This study investigated the role of the vagus nerve (VN) in mediating the effects of stress-induced gut microbiome (GM) changes on hippocampal plasticity and depressive-like behaviors in mice. Mice were subjected to unpredictable chronic mild stress (UCMS), and their fecal microbiota was transferred to healthy recipient mice. Some recipients underwent subdiaphragmatic vagotomy (Vx) before transplantation. Results showed that UCMS-derived GM activated the VN, altered neurotransmission pathways, reduced hippocampal neurogenesis, and induced neuroinflammation. Remarkably, Vx prevented these effects, indicating the VN's necessity in mediating GM's influence on brain function and behavior.