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

• Main Authors: Meike Kespohl, Niyati Vachharajani, Maik Luu, Hani Harb, Sabine Pautz, Svenja Wolff, Nina Sillner, Alesia Walker, Philippe Schmitt-Kopplin, Thomas Boettger, Harald Renz, Stefan Offermanns, Ulrich Steinhoff, Alexander Visekruna
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-08-01
• Series: Frontiers in Immunology
• Subjects: short-chain fatty acids; butyrate; regulatory T cells; interferon-gamma; inhibition of histone deacetylase activity
• Online Access: http://journal.frontiersin.org/article/10.3389/fimmu.2017.01036/full

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.