Natural polysaccharides modulate the microbiota-gut-brain axis through multiple targets: A new perspective on the...

Depression is increasingly understood as a systemic disorder involving microbiota-gut-brain axis (MGBA) dysfunction rather than only central monoaminergic imbalance. Gut microbial dysbiosis, barrier disruption, immune inflammation, metabolic disturbance, oxidative stress, mitochondrial injury, and impaired neuroplasticity jointly drive depressive pathology. Natural polysaccharides offer a structurally diverse class of MGBA-oriented adjunctive candidates. Their effects are governed not simply by source or total sugar content, but by monosaccharide composition, glycosidic linkages, branching architecture, and molecular-weight distribution. These features determine microbial accessibility, fermentation kinetics, metabolite output, mucus and epithelial interactions, receptor recognition, and possible epithelial uptake, thereby defining distinct routes of MGBA regulation. Through these structure-dependent routes, natural polysaccharides may alleviate depression-related abnormalities by rebuilding gut microbial ecology, reprogramming short-chain fatty acids, tryptophan-derived indoles and bile acid metabolism, restoring intestinal and blood-brain barrier integrity, suppressing neuroimmune activation and oxidative injury, supporting mitochondrial homeostasis and promoting BDNF-TrkB-related neurogenesis and synaptic plasticity. This Review highlights structure-guided MGBA modulation and discusses translational challenges, including activity attribution, quality control, pharmacokinetics, and microbiome-dependent response variability for stratified, mechanism-guided adjunctive use.