Unveiling the gut-vascular connection: Gut microbiota regulates cardiovascular toxicity induced by combined exposure to PM2.5 and high-fat diet via butyric acid/NLRP3 pathway.

Environmental particulate matter and dietary factors have been found to induce gut microbiota dysbiosis and exert an impact on cardiovascular toxicity. However, the underlying biological connections among them remain unclear. Our results indicated co-exposure to PM2.5 and high-fat diet (HFD) notably elevated blood pressure and blood lipid in mice and serum nitric oxide and endothelin-1 were abnormal. Meanwhile, vascular diameter and end-diastolic velocity (EDV) decreased, while resistance index (RI) increased. There was a synergistic effect of co-exposure on EDV and RI. Furthermore, significant damage to colon was observed. 16S rDNA sequencing of fecal microbiota indicated PM2.5 and HFD led to gut microbiota dysbiosis. Desulfovibrio was positively correlated with blood pressure, while Parabacteroides was negatively correlated. Fecal microbiota transplantation from donor mice exposed to hazardous substances successfully exacerbated cardiovascular toxicity in recipient mice. Further analysis of short chain fatty acids using metabolomics showed exposure to PM2.5 and HFD decreased serum butyric acid. Supplementation with sodium butyrate (SB) successfully alleviated the damage to cardiovascular system. Both in vivo and vitro experiments demonstrated SB supplementation significantly inhibited NLRP3 inflammasome. These findings indicate that modulating gut microbiota and its metabolite butyric acid may prevent the adverse cardiovascular effects of environmental PM2.5 exposure and HFD.