Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis

Mingming Sun, Wei Wu, Liang Chen, Wenjing Yang, Xiangsheng Huang, Caiyun Ma, Feidi Chen, Yi Xiao, Ye Zhao, Chunyan Ma, Suxia Yao, Victor H. Carpio, Sara M. Dann, Qihong Zhao, Zhanju Liu () and Yingzi Cong ()
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Mingming Sun: Tongji University
Wei Wu: Tongji University
Liang Chen: Tongji University
Wenjing Yang: Tongji University
Xiangsheng Huang: The University of Texas Medical Branch
Caiyun Ma: Tongji University
Feidi Chen: University of Texas Medical Branch
Yi Xiao: The University of Texas Medical Branch
Ye Zhao: The University of Texas Medical Branch
Chunyan Ma: The University of Texas Medical Branch
Suxia Yao: The University of Texas Medical Branch
Victor H. Carpio: The University of Texas Medical Branch
Sara M. Dann: The University of Texas Medical Branch
Qihong Zhao: Bristol-Myers Squibb
Zhanju Liu: Tongji University
Yingzi Cong: The University of Texas Medical Branch

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract T-cells are crucial in maintanence of intestinal homeostasis, however, it is still unclear how microbiota metabolites regulate T-effector cells. Here we show gut microbiota-derived short-chain fatty acids (SCFAs) promote microbiota antigen-specific Th1 cell IL-10 production, mediated by G-protein coupled receptors 43 (GPR43). Microbiota antigen-specific Gpr43−/− CBir1 transgenic (Tg) Th1 cells, specific for microbiota antigen CBir1 flagellin, induce more severe colitis compared with wide type (WT) CBir1 Tg Th1 cells in Rag−/− recipient mice. Treatment with SCFAs limits colitis induction by promoting IL-10 production, and administration of anti-IL-10R antibody promotes colitis development. Mechanistically, SCFAs activate Th1 cell STAT3 and mTOR, and consequently upregulate transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1), which mediates SCFA-induction of IL-10. SCFA-treated Blimp1−/− Th1 cells produce less IL-10 and induce more severe colitis compared to SCFA-treated WT Th1 cells. Our studies, thus, provide insight into how microbiota metabolites regulate Th1 cell functions to maintain intestinal homeostasis.

Date: 2018
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DOI: 10.1038/s41467-018-05901-2

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