The dual-sensitive period gut-brain crosstalk, neuroinflammation, and the biological roots of adolescent depression

The increasing burden of adolescent depression underscores the need to identify developmental vulnerabilities and biologically informed strategies for prevention and intervention. This review synthesizes evidence supporting adolescence as a "dual-sensitive period" during which concurrent maturation of the brain and gut microbiota may create a window of susceptibility to perturbations of the microbiota-gut-brain axis (MGBA). During this stage, dysregulated gut-brain communication may contribute to low-grade inflammation, impaired barrier function, altered HPA-axis responsivity, and changes in tryptophan-, short-chain fatty acid-, and neurotransmitter-related metabolism. In particular, inflammatory signaling and microglial activation may link gut dysbiosis to maladaptive synaptic remodeling, although direct causal evidence in adolescents remains limited. The review also examines the "microgenderome" framework as a lens for understanding potential sex-related differences in depression, and considers environmental exposures such as diet, antibiotics, and sleep disruption as perturbing influences on MGBA homeostasis. Translationally, psychobiotics, dietary optimization, and related microbiota-informed approaches may hold promise as adjunctive or preventive strategies, but they are not yet established standalone treatments for adolescent depression. Future studies integrating longitudinal design, multi-omics profiling, biomarkers, and adolescent-specific intervention trials will be essential to clarify causality and guide precision prevention.