Suppression of gut dysbiosis reverses Western diet-induced vascular dysfunction

• Published in: American journal of physiology: endocrinology and metabolism Vol. 314; no. 5; pp. E468 - E477
• Main Authors: Battson, Micah L, Lee, Dustin M, Jarrell, Dillon K, Hou, Shuofei, Ecton, Kayl E, Weir, Tiffany L, Gentile, Christopher L
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2018
• Subjects: Abnormalities; Advanced glycosylation end products; Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Aorta; Body weight; Cardiovascular disease; Cardiovascular diseases; Diet; Diet, Western - adverse effects; Dilation; Drinking water; Dysbacteriosis; Dysbiosis - complications; Dysbiosis - drug therapy; Dysbiosis - physiopathology; Gastrointestinal Microbiome - drug effects; Glucose tolerance; Glycosylation; Interleukin 6; Intestinal microflora; Lipopolysaccharides; LPS-binding protein; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Microbiota; NAD(P)H oxidase; NF-κB protein; NG-Nitroarginine methyl ester; Obesity; Obesity - drug therapy; Obesity - etiology; Obesity - microbiology; Obesity - physiopathology; Proteins; Stiffness; Therapeutic applications; Vascular Diseases - complications; Vascular Diseases - etiology; Vascular Diseases - physiopathology; Vascular Diseases - prevention & control; Vascular Stiffness - drug effects; Vein & artery diseases; arterial stiffness; endothelial function; microbiota; obesity
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/AJPENDO.00187.2017

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 obesity-related 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 µg/ml, P < 0.05) and interleukin-6 (IL-6) (SD 3.27 ± 0.25 vs. WD 7.09 ± 1.07 pg/ml, P < 0.05); aortic expression of phosphorylated nuclear factor-κB (p-NF-κB) ( 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-κB, 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.