Semaglutide Remodels the Gut Microbiome Beyond Its Appetite‐Suppressing Action: Sex‐Specific Gut‐Brain Axis Implications

ABSTRACT

The gut microbiome communicates bidirectionally with the brain and peripheral metabolic organs to regulate appetite and body weight. Semaglutide (SEMA), a GLP‐1 receptor agonist, produces robust weight loss by reducing food intake, largely through brain GLP‐1 receptors, yet whether its effects on the gut microbiome are secondary to this centrally driven hypophagia is poorly understood. Given the profound impact of SEMA on food intake and body weight, we propose that SEMA treatment reshapes gut microbial composition and that these shifts are correlated with metabolic outcomes. Diet‐induced obese rats received a 4‐week SEMA treatment and gut microbial composition was analyzed using 16S rRNA gene sequencing. To differentiate the impact of reduced food intake associated with SEMA from other effects of the drug treatment on the gut microbiome, a pair‐fed to SEMA group was tested. SEMA significantly reduced body weight gain and food intake in both sexes. Significant SEMA‐induced changes in microbial richness and evenness were detected. Linear discriminant analysis Effect Size (LEfSe) identified enrichment of Firmicutes taxa—particularly members of the Clostridiaceae family—in SEMA‐treated rats, whereas controls showed greater representation of Bacteroidota taxa. Sex‐specific associations between host metabolic parameters and gut microbial composition were also identified. These findings demonstrate profound, not necessarily health positive, partly sex‐specific gut microbial community shifts following GLP‐1 analogue treatment. Many of the changes in the gut microbiota were not simply driven by the decreased food intake. Thus, GLP‐1 analogue treatment engages the gut microbiome through both food intake–dependent (brain‐to‐gut) and intake‐independent pathways.