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

Wang, Pai, Yang, Xin, Zhang, Luyao, Sha, Sha, Huang, Juan, Peng, Jian, Gu, Jianlei, Pearson, James Alexander ORCID: https://orcid.org/0000-0002-2867-2269, Hu, Youjia, Zhao, Hongyu, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845, Wang, Quan and Wen, Li 2024. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis. Nature Communications 15 (1) , 4232. 10.1038/s41467-024-48611-8

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	20 May 2024
Date of Acceptance:	2 May 2024
Last Modified:	20 May 2024 09:01
URI:	https://orca.cardiff.ac.uk/id/eprint/169029

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