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

Tillett, BJ; Dwiyanto, J; Secombe, KR; George, T; Zhang, V; Anderson, D; Duggan, E; Giri, R; Loo, D; Stoll, T; Morrison, M; Begun, J; Hill, MM; Gurzov, EN; Bell, KJ; Saad, S; Barlow, CK; Creek, DJ; Chong, CW; Mariño, E; Hamilton-Williams, EE

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

Tillett, BJ Dwiyanto, J Secombe, KR George, T Zhang, V Anderson, D Duggan, E Giri, R Loo, D Stoll, T Morrison, M Begun, J Hill, MM Gurzov, EN Bell, KJ Saad, S Barlow, CK Creek, DJ Chong, CW Mariño, E Hamilton-Williams, EE

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Nat Commun, 2025, 16, (1), pp. 2893
Issue Date:: 2025-03-25

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Field	Value	Language
dc.contributor.author	Tillett, BJ
dc.contributor.author	Dwiyanto, J
dc.contributor.author	Secombe, KR
dc.contributor.author	George, T
dc.contributor.author	Zhang, V
dc.contributor.author	Anderson, D
dc.contributor.author	Duggan, E
dc.contributor.author	Giri, R
dc.contributor.author	Loo, D
dc.contributor.author	Stoll, T
dc.contributor.author	Morrison, M
dc.contributor.author	Begun, J
dc.contributor.author	Hill, MM
dc.contributor.author	Gurzov, EN
dc.contributor.author	Bell, KJ
dc.contributor.author	Saad, S
dc.contributor.author	Barlow, CK
dc.contributor.author	Creek, DJ
dc.contributor.author	Chong, CW
dc.contributor.author	Mariño, E
dc.contributor.author	Hamilton-Williams, EE
dc.date.accessioned	2026-03-12T05:55:24Z
dc.date.available	2025-03-14
dc.date.available	2026-03-12T05:55:24Z
dc.date.issued	2025-03-25
dc.identifier.citation	Nat Commun, 2025, 16, (1), pp. 2893
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/194309
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-025-58319-y
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Metabolome
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Mice
dc.subject.mesh	Fatty Acids, Volatile
dc.subject.mesh	Homeostasis
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Adult
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Intestinal Mucosa
dc.subject.mesh	Fecal Microbiota Transplantation
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Metabolomics
dc.subject.mesh	Immunity, Mucosal
dc.subject.mesh	Intestinal Mucosa
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Fatty Acids, Volatile
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Immunity, Mucosal
dc.subject.mesh	Homeostasis
dc.subject.mesh	Adult
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Metabolomics
dc.subject.mesh	Metabolome
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Fecal Microbiota Transplantation
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Metabolome
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Mice
dc.subject.mesh	Fatty Acids, Volatile
dc.subject.mesh	Homeostasis
dc.subject.mesh	Diabetes Mellitus, Type 1
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Adult
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Intestinal Mucosa
dc.subject.mesh	Fecal Microbiota Transplantation
dc.subject.mesh	Mice, Inbred NOD
dc.subject.mesh	Metabolomics
dc.subject.mesh	Immunity, Mucosal
dc.title	SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome.
dc.type	Journal Article
utslib.citation.volume	16
utslib.location.activity	England
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2026-03-12T05:55:19Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	16
utslib.citation.issue	1

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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http://hdl.handle.net/10453/194309