TY - JOUR
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
N1 - Publisher Copyright: © 2019, The Author(s).
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.
UR - http://www.scopus.com/inward/record.url?scp=85061616085&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-08711-2
DO - 10.1038/s41467-019-08711-2
M3 - مقالة
C2 - 30770822
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 760
ER -