title: Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome.
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.
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Jian
authors.initials: J
authors.lastname: Tan
authors.affiliation: 1] Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia [2] Department of Biochemistry and Immunology, Immunopharmacology Group, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Angelica T
authors.initials: AT
authors.lastname: Vieira
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Katie
authors.initials: K
authors.lastname: Leach
authors.affiliation: 1] CSIRO Animal, Food and Health Sciences, Australian Animal Health Laboratories, Private Bag 24, Geelong, Victoria 3220, Australia [2] Central Queensland University, School of Medical and Applied Sciences, Bruce Highway, Rockhampton, Queensland 4702, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Stanley
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Luong
authors.affiliation: Laboratory for Mucosal Immunity, 6 Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Mikako
authors.initials: M
authors.lastname: Maruya
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Ian McKenzie
authors.affiliation: Laboratory for Mucosal Immunity, 6 Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Connie
authors.initials: C
authors.lastname: Wong
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Lauren
authors.initials: L
authors.lastname: Binge
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Alison N
authors.initials: AN
authors.lastname: Thorburn
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Nina
authors.initials: N
authors.lastname: Chevalier
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ang
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Eliana
authors.initials: E
authors.lastname: Marino
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Remy
authors.initials: R
authors.lastname: Robert
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Ludwigstraße 43, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Biochemistry and Immunology, Immunopharmacology Group, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: 1] CSIRO Animal, Food and Health Sciences, Australian Animal Health Laboratories, Private Bag 24, Geelong, Victoria 3220, Australia [2] ARC Centre of Excellence in Structural and Functional Microbial Genomics, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Moore
authors.affiliation: 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Laboratory for Mucosal Immunity, 6 Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology Tsurumi, Yokohama 230-0045, Japan.
authors.forename: Sidonia
authors.initials: S
authors.lastname: Fagarasan
authors.affiliation: Department of Immunology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000378:metabolism*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004043:Dietary Fiber / Q000494:pharmacology*; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D005285:Fermentation; D000069196:Gastrointestinal Microbiome; D006706:Homeostasis / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D000085:Acetates; D002087:Butyrates; D002352:Carrier Proteins; D004043:Dietary Fiber; D005232:Fatty Acids, Volatile; C506481:Ffar2 protein, mouse; C473652:Hcar2 protein, mouse; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic