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

Key points summary

Age‐related arterial dysfunction, characterized by oxidative stress‐ and inflammation‐mediated endothelial dysfunction and arterial stiffening, is the primary risk factor for cardiovascular diseases (CVD). 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 aging altered abundance of microbial taxa associated with gut dysbiosis and increased plasma levels of the adverse gut‐derived metabolite trimethylamine‐N‐oxide. Our results 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 to preserve arterial function with ageing, thereby reducing CVD risk.

Abstract

Oxidative stress‐mediated arterial dysfunction, e.g. endothelial dysfunction and large elastic artery stiffening, is the primary mechanism driving age‐related cardiovascular disease. Accumulating evidence suggests the gut microbiome modulates host physiology, as dysregulation ("gut dysbiosis") has systemic consequences, including promotion of oxidative stress. Aim: To determine whether the gut microbiome modulates arterial function with ageing. Methods: We measured arterial function in young and older mice following 3–4 weeks 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). Results: In old mice, antibiotics reversed endothelial dysfunction (area‐under‐the‐curve carotid artery dilation to acetylcholine in young: 345±16A.U. vs. old control [OC]: 220±34A.U., p<0.01; vs. old antibiotic‐treated [OA]: 334±15A.U.; p<0.01 vs. OC), and arterial stiffening (aortic pulse wave velocity in young: 3.62±0.15m^.s⁻¹ vs. OC: 4.43±0.38m^.s⁻¹ vs. OA: 3.52±0.35m^.s⁻¹; p = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6±0.4 vs. OC: 7.2±2.0μmol^.L⁻¹; p<0.0001) and suppressed by antibiotic treatment (OA: 1.2±0.2μmol^.L⁻¹; p<0.0001 vs. OC). Conclusion: Our results provide the first evidence for the gut microbiome as an important mediator of age‐related arterial dysfunction and oxidative stress and suggest therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.

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