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Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis

Author

Listed:
  • Panpan Tian

    (Cheeloo Medical College of Shandong University)

  • Wenwen Yang

    (Cheeloo Medical College of Shandong University)

  • Xiaowei Guo

    (Cheeloo Medical College of Shandong University)

  • Tixiao Wang

    (Cheeloo Medical College of Shandong University)

  • Siyu Tan

    (Cheeloo Medical College of Shandong University)

  • Renhui Sun

    (Cheeloo Medical College of Shandong University)

  • Rong Xiao

    (Cheeloo Medical College of Shandong University)

  • Yuzhen Wang

    (Cheeloo Medical College of Shandong University)

  • Deyan Jiao

    (Cheeloo Medical College of Shandong University)

  • Yachen Xu

    (Cheeloo Medical College of Shandong University)

  • Yanfei Wei

    (Cheeloo Medical College of Shandong University)

  • Zhuanchang Wu

    (Cheeloo Medical College of Shandong University
    Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong)

  • Chunyang Li

    (School of Basic Medical Science, Shandong University)

  • Lifen Gao

    (Cheeloo Medical College of Shandong University
    Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong)

  • Chunhong Ma

    (Cheeloo Medical College of Shandong University
    Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong)

  • Xiaohong Liang

    (Cheeloo Medical College of Shandong University
    Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong)

Abstract

Liver-resident natural killer cells, a unique lymphocyte subset in liver, develop locally and play multifaceted immunological roles. However, the mechanisms for the maintenance of liver-resident natural killer cell homeostasis remain unclear. Here we show that early-life antibiotic treatment blunt functional maturation of liver-resident natural killer cells even at adulthood, which is dependent on the durative microbiota dysbiosis. Mechanistically, early-life antibiotic treatment significantly decreases butyrate level in liver, and subsequently led to defective liver-resident natural killer cell maturation in a cell-extrinsic manner. Specifically, loss of butyrate impairs IL-18 production in Kupffer cells and hepatocytes through acting on the receptor GPR109A. Disrupted IL-18/IL-18R signaling in turn suppresses the mitochondrial activity and the functional maturation of liver-resident natural killer cells. Strikingly, dietary supplementation of experimentally or clinically used Clostridium butyricum restores the impaired liver-resident natural killer cell maturation and function induced by early-life antibiotic treatment. Our findings collectively unmask a regulatory network of gut-liver axis, highlighting the importance of the early-life microbiota in the development of tissue-resident immune cells.

Suggested Citation

  • Panpan Tian & Wenwen Yang & Xiaowei Guo & Tixiao Wang & Siyu Tan & Renhui Sun & Rong Xiao & Yuzhen Wang & Deyan Jiao & Yachen Xu & Yanfei Wei & Zhuanchang Wu & Chunyang Li & Lifen Gao & Chunhong Ma & , 2023. "Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37419-7
    DOI: 10.1038/s41467-023-37419-7
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