Ultrafine particulate matter exposure induces gut microbiota dysbiosis together with ER stress in the liver and worsened atherosclerosis

Air pollution exposure is associated with increased cardiovascular morbidity and mortality worldwide. Previous studies provide a causal relationship between exposure to particulate matter (PM) and atherosclerosis development. We have previously demonstrated increased aortic atherosclerosis and adverse metabolic effects in hyperlipidemic mice exposed to ambient ultrafine PM. However, the underlying mechanisms by which ambient PM promotes systemic effects leading to worsened atherosclerosis remain unknown. We have recently shown that the gut microbiota composition was altered in mice exposed to re-aerosolized PM in the ultrafine-size range for 10 weeks. We hypothesized that sub-chronic exposure to ultrafine PM induces gut dysbiosis in association with systemic prooxidative effects and atherosclerotic lesion development. Male apolipoprotein E knockout (ApoE^-/-) mice were fed a chow diet and exposed to re-aerosolized PM, highly enriched in particles in the ultrafine-size range (ultrafine PM) vs. filtered air (FA) by inhalation (6 h/day, 3 days/week for 10 weeks). Ultrafine PM-exposed mice exhibited marked differences in the gut microbiota composition, which significantly associated with worsened atherosclerotic lesions in the innominate artery and aorta. Ultrafine PM-exposed mice also displayed significantly elevated levels of short chain fatty acids (SCFAs) in the feces, malondialdehyde (MDA) content in the liver and upregulation of hepatic antioxidant and endoplasmic reticulum (ER) stress response genes, all of which correlated with changes in the gut microbiota composition. In conclusion, inhaled PM in the ultrafine-size range induced changes in the gut microbiota composition and its metabolites, which correlated with systemic prooxidative effects, hepatic ER stress and worsened atherosclerosis.