Gut microbiota regulate stress resistance by influencing microglia-neuron interactions in the hippocampus. Stress resistance in mice is associated with higher levels of Lactobacillus and Akkermansia in the gut, and lower levels of Bacteroides, Alloprevotella, Helicobacter, Lachnoclostridium, Blautia, Roseburia, Colidextibacter, and Lachnospiraceae NK4A136. Stress-sensitive mice show increased intestinal permeability, stronger immune responses, and higher levels of pro-inflammatory cytokines, along with more extensive microglial activation and abnormal microglia-neuron interactions in the hippocampus. Transplanting fecal microbiota from stress-sensitive mice into naive ones impairs hippocampal synaptic plasticity and increases depression-like behavior after stress exposure, while transplantation from stress-resistant mice protects microglia and preserves synaptic plasticity, reducing depression-like behavior. These findings suggest that gut microbiota influence stress resilience by regulating microglia-neuron interactions in the hippocampus. Stress resistance is linked to lower immune responses and stronger tight junctions in the colon, while stress sensitivity is associated with altered intestinal permeability and increased immune responses. Stress-sensitive mice also show higher microglial activation and altered microglia-neuron interactions in the hippocampus and prefrontal cortex. Stress-sensitive mice exhibit reduced synaptic plasticity in the hippocampus, while stress-resistant mice show enhanced synaptic plasticity. Fecal microbiota transplantation from stress-resistant mice promotes hippocampal synaptic plasticity and confers resistance to stress, while transplantation from stress-sensitive mice has the opposite effect. These results indicate that gut microbiota can influence stress-induced depression-like behaviors by modulating microglia-neuron interactions and synaptic plasticity in the hippocampus. The study highlights the importance of gut microbiota in stress resilience and suggests that modulating gut microbiota may be a potential therapeutic approach for stress-related disorders.Gut microbiota regulate stress resistance by influencing microglia-neuron interactions in the hippocampus. Stress resistance in mice is associated with higher levels of Lactobacillus and Akkermansia in the gut, and lower levels of Bacteroides, Alloprevotella, Helicobacter, Lachnoclostridium, Blautia, Roseburia, Colidextibacter, and Lachnospiraceae NK4A136. Stress-sensitive mice show increased intestinal permeability, stronger immune responses, and higher levels of pro-inflammatory cytokines, along with more extensive microglial activation and abnormal microglia-neuron interactions in the hippocampus. Transplanting fecal microbiota from stress-sensitive mice into naive ones impairs hippocampal synaptic plasticity and increases depression-like behavior after stress exposure, while transplantation from stress-resistant mice protects microglia and preserves synaptic plasticity, reducing depression-like behavior. These findings suggest that gut microbiota influence stress resilience by regulating microglia-neuron interactions in the hippocampus. Stress resistance is linked to lower immune responses and stronger tight junctions in the colon, while stress sensitivity is associated with altered intestinal permeability and increased immune responses. Stress-sensitive mice also show higher microglial activation and altered microglia-neuron interactions in the hippocampus and prefrontal cortex. Stress-sensitive mice exhibit reduced synaptic plasticity in the hippocampus, while stress-resistant mice show enhanced synaptic plasticity. Fecal microbiota transplantation from stress-resistant mice promotes hippocampal synaptic plasticity and confers resistance to stress, while transplantation from stress-sensitive mice has the opposite effect. These results indicate that gut microbiota can influence stress-induced depression-like behaviors by modulating microglia-neuron interactions and synaptic plasticity in the hippocampus. The study highlights the importance of gut microbiota in stress resilience and suggests that modulating gut microbiota may be a potential therapeutic approach for stress-related disorders.