Excessive Dietary n‐6 Polyunsaturated Fatty Acids Aggravate Asthma via the Arachidonic Acid Pathway

This study aimed to evaluate the association between dietary n-6 PUFA intake and asthma risk and to investigate the underlying mechanisms using animal and cellular models. A cross-sectional analysis was conducted using data from 13 805 participants in the National Health and Nutrition Examination Survey (NHANES, 2003-2020). Weighted logistic regression, restricted cubic splines, and subgroup analyses were performed to assess the association between n-6 PUFA intake and asthma risk. In animal experiments, female C57BL/6 mice were intragastrically administered low-dose (50 mg/kg/day) or high-dose (500 mg/kg/day) linoleic acid (LA) followed by house dust mite (HDM)-induced allergic airway inflammation. Airway hyperresponsiveness, bronchoalveolar lavage fluid (BALF) cell counts, histopathology, and lung arachidonic acid (AA) levels were evaluated. In vitro, BEAS-2B human bronchial epithelial cells were treated with AA and interleukin-13 (IL-13), and the expression of Type 2 chemokines (CCL11, CCL24, and CCL26) was measured. In the NHANES population, dietary n-6 PUFA intake showed a nonlinear dose-response relationship with asthma risk in females, with a threshold of 21.13 g/day. Above this level, asthma risk increased significantly (OR per 1 g/day increase = 1.032, 95% CI: 1.015-1.049, p = 0.002). No significant association was observed in males. In the mouse model, high-dose LA, but not low-dose LA, significantly exacerbated HDM-induced airway hyperresponsiveness, eosinophilic inflammation, mucus secretion, and lung AA accumulation. In vitro, AA (100 μg/mL) significantly upregulated IL-13-induced CCL11 and CCL26 expression in BEAS-2B cells. High dietary n-6 PUFA intake is associated with an increased risk of asthma in a nonlinear, dose-dependent, and female-specific manner. High-dose linoleic acid promotes AA accumulation and aggravates Type 2 airway epithelial inflammation, suggesting that n-6 PUFAs act as metabolic regulators rather than simple nutrients. These findings highlight the importance of considering dietary fatty acid composition and individualized thresholds in asthma prevention and management.