The Microbial Metabolite Butyrate Induces Expression of Th1-Associated Factors in CD4+ T Cells

Abstract

Short-chain fatty acids (SCFAs), which are generated by the bacterial fermentation of dietary fibers, promote expansion of regulatory T cells (Tregs). Potential therapeutic value of SCFAs has been recently highlighted in the experimental models of T cell-mediated autoimmunity and allergic inflammation. These studies suggest that physiological intestinal concentrations of SCFAs within the millimolar range are crucial for dampening inflammation-mediated processes. Here, we describe opposing effects of SCFAs on T cell-mediated immune responses. In accordance with published data, lower butyrate concentrations facilitated differentiation of Tregs in vitro and in vivo under steady-state conditions. In contrast, higher concentrations of butyrate induced expression of the transcription factor T-bet in all investigated T cell subsets resulting in IFN-γ-producing Tregs or conventional T cells. This effect was mediated by the inhibition of histone deacetylase activity and was independent of SCFA-receptors FFA2 and FFA3 as well as of Na+-coupled SCFA transporter Slc5a8. Importantly, while butyrate was not able to induce the generation of Tregs in the absence of TGF-β1, the expression of T-bet and IFN-γ was triggered upon stimulation of CD4+ T cells with this SCFA alone. Moreover, the treatment of germ-free mice with butyrate enhanced the expression of T-bet and IFN-γ during acute colitis. Our data reveal that, depending on its concentration and immunological milieu, butyrate may exert either beneficial or detrimental effects on the mucosal immune system.

Effects of Prebiotic Fiber Xylooligosaccharide in Adenine‐Induced Nephropathy in Mice

“…Only a small portion of them pass into the circulation and exert anti‐inflammatory and metabolic effects under normal physiological conditions . Other studies have also reported that oral administration of high dose of SCFAs induced strong immune response in renal tissue . Our correlation analysis showed a strong negative correlation between blood propionate and all three major cecal SCFAs with BUN, suggesting their protective effect in CKD mice.…”

Diet, Microbiota and Gut-Lung Connection

“…In vitro studies further established the role of butyrate in regulation of forkhead transcription factor FOXP3 (a lineage specification factor). Butyrate works as an inhibitor of histone deacetylases (HDAC) and promotes acetylation of histone H3 at the promoter of the gene encoding FOXP3 (Zeng and Chi, 2015 ; Kespohl et al, 2017 ; Supplementary Figure S1 ). SCFAs also influence the development of dendritic cells and inflammatory cytokines, thereby regulating the intestinal macrophages (Chauvistré et al, 2014 ; Supplementary Figure S1 ).…”

Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate

“…While the anti-inflammatory capacity of butyrate and other SCFAs has been extensively investigated, novel studies have revealed that CD4 + effector T cells might also be a cellular target for SCFAs 11 – 14 . Therefore, it will be particularly interesting to better understand the molecular mechanisms underlying cell- and tissue-specific responsive immune cell subsets in order to develop and provide a safe SCFA-based therapy for patients with autoimmune diseases.…”