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

Maik Luu, Sabine Pautz, Vanessa Kohl, Rajeev Singh, Rossana Romero, Sébastien Lucas, Jörg Hofmann, Hartmann Raifer, Niyati Vachharajani, Lucia Campos Carrascosa, Boris Lamp, Andrea Nist, Thorsten Stiewe, Yoav Shaul, Till Adhikary, Mario M. Zaiss, Matthias Lauth, Ulrich Steinhoff and Alexander Visekruna ()
Additional contact information
Maik Luu: Philipps-University Marburg
Sabine Pautz: Philipps-University Marburg
Vanessa Kohl: Philipps-University Marburg
Rajeev Singh: Philipps-University Marburg
Rossana Romero: Philipps-University Marburg
Sébastien Lucas: Friedrich-Alexander-University-Erlangen-Nürnberg and Universitätsklinikum Erlangen
Jörg Hofmann: Friedrich-Alexander-University-Erlangen-Nürnberg
Hartmann Raifer: Philipps-University Marburg
Niyati Vachharajani: Philipps-University Marburg
Lucia Campos Carrascosa: Philipps-University Marburg
Boris Lamp: Philipps-University Marburg
Andrea Nist: Philipps-University Marburg
Thorsten Stiewe: Philipps-University Marburg
Yoav Shaul: The Hebrew University-Hadassah Medical School
Till Adhikary: Philipps-University Marburg
Mario M. Zaiss: Friedrich-Alexander-University-Erlangen-Nürnberg and Universitätsklinikum Erlangen
Matthias Lauth: Philipps-University Marburg
Ulrich Steinhoff: Philipps-University Marburg
Alexander Visekruna: Philipps-University Marburg

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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 mono-colonized 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.

Date: 2019
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DOI: 10.1038/s41467-019-08711-2

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