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

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. Hill, Esteban N. Gurzov, Kirstine J. Bell, Sonia Saad, Christopher K. Barlow, Darren J. Creek, Chun Wie Chong, Eliana Mariño () and Emma E. Hamilton-Williams ()
Additional contact information
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
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
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
Darren J. Creek: Monash University
Chun Wie Chong: Monash University Malaysia
Eliana Mariño: Monash University
Emma E. Hamilton-Williams: The University of Queensland

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58319-y

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