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

Yinghong Zhu, Xingxing Jian, Shuping Chen, Gang An, Duanfeng Jiang, Qin Yang, Jingyu Zhang, Jian Hu, Yi Qiu, Xiangling Feng, Jiaojiao Guo, Xun Chen, Zhengjiang Li, Ruiqi Zhou, Cong Hu, Nihan He, Fangming Shi, Siqing Huang, Hong Liu, Xin LiLu Xie, Yan Zhu, Lia Zhao, Yichuan Jiang, Jian Li, Jinuo Wang, Lugui Qiu, Xiang Chen*, Wei Jia*, Yanjuan He*, Wen Zhou*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review


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.

Original languageEnglish
Pages (from-to)159-175, e1-e8
Number of pages25
JournalCell Metabolism
Issue number1
Publication statusPublished - 2 Jan 2024

Scopus Subject Areas

  • Physiology
  • Molecular Biology
  • Cell Biology

User-Defined Keywords

  • ammonium
  • Citrobacter freundii
  • Clostridium butyricum
  • furosemide
  • gut microbiome
  • metagenomics
  • multiple myeloma
  • nitrogen-recycling intestinal bacteria
  • probiotics


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