Lactobacillus gasseri alleviates type 2 diabetes via modulation of gut microbiota-host metabolic networks

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterized by insulin resistance, dyslipidemia and inflammation. Although probiotics have shown potential in improving glycemic control in T2DM, the systemic mechanisms underlying their therapeutic effects remain largely unclear.

A high glucose-induced insulin-resistant zebrafish model was established to explore the interventional effects of Lactobacillus gasseri GDMCC AM63 (L. gasseri). Biochemical assays combined with untargeted metabolomics were used to comprehensively evaluate the efficacy of L. gasseri intervention.

L. gasseri intervention significantly reduced fasting blood glucose levels, inhibited the expression of pro-inflammatory cytokines (tnfα and il-6), and upregulated the anti-inflammatory cytokine il-10. Metabolomic profiling identified 210 shared annotated DAMs in pairwise comparisons (T2DM_vs_control (Ctrl) group, and L. gasseri intervention (LG)_vs_T2DM group), which were mainly involved in lipid, amino acid, and carbohydrate metabolism. Pathway enrichment analysis showed significant enrichment of glycerophospholipid, fructose-mannose, pentose phosphate, riboflavin, and linoleic acid metabolic pathways. After FDR correction, 27 shared annotated significant DAMs (SDAMs) were identified. Integrated metabolomics and network pharmacology analysis suggested that L. gasseri may exert a therapeutic effect on T2DM by indirectly regulating signaling pathways such as PI3K/Akt and JAK/STAT. Randomforest analysis highlighted 18R-Hepe and Azii as potential metabolic biomarkers with predictive value.

This study systematically investigated the metabolic regulatory mechanisms by which L. gasseri ameliorates T2DM, providing experimental evidence to support its potential as an effective interventional strategy for improving insulin resistance and related metabolic dysfunctions.