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

Tillett BJ 1 , Dwiyanto J 2 , Secombe KR 1 , George T 1 , Zhang V 1 , Anderson D 3 Show all authors , Duggan E 4 , Giri R 5 , Loo D 4 , Stoll T 6 , Morrison M 1 , Begun J 5 , Hill MM 6 , Gurzov EN 7 , Bell KJ 8 , Saad S 9 , Barlow CK 10 , Creek DJ 3 , Chong CW 11 , Mariño E 12 , Hamilton-Williams EE 13

Affiliations 

  • 1 Frazer Institute, The University of Queensland, Brisbane, QLD, Australia
  • 2 Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 3 Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia
  • 4 Translational Research Institute, Brisbane, QLD, Australia
  • 5 Mater Research Institute-The University of Queensland, Brisbane, QLD, Australia
  • 6 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 7 Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
  • 8 Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia
  • 9 Department of Medicine, Kolling Institute, University of Sydney, Sydney, NSW, Australia
  • 10 Monash Proteomics and Metabolomics Platform, Monash University, MelbourneVIC, Australia
  • 11 Monash University Microbiome Research Centre, School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
  • 12 Department of Biochemistry, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia. eliana.marino@monash.edu
  • 13 Frazer Institute, The University of Queensland, Brisbane, QLD, Australia. e.hamiltonwilliams@uq.edu.au
Nat Commun, 2025 Mar 25;16(1):2893.
PMID: 40133336 DOI: 10.1038/s41467-025-58319-y

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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