2. Academic Validation
  3. Early life gut microbiota sustains liver-resident natural killer cells maturation via the butyrate-IL-18 axis

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

  • Nat Commun. 2023 Mar 27;14(1):1710. doi: 10.1038/s41467-023-37419-7.
Panpan Tian 1,  Wenwen Yang 1,  Xiaowei Guo 1,  Tixiao Wang 1,  Siyu Tan 1,  Renhui Sun 1,  Rong Xiao 1,  Yuzhen Wang 1,  Deyan Jiao 1,  Yachen Xu 1,  Yanfei Wei 1,  Zhuanchang Wu 1 2,  Chunyang Li 3,  Lifen Gao 1 2,  Chunhong Ma 4 5,  Xiaohong Liang 6 7
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China.
  • 2 Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China.
  • 3 Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, China.
  • 4 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China. [email protected].
  • 5 Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China. [email protected].
  • 6 Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, 250012, Shandong, China. [email protected].
  • 7 Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Jinan, 250012, Shandong, China. [email protected].
PMID: 36973277 DOI: 10.1038/s41467-023-37419-7
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.

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