Abstract 517: Diesel Exhaust Induces Gut Dysbiosis Along With Reduced Fecal Acetate Levels And Altered Lipid Metabolism

Ambient air pollution exposure leads to increased cardiovascular morbidity and mortality. Previous studies support a causal link between particulate matter (PM) exposure and cardiometabolic effects including atherosclerosis. We have previously reported that whole diesel exhaust (DE) exposure for 16 weeks led to increased hepatic triglycerides (TG), 9- and 13-hydroxyoctadecadienoic acid (HODEs), plasma cholesterol and TG in apolipoprotein E -/- (ApoE) mice. Furthermore, gut microbiota composition was altered in mice exposed to ambient ultrafine particles by oral gavage for 10-weeks, that significantly associated with atherogenic lipid metabolites. Thus, we hypothesized that chronic exposure to DE leads to dysbiosis that could likely mediate oxidative and metabolic effects in the liver. Male ApoE -/- mice at 31 weeks of age were randomly assigned to two groups (n=10/group) exposed to either DE or filtered air (FA) for 16 weeks (6 hours/day, 5 days/week). 16S sequencing of the cecum exhibited significant differences in the abundance of bacterial taxa, as well as alpha and beta diversity indices of the DE-exposed gut microbiome vs. FA (p<0.05). There were also significant positive associations between these cecum bacterial species and plasma and hepatic lipids. Furthermore, DE-exposed mice had significantly elevated mRNA and protein levels of hepatic 12-lipoxygenase (12-LO). Interestingly, DE-exposed mice showed markedly reduced fecal acetate levels that significantly associated with lipids and cecal microbiome. A direct effect of short chain fatty acids on hepatocytes was observed after treatment of HepG2 cells with whole DE particles (DEP) together with acetate, which significantly inhibited 12-LO mRNA expression as compared to DEP alone. In conclusion, DE inhalation led to marked alterations in cecal microbiota and fecal acetate, which associated with liver 9- and 13-HODEs as well as plasma cholesterol and TG. Acetate may exert a protective role against the pro-oxidative effects induced by DE exposure. Additional work is required to determine the mechanisms how changes in gut microbiota could lead to pro-oxidative effects in the liver, hepatic steatosis and dyslipidemia, and whether those include the production of acetate in the intestines.