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

ABSTRACT

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.