Splenic γδ T cells are required for vagotomy-mediated protection against LPS-induced depression- and anxiety-like behaviors through the spleen-brain axis.

Depression is increasingly linked to inflammation, yet its underlying mechanisms remain only partially understood. In this study, we examined the role of the vagus nerve-mediated spleen-brain axis-focusing on γδ T cells and gut microbiota-in modulating lipopolysaccharide (LPS)-induced depression- and anxiety-like behaviors in mice. Subdiaphragmatic vagotomy (SDV) was performed to evaluate its effects on behavioral, immunological, and microbiological parameters. Two weeks after SDV, mice were administered LPS (1.0 mg/kg) or saline, and their behaviors were assessed using the open field and forced swimming tests. SDV significantly prevented LPS-induced anxiety- and depression-like behaviors, mitigated body weight loss and splenomegaly, and reduced elevated blood interleukin-6 (IL-6) levels. Moreover, SDV prevented LPS-induced decreases in the expression of key synaptic proteins (PSD-95 and GluA1) in the prefrontal cortex. Flow cytometry revealed that LPS disrupted immune homeostasis by increasing macrophages in both the spleen and blood, and by altering γδ T cell distributions-effects that were normalized by SDV. Gut microbiota analysis further demonstrated that SDV prevented LPS-induced changes in bacterial diversity and composition. Notably, administration of anti-γδ TCR antibodies significantly counteracted the beneficial effects of SDV, implicating peripheral γδ T cells as critical mediators in this protective process. These findings suggest that splenic γδ T cells are essential for SDV-induced protection against LPS-driven behavioral and inflammatory deficits.