In December 2023, a study led by Professors Wen Zhou from Central South University and Professor Wei Jia from Hong Kong Baptist University was published in the top international academic journal Cell Metabolism (IF=31.373), titled “Targeting gut microbial nitrogen recycling and cellular uptake of ammonia to improve cellular resistance in multiple myeloma”. This study found that targeting the nitrogen cycle of gut microbiota and cellular uptake of ammonium can improve bortezomib resistance in multiple myeloma, providing new therapeutic targets and strategies for the progression of MM and intervention of drug resistance. This study was also recently selected as one of the "Top 10 Research Advances in Hematology in China in 2023".
Multiple myeloma (MM) is a challenging hematological malignancy characterized by the proliferation of malignant plasma cells. Drug resistance and relapse remain major obstacles in the treatment of MM, emphasizing the need for a deeper understanding of the mechanisms driving resistance. Recent studies have highlighted the role of the gut microbiome in MM treatment, suggesting a potential link between gut microbes and drug resistance in MM patients.
The researchers investigated the potential role of gut microbial nitrogen recycling in bortezomib resistance in multiple myeloma. The study utilized a combination of in vitro and in vivo experiments, as well as analysis of clinical samples from MM patients.
The researchers identified Citrobacter freundii as a key gut microbial species associated with bortezomib resistance in MM patients. They found that C. freundii induced drug resistance by increasing levels of circulating ammonium, which entered myeloma cells through the transmembrane channel protein SLC12A2. This led to enhanced stability of the NEK2 protein, promoting chromosomal instability and drug resistance. Importantly, the administration of furosemide, a loop diuretic, inhibited ammonium uptake by myeloma cells and improved the effectiveness of bortezomib.
The study provides valuable insights into the role of gut microbial nitrogen recycling in bortezomib resistance in multiple myeloma. By targeting the gut microbial species C. freundii and modulating ammonium levels and cellular uptake, potential strategies to overcome drug resistance and improve treatment outcomes may be developed. Further research is needed to validate these findings and identify additional therapeutic targets.
