title: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes.
abstract: Gut dysbiosis might underlie the pathogenesis of type 1 diabetes. In mice of the non-obese diabetic (NOD) strain, we found that key features of disease correlated inversely with blood and fecal concentrations of the microbial metabolites acetate and butyrate. We therefore fed NOD mice specialized diets designed to release large amounts of acetate or butyrate after bacterial fermentation in the colon. Each diet provided a high degree of protection from diabetes, even when administered after breakdown of immunotolerance. Feeding mice a combined acetate- and butyrate-yielding diet provided complete protection, which suggested that acetate and butyrate might operate through distinct mechanisms. Acetate markedly decreased the frequency of autoreactive T cells in lymphoid tissues, through effects on B cells and their ability to expand populations of autoreactive T cells. A diet containing butyrate boosted the number and function of regulatory T cells, whereas acetate- and butyrate-yielding diets enhanced gut integrity and decreased serum concentration of diabetogenic cytokines such as IL-21. Medicinal foods or metabolites might represent an effective and natural approach for countering the numerous immunological defects that contribute to T cell-dependent autoimmune diseases.
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Eliana
authors.identifier: 0000-0001-5371-8778
authors.initials: E
authors.lastname: Mariño
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: James L
authors.initials: JL
authors.lastname: Richards
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Keiran H
authors.initials: KH
authors.lastname: McLeod
authors.affiliation: Central Queensland University, School of Medical and Applied Sciences, Rockhampton, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Stanley
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Yu Anne
authors.initials: YA
authors.lastname: Yap
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Jacinta
authors.initials: J
authors.lastname: Knight
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: McKenzie
authors.affiliation: Institute for Immunology, Ludwig Maximilians University, Munich, Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kranich
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Oliveira
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.|Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Fernando J
authors.identifier: 0000-0003-3885-8777
authors.initials: FJ
authors.lastname: Rossello
authors.affiliation: Islet Biology Laboratory, St Vincent's Institute, Fitzroy, Australia.
authors.forename: Balasubramanian
authors.initials: B
authors.lastname: Krishnamurthy
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.|Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Nefzger
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.|Nutritional Immunometabolism Node Laboratory, Charles Perkins Centre, University of Sydney, Sydney, Australia.|School of Medical Sciences, University of Sydney, Sydney, Australia.
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Alison
authors.initials: A
authors.lastname: Thorburn
authors.affiliation: Comparative Genomics Centre, Molecular Sciences, James Cook University, Townsville, Australia.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Baxter
authors.affiliation: Harry Perkins Institute for Medical Research, Nedlands, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Lee H
authors.initials: LH
authors.lastname: Wong
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.|Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Clayton, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Polo
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, Australia.|School of Science, RMIT University, Bundoora West Campus, Bundoora, Australia.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Moore
authors.affiliation: CSIRO Health and Biosecurity, North Ryde, Australia.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Lockett
authors.affiliation: CSIRO Health and Biosecurity, Adelaide, Australia.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Clarke
authors.affiliation: CSIRO Health and Biosecurity, Adelaide, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Topping
authors.affiliation: Walter &Eliza Hall Institute of Medical Research, Parkville, Australia.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
authors.affiliation: Infection and Immunity Program, Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton, Australia.
authors.forename: Charles R
authors.identifier: 0000-0002-6338-7340
authors.initials: CR
authors.lastname: Mackay
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000382:microbiology; D002087:Butyrates / Q000378:metabolism*; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000178:diet therapy*; D004035:Diet Therapy; D064806:Dysbiosis / Q000178:diet therapy*; D000069196:Gastrointestinal Microbiome; D007378:Interleukins / Q000097:blood; D051379:Mice; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology; D000098546:Interleukin-21
chemical_list: D000085:Acetates; D002087:Butyrates; D007378:Interleukins; D000098546:Interleukin-21