Caffeine Intake is Associated with Reduced Risk of Obesity-Related Asthma through a Gut Microbiota-Mediated Genetic Mechanism

Background Obesity-related asthma (OB-AS) is characterized by a suboptimal response to standard therapies and an elevated risk of refractory asthma. While caffeine demonstrates protective associations against both asthma and obesity, its role in OB-AS remains unclear. Methods A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (2007–March 2020). Weighted multiple regression and restricted cubic spline models were employed to assess the relationship between caffeine intake and OB-AS risk. A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal relationship between coffee consumption and OB-AS risk, followed by a mediation analysis to examine the gut microbiota’s role. Additionally, core genes of caffeine's effect on OB-AS were identified to explore underlying biological mechanisms. Results After screening, 3751 asthma cases and 27 935 non-asthma controls were included. Caffeine intake was inversely correlated with OB-AS risk (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.70–0.97, P = 0.020). A significant non-linear association between caffeine intake and OB-AS risk was observed among males (P for non-linearity = 0.009). MR analysis confirmed a causal association between coffee consumption and reduced OB-AS risk (inverse-variance weighted method: OR = 0.133, 95% CI = 0.025–0.712, P = 0.019). Mediation analysis revealed that Collinsella mediated 14.9% of this association. We identified 42 core genes associated with caffeine's effect on OB-AS, with enrichment observed in corticosteroid response pathways. Conclusions Caffeine intake demonstrates a protective effect against OB-AS risk, partially mediated by Collinsella. It is hypothesized that caffeine might influence OB-AS via corticosteroid response pathways.