Volume 597, Issue 9 p. 2361-2378
Research Paper
Free to Read

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

Vienna E. Brunt

Corresponding Author

Vienna E. Brunt

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

These authors contributed equally to this work.

Corresponding author Vienna E. Brunt: Department of Integrative Physiology, University of Colorado Boulder, 1725 Pleasant St., 354 UCB, Boulder, CO 80309, USA. Email: [email protected]Search for more papers by this author
Rachel A. Gioscia-Ryan

Rachel A. Gioscia-Ryan

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

These authors contributed equally to this work.

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James J. Richey

James J. Richey

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

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Melanie C. Zigler

Melanie C. Zigler

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

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Lauren M. Cuevas

Lauren M. Cuevas

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

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Antonio Gonzalez

Antonio Gonzalez

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

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Yoshiki Vázquez-Baeza

Yoshiki Vázquez-Baeza

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

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Micah L. Battson

Micah L. Battson

Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO, USA

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Andrew T. Smithson

Andrew T. Smithson

Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

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Andrew D. Gilley

Andrew D. Gilley

Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

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Gail Ackermann

Gail Ackermann

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

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Andrew P. Neilson

Andrew P. Neilson

Department of Food Science and Technology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

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Tiffany Weir

Tiffany Weir

Department of Food Science & Human Nutrition, Colorado State University, Fort Collins, CO, USA

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Kevin P. Davy

Kevin P. Davy

Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

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Rob Knight

Rob Knight

Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA

Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA

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Douglas R. Seals

Douglas R. Seals

Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA

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First published: 04 February 2019
Citations: 113

Edited by: Harold Schultz & David Grundy

This is an Editor's Choice article from the 1 May 2019 issue.

Linked articles: This article is highlighted in a Perspectives article by Cryan et al. To read this article, visit https://doi.org/10.1113/JP277784.

Abstract

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, < 0.01; vs. old antibiotic-treated (OA): 334 ± 15 AU; < 0.01 vs. OC] and arterial stiffening (aortic pulse wave velocity in young: 3.62 ± 0.15 m s−1 vs. OC: 4.43 ± 0.38 m s−1; vs. OA: 3.52 ± 0.35 m s−1; 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−1  vs. OC: 7.2 ± 2.0 μmol L−1; < 0.0001) and suppressed by antibiotic treatment (OA: 1.2 ± 0.2 μmol L−1; < 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.