Targeting Enterobacter cloacae attenuates osteolysis by reducing ammonium in multiple myeloma.

IF 21 1区 医学 Q1 HEMATOLOGY
Blood Pub Date : 2024-12-30 DOI:10.1182/blood.2024025694
Qin Yang, Yinghong Zhu, Xingxing Jian, Yi Qiu, Yan Zhu, Lia Zhao, Yanjuan He, Gang An, Lugui Qiu, Jiaojiao Guo, Nihan He, Huerxidan Abudumijiti, Cong Hu, Xun Chen, Siqing Huang, Xiangling Feng, Xin Li, Jing Liu, Yajing Xu, Wen Zhou
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引用次数: 0

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 E. cloacae is significantly enriched in MM patients 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 CCL3 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.

靶向阴沟肠杆菌通过减少多发性骨髓瘤中的铵来减轻骨溶解。
多发性骨髓瘤(MM)引起的骨病不仅影响患者的生活质量,而且影响患者的总体生存。我们之前的工作表明,肠道微生物组在MM的进展和耐药性中起着至关重要的作用。然而,肠道菌群改变在MM骨病中的作用尚不清楚。在这项研究中,我们发现肠阴沟芽胞杆菌在MM溶骨患者中显著富集。通过5TGM1 MM小鼠模型的粪便微生物移植和单细菌定植实验,我们发现阴沟肠杆菌的肠道定植通过增加循环铵水平来促进骨溶解。升高的铵通过增加破骨细胞前体中的Trap蛋白水平和乙酰化和稳定MM细胞中的CCL3蛋白来促进破骨细胞的发生。使用缺失dcd基因的阴沟肠杆菌抑制氨合成,并辅以益生菌,可减轻MM的骨溶解。总之,我们的研究表明,阴沟肠杆菌通过合成氨促进MM的骨溶解。这为MM伴骨溶解的治疗建立了一种新的机制和潜在的干预策略。
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来源期刊
Blood
Blood 医学-血液学
CiteScore
23.60
自引率
3.90%
发文量
955
审稿时长
1 months
期刊介绍: Blood, the official journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology and Immunotherapy scope; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Papers can be listed under more than one category as appropriate.
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