The short chain fatty acid, butyrate is produced by fermentation of dietry fiber by the intestinal microbiota; butyrate is the primary energy source of colonocytes and has immunomodulatory effects. Having shown that macrophages differentiated with IL-4 (M(IL-4)s) can suppress colitis, we hypothesized that butyrate would reinforce an M(IL-4) phenotype. Here, we show that in the presence of butyrate, M(IL-4)s display reduced expression of their hallmark markers Arg1 and Ym1, and significantly suppressed LPS-induced nitric oxide, IL-12p40 and IL-10 production. Butyrate treatment likely altered the M(IL-4) phenotype via inhibition of histone deacetylation. Functionally, M(IL-4)s treated with butyrate showed increased phagocytosis and killing of bacteria, compared to M(IL-4) and this was not accompanied by enhanced pro-inflammatory cytokine production. Culture of regulatory T cells with M(IL-4)s and M(IL-4+butyrate)s revealed that both macrophage subsets suppressed expression of the regulatory T cell marker, Foxp3. However, Tregs co-cultured with M(IL-4+butyrate) produced less IL-17A than Tregs co-cultured with M(IL-4). These data illustrate the importance of butyrate, a microbial-derived metabolite, in the regulation of gut immunity: the demonstration that butyrate promotes phagocytosis in M(IL-4)s that can also limit T cell production of IL-17A reveals novel aspects of bacterial-host interaction in the regulation of intestinal homeostasis.
- innate immunity
- intestinal homeostasis
- Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology