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

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 () and Li Wen ()
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Pai Wang: Changchun
Xin Yang: Yale University
Luyao Zhang: Changchun
Sha Sha: Yale University
Juan Huang: Yale University
Jian Peng: Yale University
Jianlei Gu: Yale School of Public Health
James Alexander Pearson: Yale University
Youjia Hu: Yale University
Hongyu Zhao: Yale School of Public Health
F. Susan Wong: Cardiff University
Quan Wang: Changchun
Li Wen: Yale University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48611-8

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