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Microbial modulation of cardiovascular disease

Key Points

  • Microbial communities are associated with the human host, primarily in the intestinal tract, where they affect host metabolism and contribute to the pathogenesis of cardiovascular disease.

  • The susceptibility to atherosclerosis and thrombosis can be transmitted via gut microbial transplantation in mouse models.

  • Microbial-associated molecular patterns are sensed by host pattern recognition receptors and affect cardiovascular disease pathogenesis.

  • Microbial metabolism of common dietary nutrients produces both anti-atherogenic and pro-atherogenic metabolites that engage distinct host receptor systems and affect cardiovascular disease pathogenesis.

  • Plasma levels of the gut microbial metabolite trimethylamine-N-oxide are associated with incident development of cardiovascular disease and its adverse outcomes in humans.

  • Bacterially derived short-chain fatty acids (acetate, propionate and butyrate) can engage host receptor systems and potentially affect cardiovascular pathogenesis.

  • Bacterially derived secondary bile acids can modulate dietary fat absorption and signal through cell-surface and nuclear hormone receptors, potentially affecting cardiovascular disease pathogenesis.

  • Gut microorganism-targeted therapeutic strategies hold promise for the prevention and/or treatment of cardiovascular disease.

Abstract

Although diet has long been known to contribute to the pathogenesis of cardiovascular disease (CVD), research over the past decade has revealed an unexpected interplay between nutrient intake, gut microbial metabolism and the host to modify the risk of developing CVD. Microbial-associated molecular patterns are sensed by host pattern recognition receptors and have been suggested to drive CVD pathogenesis. In addition, the host microbiota produces various metabolites, such as trimethylamine-N-oxide, short-chain fatty acids and secondary bile acids, that affect CVD pathogenesis. These recent advances support the notion that targeting the interactions between the host and microorganisms may hold promise for the prevention or treatment of CVD. In this Review, we summarize our current knowledge of the gut microbial mechanisms that drive CVD, with special emphasis on therapeutic interventions, and we highlight the need to establish causal links between microbial pathways and CVD pathogenesis.

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Figure 1: Direct engagement of pattern recognition receptors by microorganism-associated molecular patterns driving cardiovascular disease.
Figure 2: The metaorganismal trimethylamine-N-oxide pathway as a driver of cardiovascular disease.
Figure 3: Microbial production of secondary bile acids in cardiovascular disease.

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Acknowledgements

The authors are supported by grants from the US National Heart Lung and Blood Institute, the US Office of Dietary Supplements and the US National Institute on Alcohol Abuse and Alcoholism (grants R01HL122283 (J.M.B.), P50AA024333 (J.M.B.), R01HL103866 (S.L.H.), P01HL076491 (S.L.H.), R01HL126827 (S.L.H.) and R01DK106000 (S.L.H.)) as well as the Cleveland Clinic Liver Tumor Center of Excellence.

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J.M.B. and S.L.H. substantially contributed to the discussion of content and the review and editing of the manuscript before submission.

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Correspondence to J. Mark Brown or Stanley L. Hazen.

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Competing interests

S.L.H. is named as inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is also a paid consultant for P&G and has received research funds from Astra Zeneca, P&G, Pfizer Inc., Roche Diagnostics and Takeda. S.L.H. has also received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Esperion and Siemens. J.M.B. declares no competing interests.

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Glossary

Pattern recognition receptors

(PRRs). Host sensors that detect molecules typical for pathogens.

Atherosclerosis

A disease process in which the wall of an artery becomes thickened and inflamed owing to the accumulation of inflammation cells and lipids.

Thrombosis

The formation of a clot inside a vessel.

Ischaemic stroke

A stroke that occurs when a blood vessel to the brain is blocked by a blood clot.

Metabolome

The complete set of small-molecule chemicals found within a biological sample.

Transient ischaemic attack

A brief episode of neurological dysfunction caused by lack of blood flow to the brain; also called a 'mini-stroke'.

Glycaemia

The level of glucose in an individual's blood

Detergents

A surfactant or mix of surfactants that has cleaning or membrane-disturbing properties.

Taurine

A major sulfur-containing amino acid.

Postprandial state

The state immediately following a meal.

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Brown, J., Hazen, S. Microbial modulation of cardiovascular disease. Nat Rev Microbiol 16, 171–181 (2018). https://doi.org/10.1038/nrmicro.2017.149

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