Butyrate directly decreases human gut lamina propria CD4 T cell function through histone deacetylase (HDAC) inhibition and GPR43 signaling

Abstract

An important function of the gut microbiome is the fermentation of non-digestible dietary fibers into short chain fatty acids (SCFAs). The three primary SCFAs: acetate, propionate, and butyrate, are key mediators of metabolism and immune cell function in the gut mucosa. We previously demonstrated that butyrate at high concentrations decreased human gut lamina propria (LP) CD4 T cell activation in response to enteric bacteria exposure in vitro. However, to date, the mechanism by which butyrate alters human gut LP CD4 T cell activation remains unknown. In this current study, we sought to better understand how exposure to SCFAs across a concentration range impacted human gut LP CD4 T cell function and activation. LP CD4 T cells were directly activated with T cell receptor (TCR) beads in vitro in the presence of a physiologic concentration range of each of the primary SCFAs. Exposure to butyrate potently inhibited CD4 T cell activation, proliferation, and cytokine (IFNγ, IL-17) production in a concentration dependent manner. Butyrate decreased the proliferation and cytokine production of T helper (Th) 1, Th17 and Th22 cells, with differences noted in the sensitivity of LP versus peripheral blood Th cells to butyrate’s effects. Higher concentrations of propionate and acetate relative to butyrate were required to inhibit CD4 T cell activation and proliferation. Butyrate directly increased the acetylation of both unstimulated and TCR-stimulated CD4 T cells, and apicidin, a Class I histone deacetylase inhibitor, phenocopied butyrate’s effects on CD4 T cell proliferation and activation. GPR43 agonism phenocopied butyrate’s effect on CD4 T cell proliferation whereas a GPR109a agonist did not. Our findings indicate that butyrate decreases in vitro human gut LP CD4 T cell activation, proliferation, and inflammatory cytokine production more potently than other SCFAs, likely through butyrate’s ability to increase histone acetylation, and potentially via signaling through GPR43. These findings have relevance in furthering our understanding of how perturbations of the gut microbiome alter local immune responses in the gut mucosa.