Lactoferrin mitigates high-fat high-sugar-induced depressive-like behaviors in mice by regulating microglia homeostasis

Depression is a prevalent mental disorder. This study aims to investigate the effects of lactoferrin (Lf) on high-fat high-sugar-induced depressive-like behaviors in mice and its underlying mechanisms. Mice were fed a Western-style diet (WD) to induce depressive-like behaviors and divided into control, WD, and Lf intervention groups (Lf administered intragastrically at 500 mg/kg for 16 weeks). Behavioral tests and brain tissue analysis were conducted to assess depressive-like behaviors, inflammation levels, microglia activation and phagocytic capacity. WD-fed mice exhibited depressive-like behaviors, elevated pro-inflammatory cytokines, and microglia overactivation. Lf intervention reduced cytokine levels, improved microglia morphology, inhibited overactivation, shifted microglia polarization from M1 to M2, inhibited apoptosis, and enhanced phagocytic capacity for apoptotic neutrophils. Thus, Lf alleviates WD diet-induced depressive-like behaviors in mice by reducing neuroinflammation, inhibiting microglia overactivation, and enhancing their phagocytic function.