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-gamma-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-beta1, the expression of T-bet and IFN-gamma 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-gamma 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.
- Kespohl, M.
- Vachharajani, N.
- Luu, M.
- Harb, H.
- Pautz, S.
- Wolff, S.
- Sillner, N.
- Walker, A.
- Schmitt-Kopplin, P.
- Boettger, T.
- Renz, H.
- Offermanns, S.
- Steinhoff, U.
- Visekruna, A.
Keywords
- butyrate
- inhibition of histone deacetylase activity
- interferon-gamma
- regulatory T cells
- short-chain fatty acids