The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice

Kiouptsi, Klytaimnistra; Jäckel, Sven; Pontarollo, Giulia; Grill, Alexandra; Kuijpers, Marijke J. E.; Wilms, Eivor; Weber, Christian; Sommer, Felix; Nagy, Magdolna; Neideck, Carlos; Jansen, Yvonne; Ascher, Stefanie; Formes, Henning; Karwot, Cornelia; Bayer, Franziska; Kollar, Bettina; Subramaniam, Saravanan; Molitor, Michael; Wenzel, Philip; Rosenstiel, Philip; Todorov, Hristo; Gerber, Susanne; Walter, Ulrich; Jurk, Kerstin; Heemskerk, Johan W. M.; Döring, Yvonne; Reinhardt, Carsten

doi:10.1128/mbio.02298-19

Cited by 63 publications

(75 citation statements)

References 56 publications

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“…Collagen-triggered granulophysin release, P-selectin surface expression, and exposure of activated integrin α IIb β 3 on the platelet surface was found reduced in platelets from GF mice [51]. This data was also confirmed in the GF Ldlr −/− mouse model under chow diet feeding conditions with adhesion-induced platelet deposition [48]. In addition, the meta-organismal TMAO pathway, which activation depends on choline-rich diet, was reported to promote arterial thrombus growth in the ferric chloride carotid artery thrombosis model [82].…”

Section: Evidence Linking the Microbiota With Cvd And Arterial Thrombsupporting

confidence: 62%

“…In in vivo as well as ex vivo experiments on Ldlr −/− mice, fed with a high-fat Western diet for sixteen-weeks, differences were noted when mice grew up under GF conditions. GF Ldlr −/− mice presented lower leucocyte adhesion to the atherosclerotic vessel wall [48]. In conclusion, experiments on GF mouse models can give unique insights into the interplay between the gut microbiota and the host's organ function, platelet reactivity and the immune system [17,48,95].…”

Section: Figurementioning

confidence: 88%

“…While the presence of a gut microbiota resulted in reduced serum cholesterol levels under low-cholesterol feeding conditions, this effect was abolished on a cholesterol-rich diet in the low-density lipoprotein receptor-deficient mouse model (Ldlr −/− ). In CONV-R Ldlr −/− mice, no microbiota-dependent effects were observed on late atherosclerotic lesion size on a γ-irradiated cholesterol-rich diet at sixteen-weeks of Western diet feeding with respect to GF counterparts [48]. In accordance to this recent work, Lindskog Jonsson et al did not find a correlation between plasma TMAO concentration and atherosclerotic lesion size in the aortic root and the relative aortic root lesion size was not significantly different in GF Apoe −/− C57BL/6J mice, compared to CONV-R Apoe −/− C57BL/6J mice treated with a Western diet [9,14].…”

Section: Patterns and Metabolites From The Gut Microbiota As Driversmentioning

confidence: 88%

“…GF Ldlr −/− mice presented lower leucocyte adhesion to the atherosclerotic vessel wall [48]. In conclusion, experiments on GF mouse models can give unique insights into the interplay between the gut microbiota and the host's organ function, platelet reactivity and the immune system [17,48,95]. This technology is indeed one of the most meaningful experimental animal models, as it is complementary and reduces risks linked to the use of antibiotics in animal experiments [33].…”

Section: Figurementioning

confidence: 96%

“…It was demonstrated that the composition of the gut microbiota impacts the balance of T-cells (regulatory T cells vs Th17 cells), thus affecting the development of hypertension [47]. Tissue infiltration by T-cells causes higher levels of chemokines and cytokines, which recruit immune cells to the site of inflammation [42,47,48]. Predominant cytokines in hypertensic patients are IFN-γ, TNF-α, and IL-17A, all being influenced by the presence of MAMPs derived from the gut microbiota [47].…”

Section: Introductionmentioning

confidence: 99%

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The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis

et al. 2019

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The gut microbiota has emerged as a contributing factor in the development of atherosclerosis and arterial thrombosis. Metabolites from the gut microbiota, such as trimethylamine N-oxide and short chain fatty acids, were identified as messengers that induce cell type-specific signaling mechanisms and immune reactions in the host vasculature, impacting the development of cardiovascular diseases. In addition, microbial-associated molecular patterns drive atherogenesis and the microbiota was recently demonstrated to promote arterial thrombosis through Toll-like receptor signaling. Furthermore, by the use of germ-free mouse models, the presence of a gut microbiota was shown to influence the synthesis of endothelial adhesion molecules. Hence, the gut microbiota is increasingly being recognized as an influencing factor of arterial thrombosis and attempts of dietary pre-or probiotic modulation of the commensal microbiota, to reduce cardiovascular risk, are becoming increasingly significant.

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Section: Evidence Linking the Microbiota With Cvd And Arterial Thrombsupporting

confidence: 62%

Section: Figurementioning

confidence: 88%

Section: Patterns and Metabolites From The Gut Microbiota As Driversmentioning

confidence: 88%

Section: Figurementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis

et al. 2019

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Human Gut Microbiota in Cardiovascular Disease

Ronen,

Rokach,

Abedat

et al. 2024

Comprehensive Physiology

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The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N ‐oxide (TMAO), short‐chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449‐5490, 2024.

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Pleiotropic activities of succinate: The interplay between gut microbiota and cardiovascular diseases

Yang

et al. 2023

iMeta

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Cardiovascular diseases (CVDs) continue to be a significant contributor to global mortality, imposing a substantial burden and emphasizing the urgent need for disease control to save lives and prevent disability. With advancements in technology and scientific research, novel mechanisms underlying CVDs have been uncovered, leading to the exploration of promising treatment targets aimed at reducing the global burden of the disease. One of the most intriguing findings is the relationship between CVDs and gut microbiota, challenging the traditional understanding of CVDs mechanisms and introducing the concept of the gut‐heart axis. The gut microbiota, through changes in microbial compositions and functions, plays a crucial role in influencing local and systemic effects on host physiology and disease development, with its metabolites acting as key regulators. In previous studies, we have emphasized the importance of specific metabolites such as betaine, putrescine, trimethylamine oxide, and N,N,N‐trimethyl‐5‐aminovaleric acid in the potential treatment of CVDs. Particularly noteworthy is the gut microbiota‐associated metabolite succinate, which has garnered significant attention due to its involvement in various pathophysiological pathways closely related to CVDs pathogenesis, including immunoinflammatory responses, oxidative stress, and energy metabolism. Furthermore, we have identified succinate as a potential biomarker, highlighting its therapeutic feasibility in managing aortic dissection and aneurysm. This review aims to comprehensively outline the characteristics of succinate, including its biosynthetic process, summarize the current evidence linking it to CVDs causation, and emphasize the host‐microbial crosstalk involved in modulating CVDs. The insights presented here offer a novel paradigm for future management and control of CVDs.

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The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice

Cited by 63 publications

References 56 publications

The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis

The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis

Human Gut Microbiota in Cardiovascular Disease

Pleiotropic activities of succinate: The interplay between gut microbiota and cardiovascular diseases

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