Abstract 165: Role of the Gut Microbiome in Obesity-Related Vascular Dysfunction

Abstract

Vascular dysfunction, characterized by arterial stiffness and endothelial dysfunction, represents an important link between obesity and cardiovascular disease. Deleterious changes to the gut microbiome, termed dysbiosis, are associated with obesity and may contribute to the development of vascular dysfunction by promoting systemic and arterial inflammation. We tested the hypothesis that antibiotic treatment in diet-induced obese mice would improve vascular function by suppressing potentially harmful gut-derived bacterial products to reduce dysbiosis-related inflammation. Male C57BL/6 mice were fed either a standard diet (SD) or Western diet (WD) for 5 months. Obese WD-fed mice were then randomized to receive 8 weeks of antibiotic treatment via drinking water. Arterial stiffness was measured via in vivo aortic pulse wave velocity and endothelial function assessed via ex vivo pressure myography in isolated mesenteric arteries. Plasma and arterial tissue samples were collected for measures of endotoxemia and inflammation and fecal samples were collected for microbial sequencing. Our results showed that mice fed a WD for 5 months had significantly higher body weight and arterial stiffness compared to SD. Antibiotic treatment significantly reduced arterial stiffness in WD-fed mice without affecting body weight. Endothelial function was impaired in WD-fed mice, whereas WD-Abx mice had similar endothelial function to SD-fed mice. Plasma levels of the pro-inflammatory cytokine IL-6 and endotoxemia marker LPS binding protein (LBP) were significantly increased in WD vs SD, but reduced in WD-Abx vs WD. Gut microbial suppression with antibiotic treatment was confirmed using quantitative PCR and ongoing analyses are being conducted to determine specific diet-induced changes to the composition of the gut microbiome. Overall, our results support the hypothesis that gut dysbiosis contributes the development of vascular dysfunction in obesity and provide evidence that a gut-targeted therapy can improve endothelial function and arterial stiffness in diet-induced obese mice. Future studies will further examine the mechanisms involved in, and help identify potential therapeutic targets for, obesity-related vascular dysfunction.