Although the gut microbiota has been strongly implicated in the development of depression, its precise molecular mechanisms are still poorly understood. This study aimed to clarify the relationship between gut microbial alterations, fluctuations in neurotransmitters, and inflammatory responses in a murine model of depression. A chronic social defeat stress (CSDS) paradigm was used to induce depressive-like states. Fecal samples were analyzed for microbial composition and neurotransmitter levels, while neurotransmitters were also assessed in colon tissue, blood, and hippocampus. Inflammatory mediators were quantified in the hippocampus. After identifying a key neurotransmitter of interest, an intervention study was conducted to investigate its therapeutic potential in mitigating depressive symptoms. The analysis revealed that six gut microbial genera differed between groups, fourteen neurotransmitters altered along the gut–brain axis, and two hippocampal cytokines—interleukin-1β (IL-1β) and interleukin-6 (IL-6)—with significant changes in the depressed mice. Strong correlations emerged between altered microbial taxa, neurotransmitter profiles, and the expression of IL-1β and IL-6. Notably, 3-O-Methyldopa (3-OMDP) showed consistent decreases in feces, colon, circulation, and hippocampus, and was closely associated with Limosilactobacillus abundance and IL-1β levels. 3-OMDP administration alleviated depressive-like behaviors and normalized hippocampal IL-1β and IL-6 levels. The findings suggest that gut microbes may influence neuroinflammation through neurotransmitter modulation, thereby contributing to depressive pathophysiology. A potential mechanistic route, the Limosilactobacillus–3-OMDP–IL-1β/IL-6 axis, was identified, with 3-OMDP showing therapeutic promise for the treatment of depression.
