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, Alexander Visekruna*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

277 Scopus citations

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.

Original languageAmerican English
Article number760
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019

Bibliographical note

Funding Information:
The authors are grateful to Dr. Alesia Walker (Helmholtz Zentrum München, Neuher-berg, Germany) for SCFA analysis. The authors thank Elena Jenike and Anne Hellhund for technical assistance. The authors also thank Dr. Wolfgang Meißner and Dr. Julia Obert for establishing the measurement of ECAR as well as Dr. Katrin Roth and members of the Core Facility Microscopy, University of Marburg for providing microscopic devices and for excellent technical support. This study was supported by a research grant from the Fritz Thyssen Foundation (Alexander Visekruna) and by Studienstiftung des deutschen Volkes and Von Behring-Röntgen-Stiftung (Maik Luu).

Publisher Copyright:
© 2019, The Author(s).

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