Abstract
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a highly prevalent metabolic disorder with increasing global incidence, linked to gut microbiota dysbiosis. This study investigated the effects of semaglutide, a long-acting GLP-1 receptor agonist, on gut microbiota composition and metabolic profiles in 15 Chinese patients with T2DM poorly controlled by metformin. METHODS: Participants received semaglutide for 12 weeks, with fecal and blood samples collected before and after treatment. 16S rRNA gene sequencing revealed significant changes in gut microbiota diversity and composition after semaglutide treatment. RESULTS: Alpha diversity indices increased, though not significantly, while beta diversity analysis showed structural shifts. At the phylum level, Firmicutes decreased, while Bacteroidota, Actinobacteriota and Proteobacteria increased. At the genus level, beneficial bacteria like Bifidobacterium increased, while potentially harmful genera like Klebsiella decreased. Metabolomic analysis identified 362 differentially expressed metabolites, with key pathways affected including Fc epsilon RI signaling, vascular smooth muscle contraction, and linoleic acid metabolism. Clinically, semaglutide improved glycemic control, reduced body weight, BMI and lipid. Significant correlations were observed between gut microbiota species, metabolites, and clinical indices such as BMI, HbA1c and lipid profiles. CONCLUSION: Taken together, this study suggested that semaglutide's therapeutic benefits may be mediated through modulation of the gut microbiota and associated metabolic pathways, highlighting the potential for targeting the gut microbiome in diabetes management.