Suppression of the gut microbiome ameliorates age‐related arterial dysfunction and oxidative stress in mice

• Published in: The Journal of physiology 2019-05, Vol.597 (9), p.2361-2378
• Main Authors: Brunt, Vienna E., Gioscia‐Ryan, Rachel A., Richey, James J., Zigler, Melanie C., Cuevas, Lauren M., Gonzalez, Antonio, Vázquez‐Baeza, Yoshiki, Battson, Micah L., Smithson, Andrew T., Gilley, Andrew D., Ackermann, Gail, Neilson, Andrew P., Weir, Tiffany, Davy, Kevin P., Knight, Rob, Seals, Douglas R.
• Format: Article
• Language: English
• Subjects: Acetylcholine; Age; Ageing; Aging; Aging - pathology; Aging - physiology; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Antioxidants; Aorta; arterial stiffness; Cardiovascular; Cardiovascular diseases; Carotid Arteries - growth & development; Carotid Arteries - metabolism; Carotid Arteries - physiology; Carotid artery; Digestive system; Dysbacteriosis; endothelial function; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiology; Gastrointestinal Microbiome - drug effects; gut dysbiosis; inflammation; Intestinal microflora; Male; Methylamines - blood; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; Oxidative stress; Oxidative Stress - drug effects; Plasma levels; Research Paper; Trimethylamine; Vascular Stiffness - drug effects; Vasodilation - drug effects
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP277336

Key points Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases. To investigate whether age‐related changes in the gut microbiome may mediate arterial dysfunction, we suppressed gut microbiota in young and old mice with a cocktail of broad‐spectrum, poorly‐absorbed antibiotics in drinking water for 3–4 weeks. In old mice, antibiotic treatment reversed endothelial dysfunction and arterial stiffening and attenuated vascular oxidative stress and inflammation. To provide insight into age‐related changes in gut microbiota that may underlie these observations, we show that ageing altered the abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide. The results of the present study provide the first proof‐of‐concept evidence that the gut microbiome is an important mediator of age‐related arterial dysfunction and therefore may be a promising therapeutic target for preserving arterial function with ageing, thereby reducing the risk of cardiovascular diseases. Oxidative stress‐mediated arterial dysfunction (e.g. endothelial dysfunction and large elastic artery stiffening) is the primary mechanism driving age‐related cardiovascular diseases. Accumulating evidence suggests the gut microbiome modulates host physiology because dysregulation (‘gut dysbiosis’) has systemic consequences, including promotion of oxidative stress. The present study aimed to determine whether the gut microbiome modulates arterial function with ageing. We measured arterial function in young and older mice after 3–4 weeks of treatment with broad‐spectrum, poorly‐absorbed antibiotics to suppress the gut microbiome. To identify potential mechanistic links between the gut microbiome and age‐related arterial dysfunction, we sequenced microbiota from young and older mice and measured plasma levels of the adverse gut‐derived metabolite trimethylamine N‐oxide (TMAO). In old mice, antibiotics reversed endothelial dysfunction [area‐under‐the‐curve carotid artery dilatation to acetylcholine in young: 345 ± 16 AU vs. old control (OC): 220 ± 34 AU, P