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.
Bibliographical noteFunding 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).
© 2019, The Author(s).