Targeting <i>Enterobacter cloacae</i> attenuates osteolysis by reducing ammonium in multiple myeloma
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.
Authors
- Xingxing Jian (ORCID: https://orcid.org/0000-0003-3587-662X)
- Huerxidan Abudumijiti
- Yi Qiu (ORCID: https://orcid.org/0009-0002-4158-0737)
- Gang An (ORCID: https://orcid.org/0000-0003-4922-4614)
- Xun Chen (ORCID: https://orcid.org/0000-0003-0327-1888)
- Lugui Qiu (ORCID: https://orcid.org/0000-0002-7438-8277)
- Nihan He
- Wen Zhou (ORCID: https://orcid.org/0000-0003-4085-7714)
- Yanjuan He (ORCID: https://orcid.org/0000-0001-9905-0160)
- Xiangling Feng (ORCID: https://orcid.org/0000-0003-4668-6709)
- Xin Li (ORCID: https://orcid.org/0000-0001-9024-7522)
- Yang Qin (ORCID: https://orcid.org/0000-0001-9022-3061)
- Yan Zhu
- Siqing Huang
- Lia Zhao
- Yinghong Zhu (ORCID: https://orcid.org/0000-0002-9987-073X)
- Yajing Xu
- Cong Hu (ORCID: https://orcid.org/0000-0002-8595-4713)
- Jiaojiao Guo (ORCID: https://orcid.org/0000-0003-2110-8400)
- Jing Liu (ORCID: https://orcid.org/0000-0001-9513-3591)
Institutions
- Central South University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Ministry of Education (SA)
- Ministry of Education (ET)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Third Xiangya Hospital (CN)
- Xiangya Hospital Central South University (CN)
Publication Details
- Journal
- Blood
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1182/blood.2024025694
- Citations
- 2
- Primary Topic
- Coccidia and coccidiosis research
- Type
- article
- Field-Weighted Citation Impact
- 0.68