Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against colitis. SCFAs binding to the 'metabolite-sensing' receptors GPR43 and GPR109A in non-haematopoietic cells mediate these protective effects. The inflammasome pathway has hitherto been reported as a principal pathway promoting gut epithelial integrity. SCFAs binding to GPR43 on colonic epithelial cells stimulates K þ efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. Dietary fibre also shapes gut bacterial ecology, resulting in bacterial species that are more effective for inflammasome activation. SCFAs and metabolite receptors thus explain health benefits of dietary fibre, and how metabolite signals feed through to a major pathway for gut homeostasis.

L.X. planned and performed most of the experiments and wrote the manuscript. C.I.M. planned and performed mouse in vitro experiments. X.Q., Y.M., and Q.W. planned and performed human study. N.B. planned and performed the phenomewide association study. K.N. and M.J.A. performed animal experiments. D.Y. and F.G. provided samples for human study. C.A. performed animal experiments. R.R. and F.Z.M. discussed mechanistic concepts and edited manuscript. N.F. and D.H. performed analysis for the phenome-wide association study. O.G. discussed mechanistic concepts and edited manuscript. R.J.X. discussed mechanistic concepts and edited the manuscript. C.R.M. initiated and supervised the project and wrote the manuscript.

No abstract

No abstract