Causal effect of air pollution on the risk of cardiovascular and metabolic diseases and potential mediation by gut microbiota

Background: Epidemiological studies have explored the relationship between air pollution and cardiovascular and metabolic diseases (CVMDs). Accumulating evidence has indicated that gut microbiota deeply affects the risk of CVMDs. However, the findings are controversial and the causality remains uncertain. To evaluate whether there is the causal association of four air pollutants with 19 CVMDs and the potential effect of gut microbiota on these relationships. Methods: Genetic instruments for particulate matter (PM) with aerodynamic diameter < 2.5 mu m (PM2.5), <10 mu m (PM10), PM2.5 absorbance, nitrogen oxides (NOx) and 211 gut microbiomes were screened. Univariable Mendelian randomization (UVMR) was used to estimate the causal effect of air pollutants on CVMDs in multiple MR methods. Additionally, to account for the phenotypic correlation among pollutant, the adjusted model was constructed using multivariable Mendelian randomization (MVMR) analysis to strength the reliability of the predicted associations. Finally, gut microbiome was assessed for the mediated effect on the associations of identified pollutants with CVMDs. Results: Causal relationships between NOx and angina, heart failure and hypercholesterolemia were observed in UVMR. After adjustment for air pollutants in MVMR models, the genetic correlations between PM2.5 and hypertension, type 2 diabetes mellitus (T2DM) and obesity remained significant and robust. In addition, genus-ruminococcaceae-UCG003 mediated 7.8 % of PM2.5-effect on T2DM. Conclusions: This study firstly provided the genetic evidence linking air pollution to CVMDs and gut microbiota may mediate the association of PM2.5 with T2DM. Our findings highlight the significance of air quality in CVMDs risks and suggest the potential of modulating intestinal microbiota as novel therapeutic targets between air pollution and CVMDs.