Gut Microbiota from GAD patients with divergent early pharmacological responses transmits anxiety-like behaviors and distinct metabolic profiles in recipient mice.

The gut microbiota is implicated in the pathogenesis of generalized anxiety disorder (GAD), but whether microbial differences between GAD patients with remission (R-GAD) and those with poor early treatment response (P-GAD) causally contribute to variable therapeutic outcomes remains unclear. Here, we transplanted feces from R-GAD and P-GAD patients into antibiotic-pretreated male C57BL/6 mice. P-GAD recipients showed heightened anxiety-like behaviors (reduced central zone time in open field test and shorter open-arm duration in elevated plus-maze), lower gut microbial α-diversity, and distinct β-diversity. Linear discriminant analysis effect size (LEfSe) detected 155 differentially abundant taxa. Genera enriched in R-GAD mice included Blautia, Roseburia, and Lachnospiraceae_NK4A136_group, whereas P-GAD mice were characterized by higher abundances of Bacteroides, Ileibacterium, and Allobaculum. Metabolomic analysis revealed that P-GAD mice had higher levels of neurotoxic tryptophan metabolite indoxyl-β-D-glucuronide (Indoxyl-GlcA) and lower levels of neuroprotective metabolites (indole-3-lactic acid, ILA; L-kynurenine, L-Kyn). Among 34 fatty acids, only C22:5 N3 (docosapentaenoic acid, DPA) was significantly lower in P-GAD mice. Correlation analyses further revealed that genera enriched in P-GAD mice were positively associated with pro-anxiety behaviors and neurotoxic metabolites, whereas those enriched in R-GAD mice showed the opposite trends. These findings suggest that gut microbiota from GAD patients with poor early treatment response may transmit anxiety-like phenotypes and metabolic disturbances in mice, providing a rationale for microbiota-targeted interventions in GAD.