The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes

被引：369

作者：

Luu, Maik ^{[1
]}

Pautz, Sabine ^{[1
,2
]}

Kohl, Vanessa ^{[1
]}

Singh, Rajeev ^{[3
]}

Romero, Rossana ^{[1
]}

Lucas, Sebastien ^{[4
,5
]}

Hofmann, Joerg ^{[6
]}

Raifer, Hartmann ^{[7
]}

Vachharajani, Niyati ^{[1
,8
]}

Carrascosa, Lucia Campos ^{[1
]}

Lamp, Boris ^{[9
]}

Nist, Andrea ^{[9
]}

Stiewe, Thorsten ^{[9
,10
]}

Shaul, Yoav ^{[11
]}

Adhikary, Till ^{[3
]}

Zaiss, Mario M. ^{[4
,5
]}

Lauth, Matthias ^{[3
]}

Steinhoff, Ulrich ^{[1
]}

Visekruna, Alexander ^{[1
]}

机构：

[1] Philipps Univ Marburg, Inst Med Microbiol & Hyg, D-35043 Marburg, Germany

[2] Univ Kassel, Dept Biochem, D-34132 Kassel, Germany

[3] Philipps Univ Marburg, Inst Mol Biol & Tumor Res, Ctr Tumor & Immunobiol, D-35043 Marburg, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Dept Internal Med Rheumatol & Immunol 3, D-91054 Erlangen, Germany

[5] Univ Klinikum Erlangen, D-91054 Erlangen, Germany

[6] Friedrich Alexander Univ Erlangen Nurnberg, Div Biochem, Dept Biol, D-91054 Erlangen, Germany

[7] Philipps Univ Marburg, Flow Cytometry Core Facil, D-35043 Marburg, Germany

[8] Vanderbilt Univ, Dept Med, Div Gastroenterol, Med Ctr, Nashville, TN 37232 USA

[9] Philipps Univ Marburg, Genom Core Facil, D-35043 Marburg, Germany

[10] Philipps Univ Marburg, Inst Mol Oncol, D-35043 Marburg, Germany

[11] Hebrew Univ Jerusalem, Dept Biochem & Mol Biol, Inst Med Res Israel Canada, Hadassah Med Sch, IL-9112102 Jerusalem, Israel

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

T-CELLS; MICROBIAL METABOLITES; REGULATORY NETWORK; GUT MICROBIOME; DIETARY FIBER; B-CELLS; T(H)17; BUTYRATE; EFFECTOR; DIFFERENTIATION;

D O I：

10.1038/s41467-019-08711-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are not well understood. Here we show that pentanoate, a physiologically abundant SCFA, is a potent regulator of immunometabolism. Pentanoate induces IL-10 production in lymphocytes by reprogramming their metabolic activity towards elevated glucose oxidation. Mechanistically, this reprogramming is mediated by supplying additional pentanoate-originated acetyl-CoA for histone acetyltransferases, and by pentanoate-triggered enhancement of mTOR activity. In experimental mouse models of colitis and multiple sclerosis, pentanoate-induced regulatory B cells mediate protection from autoimmune pathology. Additionally, pentanoate shows a potent histone deacetylase-inhibitory activity in CD4(+) T cells, thereby reducing their IL-17A production. In germ-free mice monocolonized with segmented filamentous bacteria (SFB), pentanoate inhibits the generation of small-intestinal Th17 cells and ameliorates SFB-promoted inflammation in the central nervous system. Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases.

引用

页数：12

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