TY  - JOUR
AB  - 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.
AU  - Tillett, BJ
AU  - Dwiyanto, J
AU  - Secombe, KR
AU  - George, T
AU  - Zhang, V
AU  - Anderson, D
AU  - Duggan, E
AU  - Giri, R
AU  - Loo, D
AU  - Stoll, T
AU  - Morrison, M
AU  - Begun, J
AU  - Hill, MM
AU  - Gurzov, EN
AU  - Bell, KJ
AU  - Saad, S
AU  - Barlow, CK
AU  - Creek, DJ
AU  - Chong, CW
AU  - Mariņo, E
AU  - Hamilton-Williams, EE
DA  - 2025/03/25
DO  - 10.1038/s41467-025-58319-y
JO  - Nat Commun
PB  - Springer Nature
PY  - 2025/03/25
SP  - 2893
TI  - SCFA biotherapy delays diabetes in humanized gnotobiotic mice by remodeling mucosal homeostasis and metabolome.
VL  - 16
Y1  - 2025/03/25
Y2  - 2026/04/30
ER  -