Gao Lingyu, Zhang Yuhan, Hu Zhi, Chen Shengwen, Wang Qiaolin, Zeng Yong, Yin Huiqi, Zhao Junpeng, Zhan Yijing, Gao Changxing, Xin Yue, Chen Bing, van der Veen Stijn, Zhao Ming, Fang Deyu, Lu Qianjin
Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China.
Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, 210042, China.
Adv Sci (Weinh). 2025 May;12(20):e2409837. doi: 10.1002/advs.202409837. Epub 2025 Apr 28.
The role of gut microbiota dysbiosis in systemic lupus erythematosus (SLE) pathogenesis remains elusive. Here, it is shown that fecal microbiota transplantation (FMT) from healthy mice to lupus mice ameliorates lupus-like symptoms. Microbiota reconstitution effectively reduces systemic class switch recombination (CSR) and elevates immunoglobulin heavy chain (IGH) naïve isotype. Microbiota profiling reveals an enrichment of Lactobacillus johnsonii post-FMT, with a significant correlation to purine metabolites. Importantly, the L. johnsonii-derived inosine, an intermediate metabolite in purine metabolism, effectively alleviates lupus pathogenesis in mice. Inosine inhibits B cell differentiation and reduces renal B cell infiltration to protect mice from lupus. At the molecular level, inosine reprograms B cells through the extracellular signal-regulated kinase (ERK)-hypoxia-inducible factor-1alpha (HIF-1α) signaling pathway. Therefore, this study highlights the discovery of a novel microbial metabolite modulating autoimmunity and suggests its potential for innovative microbiome-based therapeutic approaches.
肠道微生物群失调在系统性红斑狼疮（SLE）发病机制中的作用仍不明确。在此，研究表明将健康小鼠的粪便微生物群移植（FMT）到狼疮小鼠体内可改善狼疮样症状。微生物群重建有效减少全身类别转换重组（CSR）并提高免疫球蛋白重链（IGH）未成熟同种型。微生物群分析显示FMT后约氏乳杆菌富集，与嘌呤代谢产物显著相关。重要的是，约氏乳杆菌衍生的肌苷是嘌呤代谢的中间代谢产物，可有效减轻小鼠的狼疮发病机制。肌苷抑制B细胞分化并减少肾脏B细胞浸润以保护小鼠免受狼疮侵害。在分子水平上，肌苷通过细胞外信号调节激酶（ERK）-缺氧诱导因子-1α（HIF-1α）信号通路对B细胞进行重编程。因此，本研究突出了一种调节自身免疫的新型微生物代谢产物的发现，并表明其在基于微生物群的创新治疗方法中的潜力。
