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

• Published in: Nature communications Vol. 9; no. 1; pp. 3555 - 15
• Main Authors: Sun, Mingming, Wu, Wei, Chen, Liang, Yang, Wenjing, Huang, Xiangsheng, Ma, Caiyun, Chen, Feidi, Xiao, Yi, Zhao, Ye, Ma, Chunyan, Yao, Suxia, Carpio, Victor H., Dann, Sara M., Zhao, Qihong, Liu, Zhanju, Cong, Yingzi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.09.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/31; 13/89; 631/250/1619/554/1898; 631/250/2152/1566; 631/250/347; 64; 64/60; 692/4020; 82/29; Animals; Antigens; Chains; Colitis; Colitis - immunology; Effector cells; Fatty acids; Fatty Acids, Volatile - immunology; Fatty Acids, Volatile - metabolism; Flagellin; Flagellin - immunology; Gastrointestinal Microbiome - immunology; Gene Expression; Gene Knockout Techniques; Homeostasis; Humanities and Social Sciences; Inflammatory bowel disease; Interleukin 10; Interleukin-10 - immunology; Intestinal microflora; Intestine; Lymphocytes B; Lymphocytes T; Metabolites; Mice; Microbiota; multidisciplinary; Positive Regulatory Domain I-Binding Factor 1 - genetics; Proteins; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - immunology; Science; Science (multidisciplinary); Stat3 protein; STAT3 Transcription Factor - immunology; Th1 Cells - immunology; TOR protein; TOR Serine-Threonine Kinases - immunology; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05901-2

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. T cells play a critical role in intestinal homeostasis, with increasing evidence suggesting a role for the microbiome metabolome in modulating this response. Here the authors show short-chain fatty acids promote IL-10 production in Th1 cells.