Mayonnaise intake and depression: dose-response in humans and neurobehavioral and molecular mechanisms in zebrafish

Background Depression is the leading global cause of disability, yet dietary research has overlooked condiments as a concentrated, habitual exposure. Emulsified high-fat condiments may drive neuroinflammation independently of total caloric intake, offering a feasible prevention target, but their mental health impact remains unexamined. Methods This study comprised two phases: (1) A cross-sectional analysis of 2423 adults from NHANES 2005-2006, examining associations between condiment intake frequency and PHQ-9 scores using negative binomial regression; (2) A zebrafish experiment where adult fish were exposed to 0%, 1%, 5%, or 10% mayonnaise for 4 weeks, followed by behavioral assessment and qPCR analysis of hub genes identified by network toxicology. Results In NHANES, ≥3 times/week intake of sugar/honey (aRR = 1.22, 95%CI: 1.02-1.45), margarine (1.19, 1.01-1.41), butter (1.30, 1.09-1.55), and mayonnaise (1.37, 1.12-1.66) was associated with higher PHQ-9 scores (all P < 0.05). Mayonnaise showed the strongest association. In zebrafish, mayonnaise dose-dependently altered depression-like behaviors, including reduced top exploration and increased freezing time ( P < 0.05). Network toxicology identified 81 shared targets between mayonnaise components (linoleic and elaidic acid) and depression, with PPARA , SRC , PTGS2 , IL6 , and ESR1 as central hubs. qPCR showed dose-dependent upregulation of ppara , ptgs2a , il6 , and esr1 in zebrafish brain ( P < 0.05). Conclusions Mayonnaise and comparable emulsified high-fat condiments are independently associated with depressive symptoms, with amplified risk in specific vulnerable subgroups. Zebrafish behavioral and molecular data provide hypothesis-generating mechanistic plausibility. Targeted condiment reduction thus represents an actionable, low-barrier strategy for depression prevention.