Semaglutide partially reshapes oral microbial dysbiosis and interferon-associated transcriptional programs in diabetic mice

Abstract Type 2 diabetes (T2D) is associated with alterations in the oral microenvironment, including microbial dysbiosis and host transcriptional changes. Whether antidiabetic therapies such as semaglutide modulate these alterations in a coordinated manner remains unclear. To investigate the association between semaglutide treatment and coordinated changes in oral microbiota and host transcriptional programs. 16S rRNA sequencing and bulk RNA-seq were performed on oral samples from WT, db/db, and semaglutide-treated db/db mice. Microbial diversity, taxonomic composition, gene expression, and integrative analyses were conducted. β diversity revealed clear separation between WT and db/db groups, with treated samples partially shifting toward the WT state, while α diversity showed no significant difference. The dysbiosis index was increased in db/db mice and reduced following treatment. At the genus level, Bacillus and Delftia decreased, whereas Streptococcus increased in db/db mice, with opposite trends after treatment. Transcriptomic analysis identified interferon-enriched and metabolic-associated gene clusters, with modulation of interferon- and antiviral-response pathways following treatment. Integration analyses demonstrated reorganization of gene-microbiota networks and significant correlations between cluster-specific transcriptional programs and dysbiosis. T2D is associated with coordinated alterations in oral microbiota and host transcription, and semaglutide treatment is accompanied by partial remodeling of these features.