Low butyrate concentrations exert anti-inflammatory and high concentrations exert pro-inflammatory effects on macrophages

Butyrate is a four-carbon short-chain fatty acid produced from microbial fermentation of dietary fibers present at high millimolar concentrations in the colonic lumen. However, in an intact epithelium, macrophages residing in the lamina propria are exposed to only micromolar butyrate concentrations. Current studies show anti-inflammatory properties of butyrate and suggest that it might have therapeutic applications in inflammatory bowel disease and colonic cancer. We now show that the effect of butyrate on human macrophages is strongly concentration dependent: 0.1 mM butyrate suppresses LPS-induced production of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α. Experiments with siRNA knockdown and small molecule inhibitors suggest that this is mediated by a mechanism involving PPAR-γ signaling, whereas we observed no or only a minor effect of histone acetylation. In contrast, 10 mM butyrate promotes macrophage cell death, does not inhibit LPS-induced production of TNF-α, and promotes production of IL-1β, while production of anti-inflammatory IL-10 is reduced in a mechanism involving G protein-coupled receptors, the lipid transporter CD36, and the kinase SRC. We propose that butyrate is a signaling molecule for intestinal integrity, since intestinal disruption exposes macrophages to high butyrate concentrations.