Microbiome changes involves in mercaptopurine mediated anti-inflammatory response in acute lymphoblastic leukemia mice

Background: 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. Objective: We aimed to explore the association between 6-MP therapeutic effects and microbiome-involved inflammatory responses in ALL mice models. Study Design: 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. Results: The anti-tumor effect of 6-MP was proved in ALL mice models. The levels of pro-inflammatory factors IL6 and TNF & alpha; 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 TNF & alpha; (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. Conclusion: 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.

Automated summary

This study aimed to explore the association between the anti-inflammatory effects of 6-MP and gut microbiome changes, and their impact on inflammasome. Using a mouse model, it was proved that 6-MP has anti-tumor effects and can significantly decrease the levels of pro-inflammatory factors IL6 and TNF-α. The levels of short-chain fatty acids and the composition of gut microbiota were found to be correlated with the anti-inflammatory response of 6-MP.