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

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 () and Xiaohong Liang ()
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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
Chunyang Li: School of Basic Medical Science, Shandong University
Lifen Gao: Cheeloo Medical College of Shandong University
Chunhong Ma: Cheeloo Medical College of Shandong University
Xiaohong Liang: Cheeloo Medical College of Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37419-7

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