SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome
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Date
2025
Authors
Tillett, B.J.
Dwiyanto, J.
Secombe, K.R.
George, T.
Zhang, V.
Anderson, D.
Duggan, E.
Giri, R.
Loo, D.
Stoll, T.
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Journal article
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Nature Communications, 2025; 16(1):2893-1-2893-20
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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, Emma E. Hamilton-Williams
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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.
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© The Author(s) 2025. This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/.