Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA.
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
J Physiol. 2019 May;597(9):2361-2378. doi: 10.1113/JP277336. Epub 2019 Feb 27.
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 < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; P < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s vs. OC: 4.43 ± 0.38 m s ; vs. OA: 3.52 ± 0.35 m s ; P = 0.03). These improvements were accompanied by lower oxidative stress and greater antioxidant enzyme expression. Ageing altered the abundance of gut microbial taxa associated with gut dysbiosis. Lastly, plasma TMAO was higher with ageing (young: 2.6 ± 0.4 μmol L vs. OC: 7.2 ± 2.0 μmol L ; P < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L ; P < 0.0001 vs. OC). The results of the present study provide the first evidence for the gut microbiome being an important mediator of age-related arterial dysfunction and oxidative stress and suggest that therapeutic strategies targeting gut microbiome health may hold promise for preserving arterial function and reducing cardiovascular risk with ageing in humans.
与年龄相关的动脉功能障碍的特征是氧化应激和炎症介导的内皮功能障碍以及动脉僵硬，是心血管疾病的主要危险因素。为了研究肠道微生物组的年龄相关性变化是否可能介导动脉功能障碍，我们用广谱、吸收不良的抗生素混合物处理年轻和老年小鼠的饮用水中，持续 3-4 周来抑制肠道微生物组。在老年小鼠中，抗生素治疗逆转了内皮功能障碍和动脉僵硬，并减弱了血管氧化应激和炎症。为了深入了解可能导致这些观察结果的与年龄相关的肠道微生物组变化，我们表明衰老改变了与肠道失调相关的微生物类群的丰度，并增加了血浆中不良肠道衍生代谢物三甲胺 N-氧化物的水平。本研究的结果首次提供了证据，证明肠道微生物组是与年龄相关的动脉功能障碍的重要介质，因此可能是一种有前途的治疗靶点，可随着年龄的增长保持动脉功能，从而降低心血管疾病的风险。
氧化应激介导的动脉功能障碍（例如内皮功能障碍和大动脉僵硬）是驱动与年龄相关的心血管疾病的主要机制。越来越多的证据表明，肠道微生物组调节宿主生理，因为失调（“肠道失调”）会产生全身后果，包括促进氧化应激。本研究旨在确定肠道微生物组是否会随着年龄的增长而调节动脉功能。我们在年轻和老年小鼠接受广谱、吸收不良的抗生素治疗 3-4 周后，测量了它们的动脉功能。为了确定肠道微生物组与与年龄相关的动脉功能障碍之间的潜在机制联系，我们对年轻和老年小鼠的肠道微生物组进行了测序，并测量了血浆中不良肠道衍生代谢物三甲胺 N-氧化物（TMAO）的水平。在老年小鼠中，抗生素逆转了内皮功能障碍[年轻组颈动脉扩张至乙酰胆碱的曲线下面积：345±16 AU 与老年对照组（OC）：220±34 AU，P<0.01；与老年抗生素处理组（OA）：334±15 AU；P<0.01 与 OC]和动脉僵硬（年轻组主动脉脉搏波速度：3.62±0.15 m s 与 OC：4.43±0.38 m s；与 OA：3.52±0.35 m s；P=0.03）。这些改善伴随着氧化应激降低和抗氧化酶表达增加。衰老改变了与肠道失调相关的肠道微生物类群的丰度。最后，血浆 TMAO 随年龄增长而升高（年轻组：2.6±0.4 μmol L 与 OC：7.2±2.0 μmol L；P<0.0001），并被抗生素治疗抑制（OA：1.2±0.2 μmol L；P<0.0001 与 OC）。本研究的结果首次为肠道微生物组是与年龄相关的动脉功能障碍和氧化应激的重要介质提供了证据，并表明靶向肠道微生物组健康的治疗策略可能有希望随着年龄的增长保持动脉功能，降低心血管风险。
