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Abstract
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(+) 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.
Highlights
Diet and the gut microbiota may underpin numerous human diseases
dextran sulphate sodium (DSS) colitis in mice is characterized by the development of diarrhoea and colonic inflammation leading to blood in the faeces, measured by a clinical score, destruction of colonic tissue assessed by histological scoring of colonic tissue, as well as colon shortening
Since dietary fibre as well as SCFAs are known contributors to epithelial integrity[14,21,24], we examined the influence of diet and the SCFA receptors GPR43 on inflammasome activation and IL-18 production
Summary
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. 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 GPR43 on colonic epithelial cells stimulates K þ efflux and hyperpolarization, which lead to NLRP3 inflammasome activation. We used Gpr[43] À / À , Gpr109a À / À , Nlrp[3] À / À and Nlrp[6] À / À mice, as well as bone marrow chimaera models, to show that the beneficial effects of a high-fibre diet involved the activation of GPR43 and GPR109A in the gut epithelium, and downstream activation of the NLRP3 inflammasome pathway. Dietary fibre, gut microbiota and downstream pathways involving GPR43, GPR109A and the inflammasome combine to promote gut homeostasis
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