SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome
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.
Authors
- Bree J. Tillett (ORCID: https://orcid.org/0000-0002-0159-6649)
- E. Duggan (ORCID: https://orcid.org/0000-0002-6969-9126)
- Darren J. Creek (ORCID: https://orcid.org/0000-0001-7497-7082)
- Thomas Stoll (ORCID: https://orcid.org/0000-0002-6275-3433)
- Jacky Dwiyanto (ORCID: https://orcid.org/0000-0002-1224-5553)
- Mark Morrison (ORCID: https://orcid.org/0000-0001-9257-9133)
- Eliana Mariño (ORCID: https://orcid.org/0000-0001-5371-8778)
- Kirstine J. Bell (ORCID: https://orcid.org/0000-0001-5638-4048)
- Esteban N. Gurzov (ORCID: https://orcid.org/0000-0003-4642-0273)
- Rabina Giri (ORCID: https://orcid.org/0000-0002-6712-6076)
- Sonia Saad (ORCID: https://orcid.org/0000-0001-8067-8046)
- Jakob Begun (ORCID: https://orcid.org/0000-0001-5256-7672)
- Vivian Zhang (ORCID: https://orcid.org/0000-0002-5059-3399)
- Michelle M. Hill (ORCID: https://orcid.org/0000-0003-1134-0951)
- T. Neville George (ORCID: https://orcid.org/0009-0008-6384-9913)
- Christopher K. Barlow (ORCID: https://orcid.org/0000-0001-9309-2829)
- Dorothy Loo
- Chun Wie Chong (ORCID: https://orcid.org/0000-0002-6881-8883)
- Emma E. Hamilton‐Williams (ORCID: https://orcid.org/0000-0003-4892-3691)
- Kate R. Secombe (ORCID: https://orcid.org/0000-0003-0716-238X)
- Dovile Anderson (ORCID: https://orcid.org/0000-0003-0284-471X)
Institutions
- Monash University Malaysia (MY)
- The University of Sydney (AU)
- University Malaya Medical Centre (MY)
- Translational Research Institute (AU)
- Université Libre de Bruxelles (BE)
- The University of Queensland (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Princess Alexandra Hospital (AU)
- University of Malaya (MY)
- Mater Research (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1038/s41467-025-58319-y
- Citations
- 16
- Primary Topic
- Gut microbiota and health
- Type
- article
- Field-Weighted Citation Impact
- 12.90