Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

• Published in: Nature communications Vol. 6; no. 1; p. 6734
• Main Authors: Macia, Laurence, Tan, Jian, Vieira, Angelica T., Leach, Katie, Stanley, Dragana, Luong, Suzanne, Maruya, Mikako, Ian McKenzie, Craig, Hijikata, Atsushi, Wong, Connie, Binge, Lauren, Thorburn, Alison N., Chevalier, Nina, Ang, Caroline, Marino, Eliana, Robert, Remy, Offermanns, Stefan, Teixeira, Mauro M., Moore, Robert J., Flavell, Richard A., Fagarasan, Sidonia, Mackay, Charles R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2015; Nature Publishing Group
• Subjects: 13/51; 38; 38/77; 59; 631/250/256/2177; 631/326/2565/2134; 631/45/612/194; Acetates - metabolism; Animals; Butyrates - metabolism; Carrier Proteins - drug effects; Carrier Proteins - genetics; Carrier Proteins - metabolism; Colitis - metabolism; Colon - drug effects; Colon - metabolism; Dietary Fiber - pharmacology; Fatty Acids, Volatile - metabolism; Fermentation; Gastrointestinal Microbiome; Homeostasis - drug effects; Humanities and Social Sciences; Inflammasomes - drug effects; Inflammasomes - metabolism; Mice; Mice, Knockout; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7734

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. Dietary fibre is metabolized into short-chain fatty acids by gut bacteria. Here the authors show that these metabolites activate the NLRP3 inflammasome in gut epithelial cells and protect mice from injury-induced colitis, suggesting a mechanism for the benefits of a high-fibre diet.