Gut microbiota mediates semaglutide attenuation of diabetes-associated cognitive decline

Diabetes-associated cognitive decline (DACD), characterized by cognitive impairment, is a serious complication of diabetes mellitus (DM). Research has shown that semaglutide, a novel glucagon-like peptide-1 receptor agonist, has neurotrophic and neuroprotective properties. However, a comprehensive understanding of the specific effects and underlying mechanisms of semaglutide treatment in patients with DACD remains lacking. In this study, we evaluated the potential of semaglutide to alleviate DACD in mice with DM. Eight-week-old mice fed a high-fat diet with streptozotocin-induced DM were subcutaneously injected with semaglutide (30 ​nmol/kg qd) for 12 weeks. Semaglutide administration significantly alleviated cognitive impairment, inhibited hippocampal neuron loss, improved the hippocampal synaptic ultrastructure, and effectively mitigated neuroinflammation. Furthermore, semaglutide treatment increased the relative abundances of g_Alistipes, g_norank_f_Eubacterium_coprostanoligenes, g_Bacteroides, and g_Parabacteroides, while decreasing the relative abundances of g_ faecalibaculum, g_Colodertribacter, g_GCA-900066575, g_Erysipelatoclostridium, and g_norank_f_Lachnospiraceae. Semaglutide also induced alterations in fecal and serum metabolites, as well as transcriptomic changes in brain tissue, with significant common enrichment in neuroactive ligand-receptor interactions. Furthermore, strong correlations were observed among semaglutide-affected genes, metabolites, and microbiota, as assessed by correlation analysis and integrative modeling. In conclusion, these findings suggest a correlation between the protective effects of semaglutide against DACD and the microbiota-gut-brain axis.