ObjectiveMicroecological and metabolic disorders of the gut may be involved in the pathogenesis of generalized anxiety disorder (GAD), but clinical multi-omics evidence of this is lacking. Our study aimed to investigate characteristic alterations in the gut microbiota and plasma metabolome of patients with GAD and evaluate their clinical diagnostic value.Patients and MethodsNinety subjects (60 patients with GAD and 30 healthy volunteers) were included. We employed 16S rRNA gene sequencing to characterize the gut microbiota and targeted liquid chromatography-mass spectrometry to analyze plasma metabolomic profiles.ResultsGAD was associated with increased abundances of Actinobacteria, Bacteroidetes, and Escherichia-Shigella and decreased abundances of Firmicutes, Roseburia, Bifidobacterium, and Prevotellaceae_Prevotella. Metabolomic analysis revealed 19 differential metabolites (upregulated in GAD: e.g. glutamic acid, cortisol; downregulated in GAD: e.g. gamma-aminobutyric acid, serotonin). Enriched metabolic pathways included phenylalanine, tyrosine, and tryptophan biosynthesis; alanine, aspartate, and glutamate metabolism; and the biosynthesis of unsaturated fatty acids. Notably, microbiome-metabolome combined analysis revealed a significant correlation between intestinal flora disorders and changes in the plasma metabolic profile. The diagnostic model constructed based on the combined omics data exhibited excellent discriminatory efficacy, with areas under curve of 0.710, 0.986, and 0.997 for the microbiome, metabolome, and combined model, respectively.ConclusionThis study revealed the characteristic gut microbiome-plasma metabolome covariation pattern of GAD and identified biomarker combinations with potential diagnostic value. The identified biomarker group provides new insights into the gut-brain axis mechanism of GAD, providing important theoretical support for clarifying the pathogenesis of GAD and developing precise diagnosis strategies.