Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes
Open accessAbstract
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.
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Butyrate is associated with protection from autoimmune processes and graft-versus-host disease.
“Butyrate is associated with protection from autoimmune processes and graft-versus-host disease16,17.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [16]
Butyrate and propionate are potent regulators of the suppressive activity of Tregs in diverse experimental settings of autoimmune and inflammatory disorders.
“Particularly, butyrate and propionate seem to be potent regulators of the suppressive activity of Tregs in diverse experimental settings of autoimmune and inflammatory disorders16,38.”
From Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer (2021) · cites this paper as [16]
SCFAs promote the development of naive CD4+ T cells into regulatory T cells, induce "tolerogenic" dendritic cells in the intestinal mucosa, and limit autoimmunity.
“SCFAs promote the development of naive CD4+ T cells into regulatory T cells (31, 32), induce “tolerogenic” dendritic cells in the intestinal mucosa (33), and limit autoimmity (34, 35).”
From Respiratory viral infection-induced microbiome alterations and secondary bacterial pneumonia. (2018) · cites this paper as [34]
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- Authors
- Mariño, E., Richards, J. L., McLeod, K. H., Stanley, D., Yap, Y. A., Knight, J., McKenzie, C., Kranich, J., Oliveira, A. C., Rossello, F. J., Krishnamurthy, B., Nefzger, C. M., Macia, L., Thorburn, A., Baxter, A. G., Morahan, G., Wong, L. H., Polo, J. M., Moore, R. J., Lockett, T. J., Clarke, J. M., Topping, D. L., Harrison, L. C., & Mackay, C. R.
- Affiliations
- Monash University (AU)
- Central Queensland University (AU)
- Institut für Immunologie (DE)
- Universidade Federal do Rio de Janeiro (BR)
- Australian Regenerative Medicine Institute (AU)
- St Vincents Institute of Medical Research (AU)
- The University of Sydney (AU)
- James Cook University (AU)
- Harry Perkins Institute of Medical Research (AU)
- Commonwealth Scientific and Industrial Research Organisation (AU)
- CSIRO Health and Biosecurity (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Corresponding author
- Mariño, Eliana
- Mackay, Charles R
- ORCID
- Mariño, Eliana
- Stanley, Dragana
- Yap, Yu Anne
- McKenzie, Craig
- Kranich, Jan
- Oliveira, Ana Carolina
- Rossello, Fernando J
- Krishnamurthy, Balasubramanian
- Nefzger, Christian M
- Macia, Laurence
- Baxter, Alan G
- Morahan, Grant
- Wong, Lee H
- Polo, Jose M
- Moore, Robert J
- Lockett, Trevor J
- Clarke, Julie M
- Harrison, Leonard C
- Mackay, Charles R
- Venue
- Nature Immunology
- Published
- 2017-03-27
- Volume
- 18
- Issue
- 5
- Pages
- 552-562
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2603850261
- Cited by
- 686
- References
- 57
- Citations by year
- 2026: 39 · 2025: 61 · 2024: 55 · 2023: 87 · 2022: 94 · 2021: 80 · 2020: 88 · 2019: 77 · 2018: 71 · 2017: 33
- FWCI
- 30.06
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- figshare.com
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- ResearchOnline at James Cook University (James Cook University) (submittedVersion)
- Acquire (CQUniversity) (submittedVersion)
- RMIT Research Repository (RMIT University Library) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- type 1 diabetes, gut microbiota, microbial metabolites, acetate, butyrate, NOD mice, autoreactive T cells, regulatory T cells, B cells, intestinal barrier integrity, IL-21, dietary intervention, immune tolerance, autoimmune disease
- MeSH terms
- Gastrointestinal Microbiome, Acetates, Interleukin-21, Animals, B-Lymphocytes, Butyrates, Cells, Cultured, Colon, Diabetes Mellitus, Type 1, Diet Therapy, Interleukins, Autoimmunity, Mice, Inbred NOD, T-Lymphocytes, Regulatory, Mice, Dysbiosis
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