Effects of short chain fatty acids and GPR43 stimulation on human Treg function (IRC5P.631)

SCFA (acetate, propionate, butyrate) are produced when dietary fiber is metabolized by commensal microbiota. In the mouse, SCFA increase colonic Foxp3+ regulatory T cell (Treg) function, promote immune tolerance, and ameliorate intestinal inflammation through the G protein-coupled receptor GPR43 (FFAR2). However, despite the compelling literature in the mouse, it has not been reported whether SCFA can modulate human Treg function. Moreover, whether GPR43 stimulation is sufficient to mediate any effects of SCFA on human Treg remains unknown. Here we show that acetate or butyrate did not increase Foxp3 expression in ex vivo-differentiated human Treg. Nonetheless, consistent with a proposed effect of SCFA on Treg tolerogenic function, butyrate increased IL-10 production by ex vivo-differentiated Treg. Of note, we show that synthetic GPR43-agonists increased the in vitro suppressive capacity of human peripheral blood CD4+/CD25+ Treg in a T cell/DC co-culture system, an effect that correlated with a decreased production of pro-inflammatory cytokines. Thus, pharmacological GPR43-agonists may partially emulate SCFA effects on Treg. Our results show for the first time that SCFA can modulate human Treg function, and that pharmacological GPR43-agonists are sufficient to increase Treg suppressive capacity, with potential therapeutic implications for inflammatory/autoimmune diseases.