Abstract
BACKGROUND: This study investigated the prospective associations between adherence to a Healthy Low-Carbohydrate Diet (HLCD) and incident depression, anxiety, and their comorbidity, and explored the mediating role of inflammation. METHODS: This cohort study analyzed 173,207 participants from the UK Biobank. The HLCD score was calculated based on the intake of total carbohydrate, vegetable protein, and unsaturated fat. Cox proportional hazards models and restricted cubic splines were used to examine linear and non-linear associations, respectively. Mediation analyses assessed the contribution of inflammatory markers. RESULTS: Compared with the lowest HLCD score group (scores 0-6), the lowest risks were observed in the third group (scores 13-18) for depression (hazard ratio [HR]: 0.705, 95% confidence interval [CI]: 0.626-0.793), the fifth group (scores 25-30) for anxiety (HR: 0.791, 95% CI: 0.688-0.909), and the second group (scores 7-12) for comorbidity (HR: 0.673, 95% CI: 0.555-0.816). Restricted cubic splines revealed non-linear, "L"-shaped associations between HLCD scores and the risks of all three outcomes (all P for non-linearity < 0.05). Mediation analyses indicated that white blood cell count, C-reactive protein, and the low-grade chronic inflammation score played statistically significant but weak mediating roles in these associations. CONCLUSIONS: Higher adherence to an HLCD is associated with reduced risks of depression, anxiety, and their comorbidity, potentially following a non-linear threshold pattern. While inflammation acts as a mediator, its modest contribution suggests that other biological mechanisms may also play pivotal roles in this protective relationship.