Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma

• Published in: Cell metabolism 2024-01, Vol.36 (1), p.159-175.e8
• Main Authors: Zhu, Yinghong, Jian, Xingxing, Chen, Shuping, An, Gang, Jiang, Duanfeng, Yang, Qin, Zhang, Jingyu, Hu, Jian, Qiu, Yi, Feng, Xiangling, Guo, Jiaojiao, Chen, Xun, Li, Zhengjiang, Zhou, Ruiqi, Hu, Cong, He, Nihan, Shi, Fangming, Huang, Siqing, Liu, Hong, Li, Xin, Xie, Lu, Zhu, Yan, Zhao, Lia, Jiang, Yichuan, Li, Jian, Wang, Jinuo, Qiu, Lugui, Chen, Xiang, Jia, Wei, He, Yanjuan, Zhou, Wen
• Format: Article
• Language: English
• Subjects: ammonium; Bortezomib - metabolism; Bortezomib - pharmacology; Bortezomib - therapeutic use; Cell Line, Tumor; Citrobacter freundii; Clostridium butyricum; furosemide; Gastrointestinal Microbiome; gut microbiome; Humans; Membrane Proteins - metabolism; metagenomics; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; NIMA-Related Kinases - metabolism; NIMA-Related Kinases - therapeutic use; nitrogen-recycling intestinal bacteria; probiotics; Solute Carrier Family 12, Member 2 - pharmacology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2023.11.019

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance. [Display omitted] •Citrobacter freundii can induce bortezomib resistance in patients with multiple myeloma•Ammonium can enhance NEK2 stability, inducing bortezomib resistance of myeloma cells•Furosemide administration can attenuate bortezomib resistance of myeloma cells•Probiotics like Clostridium butyricum alleviate myeloma cell resistance to bortezomib Zhu et al. demonstrated that Citrobacter freundii induces bortezomib resistance in patients with multiple myeloma by elevating circulating ammonium level. The increased ammonium enters myeloma cells, enhancing the stability of NEK2 protein. Notably, the administration of furosemide and probiotics such as Clostridium butyricum was observed to partially alleviate bortezomib resistance.