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Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis

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  • Pai Wang

    (Changchun
    Yale University)

  • Xin Yang

    (Yale University
    Shanghai Jiao Tong University)

  • Luyao Zhang

    (Changchun
    Yale University)

  • Sha Sha

    (Yale University
    The First Affiliated Hospital of Shandong First Medical University)

  • Juan Huang

    (Yale University)

  • Jian Peng

    (Yale University)

  • Jianlei Gu

    (Yale School of Public Health)

  • James Alexander Pearson

    (Yale University
    Cardiff University)

  • Youjia Hu

    (Yale University)

  • Hongyu Zhao

    (Yale School of Public Health)

  • F. Susan Wong

    (Cardiff University)

  • Quan Wang

    (Changchun)

  • Li Wen

    (Yale University)

Abstract

Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity.

Suggested Citation

  • Pai Wang & Xin Yang & Luyao Zhang & Sha Sha & Juan Huang & Jian Peng & Jianlei Gu & James Alexander Pearson & Youjia Hu & Hongyu Zhao & F. Susan Wong & Quan Wang & Li Wen, 2024. "Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48611-8
    DOI: 10.1038/s41467-024-48611-8
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