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SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome

Author

Listed:
  • Bree J. Tillett

    (The University of Queensland)

  • Jacky Dwiyanto

    (University of Malaya)

  • Kate R. Secombe

    (The University of Queensland)

  • Thomas George

    (The University of Queensland)

  • Vivian Zhang

    (The University of Queensland)

  • Dovile Anderson

    (Monash University
    Monash University)

  • Emily Duggan

    (Translational Research Institute)

  • Rabina Giri

    (Mater Research Institute—The University of Queensland)

  • Dorothy Loo

    (Translational Research Institute)

  • Thomas Stoll

    (QIMR Berghofer Medical Research Institute)

  • Mark Morrison

    (The University of Queensland
    Princess Alexandra Hospital)

  • Jakob Begun

    (Mater Research Institute—The University of Queensland)

  • Michelle M. Hill

    (QIMR Berghofer Medical Research Institute)

  • Esteban N. Gurzov

    (Université libre de Bruxelles)

  • Kirstine J. Bell

    (University of Sydney)

  • Sonia Saad

    (University of Sydney)

  • Christopher K. Barlow

    (Monash University
    Monash University)

  • Darren J. Creek

    (Monash University
    Monash University)

  • Chun Wie Chong

    (Monash University Malaysia)

  • Eliana Mariño

    (Monash University
    ImmunoBiota Therapeutics Pty Ltd)

  • Emma E. Hamilton-Williams

    (The University of Queensland)

Abstract

Type 1 diabetes (T1D) is linked to an altered gut microbiota characterized by reduced short-chain fatty acid (SCFA) production. Oral delivery of a SCFA-yielding biotherapy in adults with T1D was followed by increased SCFAs, altered gut microbiota and immunoregulation, as well as delaying diabetes in preclinical models. Here, we show that SCFA-biotherapy in humans is accompanied by remodeling of the gut proteome and mucosal immune homeostasis. Metabolomics showed arginine, glutamate, nucleotide and tryptophan metabolism were enriched following the SCFA-biotherapy, and found metabolites that correlated with glycemic control. Fecal microbiota transfer demonstrated that the microbiota of SCFA-responders delayed diabetes progression in humanized gnotobiotic mice. The protected mice increased similar metabolite pathways to the humans including producing aryl-hydrocarbon receptor ligands and reducing inflammatory mucosal immunity and increasing IgA production in the gut. These data demonstrate that a potent SCFA immunomodulator promotes multiple beneficial pathways and supports targeting the microbiota as an approach against T1D. Trial registration: Australia New Zealand Clinical Trials Registry ACTRN12618001391268.

Suggested Citation

  • Bree J. Tillett & Jacky Dwiyanto & Kate R. Secombe & Thomas George & Vivian Zhang & Dovile Anderson & Emily Duggan & Rabina Giri & Dorothy Loo & Thomas Stoll & Mark Morrison & Jakob Begun & Michelle M, 2025. "SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58319-y
    DOI: 10.1038/s41467-025-58319-y
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    References listed on IDEAS

    as
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    4. Luis F Hernandez & Peter Buchwald & Midhat H Abdulreda, 2018. "Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 5(3), pages 1-7, January.
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