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

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

  • Cell Metab. 2023 Dec 15:S1550-4131(23)00450-3. doi: 10.1016/j.cmet.2023.11.019.
Yinghong Zhu 1 Xingxing Jian 2 Shuping Chen 3 Gang An 4 Duanfeng Jiang 5 Qin Yang 5 Jingyu Zhang 1 Jian Hu 3 Yi Qiu 3 Xiangling Feng 6 Jiaojiao Guo 1 Xun Chen 1 Zhengjiang Li 1 Ruiqi Zhou 1 Cong Hu 1 Nihan He 1 Fangming Shi 1 Siqing Huang 1 Hong Liu 7 Xin Li 5 Lu Xie 3 Yan Zhu 3 Lia Zhao 3 Yichuan Jiang 3 Jian Li 8 Jinuo Wang 8 Lugui Qiu 4 Xiang Chen 9 Wei Jia 10 Yanjuan He 11 Wen Zhou 12
Affiliations

Affiliations

  • 1 Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Furong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
  • 2 Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Furong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 3 Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Furong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China.
  • 5 Department of Hematology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 6 Xiangya School of Public Health, Central South University, Changsha, Hunan, China.
  • 7 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 8 Peking Union Medical College Hospital, Chinese Academy Medical Society & Peking Union Medical College, Beijing, China.
  • 9 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: chenxiangck@126.com.
  • 10 School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China. Electronic address: weijia1@hkbu.edu.hk.
  • 11 Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Furong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: yjuanh@csu.edu.cn.
  • 12 Haihe Laboratory of Cell Ecosystem, State Key Laboratory of Experimental Hematology, Bioinformatics Center, National Clinical Research Center for Geriatric Disorders, Key Laboratory for Carcinogenesis and Invasion, Chinese Ministry of Education, Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Furong Laboratory, Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China; Xiangya School of Public Health, Central South University, Changsha, Hunan, China. Electronic address: wenzhou@csu.edu.cn.
Abstract

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.

Keywords

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

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