Gut microbiota correlating with glycerophospholipid metabolism dysregulation is associated with brain functional alterations in adolescent depression.

Gut microbiota dysbiosis has been linked to depression; however, evidence regarding this association in adolescents remains scarce, and the underlying molecular and neuropathological mechanisms are poorly understood. We conducted an integrative multi-omics study combining fecal metagenomic sequencing, serum untargeted metabolomics, resting-state fMRI, and spatial brain transcriptomics in 160 adolescents with depression (PT) recruited from multicenter cohort and 90 local healthy controls (HC) during the same period. Multimodal neuroimaging assessed spontaneous activity, functional connectivity, and structure-function coupling. Cross-omics association, mediation analyses, and machine learning were applied to identify mechanistic pathways and robust biomarkers. Adolescents with depression exhibited distinct gut microbial dysbiosis and pronounced disruption of glycerophospholipid metabolism. Multiple phospholipids and their metabolites were significantly altered and closely associated with differential microbial taxa. Neuroimaging revealed abnormal functional reorganization and regional structure-function decoupling, prominently involving the precuneus and precentral gyrus. Transcriptomic mapping demonstrated that brain regions showing the greatest functional alterations were enriched for genes related to phospholipid metabolism. Mediation analyses indicated that gut microbiota may influence depressive symptoms through glycerophospholipid metabolites and precentral gyrus dysfunction. A cross-validated multi-omics biomarker panel showed strong predictive performance for identifying patients with depression. These findings suggested glycerophospholipid metabolism may be as a key molecular interface linking gut microbial dysbiosis to brain network dysfunction in adolescents with depression, providing a multiscale framework for microbiota-informed stratification and prevention.