Targeting <i>Enterobacter cloacae</i> attenuates osteolysis by reducing ammonium in multiple myeloma
Abstract
Abstract Multiple myeloma (MM)-induced bone disease affects not only patients’ quality of life but also their overall survival. Our previous work demonstrated that the gut microbiome plays a crucial role in MM progression and drug resistance. However, the role of altered gut microbiota in MM bone disease remains unclear. In this study, we show that intestinal Enterobacter cloacae is significantly enriched in patients with MM with osteolysis. Through fecal microbial transplantation and single bacterial colonization experiments in a 5TGM1 MM mouse model, we found that intestinal colonization of E cloacae promotes osteolysis by increasing circulating ammonium levels. Elevated ammonium promotes osteoclastogenesis by increasing Trap protein levels in osteoclast precursors and by acetylating and stabilizing chemokine ligand 3 protein in MM cells. Inhibition of ammonium synthesis, using E cloacae with a deleted dcd gene, along with probiotic supplementation, alleviated osteolysis in MM. Overall, our work suggests that E cloacae promotes osteolysis in MM by synthesizing ammonium. This establishes a novel mechanism and potential intervention strategy for managing MM with osteolysis.
Article Details
Authors (20)
Qin Yang
Department of Chemical and Biomolecular Engineering
Yinghong Zhu
1State 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
Xingxing Jian
Yi Qiu
Yan Zhu
Lia Zhao
1State 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
Yanjuan He
10Xiangya Hospital, Central South University, Department of Hematology, Changsha, China
Gang An
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China
Lugui Qiu
Jiaojiao Guo
1State 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
Nihan He
1State 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
Huerxidan Abudumijiti
1State 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
Cong Hu
Xun Chen
College of Materials Science and Engineering, College of Environment, State Key Laboratory of Advanced Separation Membrane Materials, Zhejiang Key Laboratory of Low-carbon Control Technology for Industrial Pollution
Siqing Huang
Xiangling Feng
Xin Li
Jing Liu
Yajing Xu
Wen Zhou