Postbiotic of Bifidobacterium breve i1088 alleviates type 2 diabetes by promoting GLP-1 secretion: identification of 5-hydroxyindoleacetic acid as a key active metabolite

Objective The pathogenesis of type 2 diabetes mellitus (T2DM) is intrinsically linked to the suboptimal secretion of glucagon-like peptide-1 (GLP-1). While postbiotics have emerged as a compelling therapeutic modality for metabolic modulation, the precise bioactive effectors and their underlying mechanisms remain largely elusive. This study aimed to evaluate the effect of Bifidobacterium breve i1088 ( B breve i1088) lysate on GLP-1 secretion and identify its key active molecules. Methods The GLP-1 secretory activity of i1088 lysate was assessed in human enteroendocrine NCI-H716 cells. Subsequently, the metabolic benefits of the lysate were validated in a T2DM mouse model. Untargeted metabolomics was employed to profile the bioactive substances of the lysate. Results In vitro, B breve i1088 lysate exhibited a robust, dose-dependent capacity to stimulate GLP-1 secretion. In vivo, high-dose lysate (HL) not only recapitulated the glucose and lipid-lowering and anti-inflammatory efficacy of live bacteria (LB), but also demonstrated superior stability. Mechanistically, HL treatment profoundly reprogrammed the intestinal incretin axis by upregulating preproglucagon ( GCG ) and proprotein convertase 1 ( PC1 ), thereby enhancing endogenous GLP-1 synthesis and preserving pancreatic islet function. Crucially, we identified 5-hydroxyindoleacetic acid (5-HIAA) as the pivotal bioactive signature within the B breve i1088 lysate. Cellular assays confirmed that 5-HIAA directly triggered GLP-1 release and upregulated the mRNA expression of both the GCG and PC1 genes, serving as a key molecular messenger in the B breve i1088-mediated metabolic recovery. Conclusion HL enhances GLP-1 synthesis via the upregulation of the GCG / PC1 pathway and alleviates T2DM, with 5-HIAA serving as a key functional metabolite in this postbiotic-mediated response. The potent efficacy of the B. breve i1088 lysate highlights its potential as an innovative postbiotic therapy for T2DM management.