Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

Vascular dysfunction represents a critical preclinical step in the development of cardiovascular disease. We examined the role of the gut microbiota in the development of obesityrelated vascular dysfunction. Male C57BL/6J mice were fed either a standard diet (SD) (n = 12) or Western diet (WD) (n = 24) for 5 mo. after which time WD mice were randomized to receive either unsupplemented drinking water or water containing a broad-spectrum antibiotic cocktail (WD + Abx) (n = 12/group) for 2 mo. Seven months of WD caused gut dysbiosis, increased arterial stiffness (SD 412.0 +/- 6.0 vs. WD 458.3 +/- 9.0 cm/s. P < 0.05) and endothelial dysfunction (28% decrease in max dilation. P < 0.05), and reduced L-NAME-inhibited dilation. Vascular dysfunction was accompanied by significant increases in circulating LPS-binding protein (LBP) (SD 5.26 +/- 0.23 vs. WD 11 +/- 0.86 mu g/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 +/- 0.25 vs. WD 7.09 +/- 1.07 mu g/ml, P < 0.05): aortic expression of phosphorylated nuclear factor-kB (p-NF-KB) (P < 0.05): and perivascular adipose expression of NADPH oxidase subunit p67phox (P < 0.05). Impairments in vascular function correlated with reductions in Bifidobacterium spp. Antibiotic treatment successfully abrogated the gut microbiota and reversed WD-induced arterial stiffness and endothelial dysfunction. These improvements were accompanied by significant reductions in LBP. IL-6, p-NF-KB, and advanced glycation end products (AGEs), and were independent from changes in body weight and glucose tolerance. These results indicate that gut dysbiosis contributes to the development of WD-induced vascular dysfunction, and identify the gut microbiota as a novel therapeutic target for obesity-related vascular abnormalities.