par Tillett, Bree J;Dwiyanto, Jacky;Secombe, Kate KR;George, Thomas;Zhang, Vivian;Anderson, Dovile;Duggan, Emily;Giri, Rabina;Loo, Dorothy;Stoll, Thomas;Morrison, Mark;Begun, Jakob;Hill, Michelle M;Gurzov, Esteban Nicolas 
;Bell, Kirstine J;Saad, Sonia;Barlow, Christopher CK;Creek, Darren DJ;Chong, Chun Wie;Mariño, Eliana;Hamilton-Williams, Emma E.E.
Référence Nature communications, 16, 1, page (2893)
Publication Publié, 2025-03-01
;Bell, Kirstine J;Saad, Sonia;Barlow, Christopher CK;Creek, Darren DJ;Chong, Chun Wie;Mariño, Eliana;Hamilton-Williams, Emma E.E.Référence Nature communications, 16, 1, page (2893)
Publication Publié, 2025-03-01
Article révisé par les pairs
| Résumé : | 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. |
