Beyond glycemic control: How semaglutide reshapes intestinal neuroception via transforming growth factor-β/brain-derived neurotrophic factor signaling hubs

Figure 1 Mechanism diagram. This mechanism diagram illustrates the core mechanism of semaglutide regulating the gut-brain axis: By activating the intestinal epithelial glucagon-like peptide-1 receptor, it inhibits glycogen synthase kinase-3β via the phosphatidylinositol 3-kinase/protein kinase B pathway to promote brain-derived neurotrophic factor transcription, while modulating the transforming growth factor-β/Smad pathway to improve inflammation and barrier function. Brain-derived neurotrophic factor exerts neuroprotective effects through tropomyosin receptor kinase B, remodeling enteric nervous system plasticity. In addition, the drug reshapes gut microbiota (e.g., Akkermansia, Bacteroides), increases short-chain fatty acids, inhibits harmful metabolites, indirectly modulates transient receptor potential vanilloid 1 and potassium channels, alleviates neuroinflammation, and connects to cognition via the vagal afferent pathway, achieving dual metabolic and neuroprotective effects. TRPV1: Transient receptor potential vanilloid 1; SCFA: Short-chain fatty acids; GPR43: G protein-coupled receptor 43; BDNF: Brain-derived neurotrophic factor; GLP-1R: Glucagon-like peptide 1 receptor; GLP-1: Glucagon-like peptide 1; PI3K/Akt: Phosphatidylinositol 3-kinase/protein kinase B; GSK-3: Glycogen synthase kinase 3; CREB: Cyclic adenosine monophosphate-response element-binding protein; TrkB: Tropomyosin receptor kinase B; TGF: Transforming growth factor; EMT: Epithelial-mesenchymal transition; EGC: Enteric glial cell; ENS: Enteric nervous system.