒测定血清细胞因子水平。采用 16S rRNA 基因测序分析小鼠肠道微生物组成。
6-MP 在 ALL 小鼠模型中具有抗肿瘤作用。6-MP 给药后促炎因子 IL-6 和 TNFα 水平显著降低。盲肠内容物中乙酸盐、丙酸盐和丁酸盐水平与 IL-6（相关系数：乙酸盐，-0.24；丙酸盐，-0.26；丁酸盐，-0.17）和 TNFα（相关系数：乙酸盐，-0.45；丙酸盐，-0.42；丁酸盐，-0.31）的变化呈负相关。f_Lachnospiraceae.g_ASF356 和 f_Peptococcaceae.g_uncultured 的相对丰度变化与丁酸盐水平的变化一致，与促炎水平的变化相反。
肠道微生物及其代谢产物 SCFAs，特别是丁酸盐，影响 6-MP 的抗炎反应，在改善 ALL 进展中起着重要作用。
