Abstract
The gut microbiota has emerged as an environmental risk factor that affects thrombotic phenotypes in several cardiovascular diseases. Evidence includes the identification of marker species by sequencing studies of the gut microbiomes of patients with thrombotic disease, the influence of antithrombotic therapies on gut microbial diversity, and preclinical studies in mouse models of thrombosis that have demonstrated the functional effects of the gut microbiota on vascular inflammatory phenotypes and thrombus formation. In addition to impaired gut barrier function promoting low-grade inflammation, gut microbiota-derived metabolites have been shown to act on vascular cell types and promote thrombus formation. Therefore, these meta-organismal pathways that link the metabolic capacities of gut microorganisms with host immune functions have emerged as potential diagnostic markers and novel drug targets. In this Review, we discuss the link between the gut microbiota, its metabolites and thromboembolic diseases.
Key points
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Gut microbial composition is associated with thromboembolic disease states.
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Intestinal barrier function is crucial to prevent the translocation of microbial components from the gut lumen into the blood circulation, including microbial patterns that can activate innate immune pathways and affect thrombosis potential via the gut–liver axis.
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Gut microbial metabolites can influence vascular cells and myeloid cells, affecting platelet responsiveness and cellular interactions with the vessel wall.
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Well-studied examples of gut microbial metabolites include choline-derived and carnitine-derived trimethylamine N-oxide, essential amino acid-derived metabolites (indoxyl sulfate, p-cresol sulfate and phenylacetylglutamine) and dietary fibre-derived short-chain fatty acids.
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The gut microbiota and its metabolites are promising diagnostic markers and potential novel targets for the prevention and treatment of thromboembolic diseases.
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Acknowledgements
M.P.K., N.P., and O.D. are PhD students at the Mainz Research School of Translational Biomedicine (TransMed) and members of Young DZHK. K.K. is supported by the German Center for Cardiovascular Research (DZHK) “Promotion of women scientists” Excellence Programme and is a member of Young DZHK. C.R. acknowledges funding from the Forschungsinitiative Rheinland-Pfalz and ReALity (project MORE), the Wilhelm Sander-Stiftung (Nr. 2022.131.1), the BMBF Cluster4Future CurATime (project MicrobAIome, 03ZU1202CA) and the Deutsche Zentren der Gesundheitsforschung (DZG) Innovation Fund “Microbiome” (81X2210129); is a scientist at DZHK; is a member of the Center for Translational Vascular Biology (CTVB), the Research Center for Immunotherapy (FZI), the Potentialbereich EXPOHEALTH at the Johannes Gutenberg-University Mainz, and the DFG Research Unit 5644 INFINITE (RE 3450/15-1); and was awarded a Fellowship from the Gutenberg Research College at the Johannes Gutenberg-University Mainz.
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Glossary
- Altered Schaedler flora
-
Minimal gut microbial consortium composed of eight defined common bacterial species found in mice.
- Endothelial cell adhesion molecules
-
Cell surface proteins expressed on endothelial cells that mediate the adhesion and infiltration of leukocytes and other blood cells; these adhesion molecules can be divided into integrins, selectins and immunoglobulin superfamily members.
- Germ-free mouse models
-
Mice lacking all microorganisms and housed in a sterile environment; this model is used to study gut microbiota–host interactions.
- Gnotobiotic
-
An engineered state of an organism in which all forms of life in or on it, including the gut microbiota, have been identified; model organisms can be colonized with a specific community of known microorganisms or can contain no microorganisms (germ-free).
- Gut–liver axis
-
Bidirectional relationship between the intestine, including the gut microbiota, and the liver.
- Immunothrombosis
-
Physiological host response to invading pathogens, involving the recruitment of innate immune cells and activation of the coagulation cascade; monocytes and neutrophils trigger thrombus formation, which impedes the spread and invasion of pathogens.
- Low-grade endotoxaemia
-
Low levels of circulating endotoxins that influence inflammatory and metabolic conditions.
- Microbiome
-
Collection of all microorganisms and their genomic content in a defined environment.
- Microbiota
-
Collection of all microorganisms, including eukaryotes, archaea, bacteria and viruses, inhabiting a defined environment, such as a host or a specific niche.
- Mutualistic
-
Describing a beneficial relationship between different organisms.
- Pathogen-associated molecular patterns
-
Structural motifs conserved within a group of related microorganisms that are recognized by receptors of the innate immune system.
- Prebiotic
-
Nutritional supplement that nurtures specific groups of beneficial microorganisms.
- Probiotic
-
Selected and living microorganisms that are intended to confer health benefits to consumers if consumed in sufficient amounts.
- ST-segment elevation myocardial infarction
-
Myocardial infarction caused by the occlusion of a coronary artery and associated with ST-segment elevation on an electrocardiogram.
- Synbiotics
-
Combination of selected living microorganisms (probiotics) and nutritional substrates (prebiotics) that are intended to confer a health benefit to the host.
- T helper 17 cells
-
Lineage of T helper cells that can express various cytokines, such as IL-17, and which are involved in host defence and autoimmune diseases.
- Thromboinflammation
-
Pathological process in which inflammatory and thrombotic pathways are dysregulated, contributing to tissue damage.
- Thrombosis
-
The pathological formation of a blood clot in a vessel, which can obstruct the blood flow.
- Tissue factor
-
A primary initiator of the coagulation cascade and a member of the type 2 cytokine receptor family (extrinsic coagulation pathway).
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Khuu, M.P., Paeslack, N., Dremova, O. et al. The gut microbiota in thrombosis. Nat Rev Cardiol 22, 121–137 (2025). https://doi.org/10.1038/s41569-024-01070-6
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DOI: https://doi.org/10.1038/s41569-024-01070-6
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