Targeting Enterobacter cloacae attenuates osteolysis by reducing ammonium in multiple myeloma

Area of Science:

• Microbiology
• Oncology
• Immunology

Background:

• Multiple myeloma (MM) causes bone disease, impacting patient survival.
• The gut microbiome influences MM progression and drug resistance.
• The specific role of gut microbiota in MM-induced bone disease is not well understood.

Purpose of the Study:

• To investigate the role of altered gut microbiota in multiple myeloma bone disease.
• To identify specific gut bacteria associated with osteolysis in MM patients.
• To elucidate the mechanism by which gut bacteria contribute to MM osteolysis.

Main Methods:

• Analysis of gut microbiota in MM patients with osteolysis.
• Fecal microbial transplantation and bacterial colonization in a 5TGM1 MM mouse model.
• Assessment of ammonium levels, osteoclastogenesis markers, and protein acetylation.

Main Results:

• Enterobacter cloacae was significantly enriched in MM patients with osteolysis.
• Intestinal E. cloacae colonization promoted osteolysis in a mouse model by increasing circulating ammonium.
• Elevated ammonium increased osteoclastogenesis and stabilized chemokine ligand 3 in MM cells.
• Inhibiting ammonium synthesis in E. cloacae and probiotic supplementation reduced osteolysis.

Conclusions:

• Enterobacter cloacae promotes osteolysis in multiple myeloma by synthesizing ammonium.
• This highlights a novel mechanism linking gut bacteria, ammonium, and MM bone disease.
• Targeting E. cloacae-derived ammonium presents a potential therapeutic strategy for MM osteolysis.