Microbiota-Derived Inosine Suppresses Systemic Autoimmunity via Restriction of B Cell Differentiation and Migration

  • Adv Sci (Weinh). 2025 May;12(20):e2409837. doi: 10.1002/advs.202409837.
Lingyu Gao  1  2  3 ,  Yuhan Zhang  1  2  3 ,  Zhi Hu  1  2  3 ,  Shengwen Chen  1  2  3 ,  Qiaolin Wang  1  2  3 ,  Yong Zeng  4 ,  Huiqi Yin  1  2  3 ,  Junpeng Zhao  1  2  3 ,  Yijing Zhan  1  2  3 ,  Changxing Gao  1  2  3 ,  Yue Xin  1  2  3 ,  Bing Chen  5 ,  Stijn van der Veen  6 ,  Ming Zhao  1  2  3  4 ,  Deyu Fang  7 ,  Qianjin Lu  1  2  3  4
Affiliations
  • 1. Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China.
  • 2. Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, 210042, China.
  • 3. Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, 210042, China.
  • 4. Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, 410013, China.
  • 5. Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
  • 6. Department of Microbiology, and Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
  • 7. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
PMID: 40289872 DOI: 10.1002/advs.202409837
Abstract

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.

Keywords
Lactobacillus johnsonii; B cell differentiation; B cell migration; fecal microbiota transplantation (FMT); inosine; lupus nephritis (LN); purine metabolites; systemic lupus erythematosus (SLE).
Products