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

doi:10.1038/s41467-019-08711-2

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

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

337 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 language	English
Article number	760
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08711-2
State	Published - 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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Luu, M., Pautz, S., Kohl, V., Singh, R., Romero, R., Lucas, S., Hofmann, J., Raifer, H., Vachharajani, N., Carrascosa, L. C., Lamp, B., Nist, A., Stiewe, T., Shaul, Y., Adhikary, T., Zaiss, M. M., Lauth, M., Steinhoff, U., & Visekruna, A. (2019). The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes. Nature Communications, 10(1), Article 760. https://doi.org/10.1038/s41467-019-08711-2

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

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.",

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Luu, M, Pautz, S, Kohl, V, Singh, R, Romero, R, Lucas, S, Hofmann, J, Raifer, H, Vachharajani, N, Carrascosa, LC, Lamp, B, Nist, A, Stiewe, T, Shaul, Y, Adhikary, T, Zaiss, MM, Lauth, M, Steinhoff, U & Visekruna, A 2019, 'The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes', Nature Communications, vol. 10, no. 1, 760. https://doi.org/10.1038/s41467-019-08711-2

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T1 - The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes

AU - Luu, Maik

AU - Pautz, Sabine

AU - Kohl, Vanessa

AU - Singh, Rajeev

AU - Romero, Rossana

AU - Lucas, Sébastien

AU - Hofmann, Jörg

AU - Raifer, Hartmann

AU - Vachharajani, Niyati

AU - Carrascosa, Lucia Campos

AU - Lamp, Boris

AU - Nist, Andrea

AU - Stiewe, Thorsten

AU - Shaul, Yoav

AU - Adhikary, Till

AU - Zaiss, Mario M.

AU - Lauth, Matthias

AU - Steinhoff, Ulrich

AU - Visekruna, Alexander

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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

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