TY - JOUR
T1 - Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis
AU - Sun, Mingming
AU - Wu, Wei
AU - Chen, Liang
AU - Yang, Wenjing
AU - Huang, Xiangsheng
AU - Ma, Caiyun
AU - Chen, Feidi
AU - Xiao, Yi
AU - Zhao, Ye
AU - Ma, Chunyan
AU - Yao, Suxia
AU - Carpio, Victor H.
AU - Dann, Sara M.
AU - Zhao, Qihong
AU - Liu, Zhanju
AU - Cong, Yingzi
N1 - Funding Information:
We appreciate Dr. Linsey Yeager of The University of Texas Medical Branch for proofreading the manuscript. This work was supported by NIH grants DK098370, DK105585, and DK112436, John Sealy Memorial Endowment Fund, and the National Natural Science Foundation of China grants 81630017, 81740117, and 81770546.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-05901-2
DO - 10.1038/s41467-018-05901-2
M3 - Article
C2 - 30177845
AN - SCOPUS:85052632504
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3555
ER -