Butyrate is anti-inflammatory at low and pro-inflammatory at high concentrations

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 areexposed to only sub-millimolar butyrate concentrations. Current studies show antiinflammatoryproperties of butyrate and suggest that it might have therapeuticapplications in inflammatory bowel disease and colonic cancer. We now show that theeffect of butyrate on human macrophages is strongly concentration dependent. At lowconcentrations (0.1–1 mM), butyrate suppresses LPS-induced production ofproinflammatory cytokines potentially through a combination PPAR-γ signaling andincreased histone acetylation. At high concentrations (10 mM), butyrate promotesproduction of inflammatory cytokines in a mechanism that involves G protein-coupledreceptor GPR109A, the lipid transporter CD36, and the kinase SRC. We propose thatbutyrate is a crucial signaling molecule for intestinal integrity, since intestinaldisruption exposes macrophages to high butyrate concentrations.