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  • Review Article
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Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease

Nature Reviews Cardiology volume 20, pages 24–37 (2023)Cite this article

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Abstract

Systemic inflammation has been suggested to have a pivotal role in atherothrombosis, but the factors that trigger systemic inflammation have not been fully elucidated. Lipopolysaccharide (LPS) is a component of the membrane of Gram-negative bacteria present in the gut that can translocate into the systemic circulation, causing non-septic, low-grade endotoxaemia. Gut dysbiosis is a major determinant of low-grade endotoxaemia via dysfunction of the intestinal barrier scaffold, which is a prerequisite for LPS translocation into the systemic circulation. Experimental studies have demonstrated that LPS is present in atherosclerotic arteries but not in normal arteries. In atherosclerotic plaques, LPS promotes a pro-inflammatory status that can lead to plaque instability and thrombus formation. Low-grade endotoxaemia affects several cell types, including leukocytes, platelets and endothelial cells, leading to inflammation and clot formation. Low-grade endotoxaemia has been described in patients at risk of or with overt cardiovascular disease, in whom low-grade endotoxaemia was associated with atherosclerotic burden and its clinical sequelae. In this Review, we describe the mechanisms favouring the development of low-grade endotoxaemia, focusing on gut dysbiosis and changes in gut permeability; the plausible biological mechanisms linking low-grade endotoxaemia and atherothrombosis; the clinical studies suggesting that low-grade endotoxaemia is a risk factor for cardiovascular events; and the potential therapeutic tools to improve gut permeability and eventually eliminate low-grade endotoxaemia.

Key points

  • Gut permeability can be altered by gut microbiota dysbiosis, favouring lipopolysaccharide (LPS) translocation into the systemic circulation, with ensuing development of low-grade endotoxaemia.

  • Low-grade endotoxaemia induces an inflammatory state in the arterial wall that ultimately leads to initiation and progression of atherosclerosis.

  • Low-grade endotoxaemia has effects on several cell types, such as leukocytes, platelets and endothelial cells, shifting them to a procoagulant phenotype that contributes to thrombosis.

  • Gut permeability-derived low-grade endotoxaemia might contribute to atherosclerosis and be associated with cardiovascular events in patients at risk of or with overt cardiovascular disease.

  • Modulation of gut permeability-derived low-grade endotoxaemia is a potential tool to counteract inflammation-related atherothrombosis and its clinical sequelae.

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Fig. 1: Interplay between low-grade endotoxaemia and vascular disease.
Fig. 2: Mechanisms of gut permeability-mediated low-grade endotoxaemia.
Fig. 3: Mechanisms of LPS-mediated atherosclerosis.
Fig. 4: Mechanisms of LPS-mediated thrombosis.
Fig. 5: Potential therapeutic strategies to reduce low-grade endotoxaemia.

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Author notes

  1. These authors jointly supervised this work: Roberto Carnevale and Cristina Nocella.

Authors and Affiliations

  1. Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy

    Francesco Violi, Vittoria Cammisotto, Pasquale Pignatelli & Cristina Nocella

  2. Mediterranea Cardiocentro-Napoli, Naples, Italy

    Francesco Violi, Pasquale Pignatelli & Roberto Carnevale

  3. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy

    Simona Bartimoccia & Roberto Carnevale

Authors
  1. Francesco Violi
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  2. Vittoria Cammisotto
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  4. Pasquale Pignatelli
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Contributions

F.V. developed the concept and design of the review and wrote the manuscript. All the authors contributed to the discussion of content and reviewed and edited the manuscript before submission.

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Nature Reviews Cardiology thanks Christoph Reinhardt; Christoph Thiemermann, who co-reviewed with Shireen Mohammad; Pirkko Pussinen; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Gut dysbiosis

Any change in the number or diversity of resident commensal gut microbiota relative to the community present in healthy individuals.

Trimethylamine-N-oxide

(TMAO). A small organic compound formed from trimethylamine, which is generated by metabolism of dietary choline and phosphatidylcholine by flavin monooxygenases from gut microbiota.

Endotoxaemia

The presence in the blood of endotoxins, such as lipopolysaccharide (LPS), which is a component of the outer membrane of Gram-negative bacteria.

Non-alcoholic fatty liver disease

(NAFLD). A condition caused by ectopic fat accumulation in the liver in the absence of excessive alcohol intake.

Non-alcoholic steatohepatitis

(NASH). A severe form of non-alcoholic fatty liver disease that is characterized by liver inflammation and that can progress to cirrhosis.

Intestinal adhesion proteins

The scaffold of the epithelial cell barrier that protects from the translocation of microorganisms or microbial products into the systemic circulation.

Increased gut permeability

Impaired function of epithelial cell adhesion proteins and loss of epithelial cell barrier integrity, with translocation of microorganisms and toxins into the bloodstream.

NADPH oxidase

A ubiquitous, multisubunit cellular enzyme that is a major producer of reactive oxygen species.

Neutrophil extracellular traps

(NETs). Extracellular net-like structures composed of DNA, histones and cytoplasmic granule proteins released by neutrophils after activation.

Prebiotics

Non-digestible food ingredients (fibres) that promote a shift to a healthier gut microbiota profile.

Probiotics

Live microorganisms that confer a health benefit in the host when administered in adequate amounts.

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Violi, F., Cammisotto, V., Bartimoccia, S. et al. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat Rev Cardiol 20, 24–37 (2023). https://doi.org/10.1038/s41569-022-00737-2

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