Liraglutide and Dapagliflozin Synergistically Reshape Gut Microbiota and Metabolic Profiles to Ameliorate Type-2 Diabetes in Mice

Background: Type-2 diabetes mellitus (T2DM) poses a formidable global health challenge, characterized by persistent hyperglycemia resulting from insulin resistance and progressive β-cell dysfunction. Liraglutide (LIRA), a GLP-1 receptor agonist, and dapagliflozin (DAPA), an SGLT2 inhibitor, are established therapies with complementary mechanisms. However, the potential synergy of their combination, particularly through modulation of the gut microbiota and host metabolism, remains incompletely understood. To elucidate the gut microbiota–metabolite axis underlying the therapeutic effects of combination therapy in T2DM, we explored the interplay between β-cell function, fecal microbiota composition, and microbial metabolites. Methods: A T2DM mouse model was induced by a high-fat diet and streptozotocin. Mice were treated for 4 weeks with LIRA, DAPA, or their combination (COM). We assessed glycemic control, insulin sensitivity, pancreatic islet morphology, serum biochemistry, gut microbiota (shotgun metagenomic sequencing), and plasma metabolome (nontargeted metabolomics). Integrated multiomics analysis was performed to elucidate microbiota–metabolite interactions. Results: Combination treatment demonstrated superior efficacy compared to monotherapies, resulting in significantly greater improvements in body weight, glucose tolerance, insulin sensitivity, lipid profiles, and liver function. Histologically, COM most effectively restored pancreatic islet architecture, increased β-cell mass, and normalized α/β-cell ratio. Metagenomic analysis revealed that COM induced a unique and restorative remodeling of the gut microbiota, distinct from monotherapies. This was characterized by suppression of pathobionts (e.g., Klebsiella and Enterorhabdus) and enrichment of beneficial taxa (e.g., Akkermansia, Lactobacillus, and Faecalibaculum). Metabolomics profiling showed that COM extensively normalized the diabetic plasma metabolome. Key altered pathways included tryptophan metabolism, sphingolipid metabolism, and branched-chain amino acid degradation. Integrated correlation analysis unveiled significant associations between specific microbial genera and host metabolites, suggesting a functional gut microbiota–metabolite axis underpinning the synergistic benefits. Conclusions: The combination of liraglutide and dapagliflozin exerts synergistic antidiabetic effects that extend beyond glycemic control to encompass pancreatic protection and systemic metabolic improvement. This synergy is mechanistically linked to collaborative remodeling of the gut ecosystem and consequent normalization of host metabolic pathways. Our findings provide a novel rationale for this combination therapy and highlight the gut microbiota as a pivotal target for T2DM management.