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.