Haihe Laboratory of Cell Ecosystem, State 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; Cancer Research Institute, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
Haihe Laboratory of Cell Ecosystem, State 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; Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cell Metab. 2024 Jan 2;36(1):159-175.e8. doi: 10.1016/j.cmet.2023.11.019. Epub 2023 Dec 18.
The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.
肠道微生物组被发现对多发性骨髓瘤（MM）的治疗起着至关重要的作用，由于耐药性，多发性骨髓瘤仍被认为是不可治愈的。在之前的研究中，我们证明了肠道氮循环细菌在 MM 患者中富集。然而，它们在 MM 复发中的作用尚不清楚。本研究强调了柠檬酸杆菌（C. freundii）在复发性 MM 患者中的特异性富集。通过粪便微生物移植实验，我们证明 C. freundii 通过增加循环铵的水平在诱导 MM 耐药性方面发挥着关键作用。铵通过跨膜通道蛋白 SLC12A2 进入 MM 细胞，通过稳定 NEK2 蛋白促进染色体不稳定性和耐药性。我们表明，速尿，一种袢利尿剂，下调 SLC12A2，从而抑制 MM 细胞对铵的摄取，并改善无进展生存期和疗效评分。这些发现为干预 MM 进展和耐药性提供了新的治疗靶点和策略。
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