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.

Biology and therapeutic potential of interleukin-10

“…Journal of Experimental Medicine expression in regulatory B cells (Luu et al, 2019). Interestingly, gut microbiota-derived short-chain fatty acids have also been shown to induce Th1 cells to produce IL-10 to maintain intestinal homeostasis, through the activation of STAT3 and mTOR, upstream of Blimp-1 up-regulation .…”

Strategies to Dissect Host-Microbial Immune Interactions That Determine Mucosal Homeostasis vs. Intestinal Inflammation in Gnotobiotic Mice

“…Other SCFA also have immunoregulatory activities. Pentanoic acid (pentenoate) is present in high concentrations in SPF, but not GF feces (62). Pentenoate induces IL-10 in lymphocytes by elevating glucose oxidation, a function mediated by increasing acetyl CoA for histone acetyl transferase and activating mTOR.…”

Interleukin‐17 Inhibition in Spondyloarthritis Is Associated With Subclinical Gut Microbiome Perturbations and a Distinctive Interleukin‐25–Driven Intestinal Inflammation

“…In turn, changes in the relative abundance of key taxa correlated with shifts in intestinal levels of IL‐23/Th17‐related cytokines and beneficial short‐chain FAs such as propionic acid, linked to Treg cell expansion and abrogation of gut inflammation . In the fungal community, changes in Candida correlated positively with sIgA and negatively with valeric acid, which has been associated with IL‐10 production and reduction of IL‐17A . Moreover, metagenomic analysis demonstrated that treatment with IL‐17i was associated with up‐regulation of l ‐tryptophan biosynthesis.…”