Contribution of the commensal microbiota to atherosclerosis and arterial thrombosis

Abstract

The commensal gut microbiota is an environmental factor that has been implicated in the development of cardiovascular disease. The development of atherosclerotic lesions is largely influenced not only by the microbial-associated molecular patterns of the gut microbiota but also by the meta-organismal trimethylamine N-oxide pathway. Recent studies have described a role for the gut microbiota in platelet activation and arterial thrombosis. This review summarizes the results from gnotobiotic mouse models and clinical data that linked microbiota-induced pattern recognition receptor signalling with atherogenesis. Based on recent insights, we here provide an overview of how the gut microbiota could affect endothelial cell function and platelet activation, to promote arterial thrombosis. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc.

The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols

“…Dietary L-carnitine, choline, and lecithin are converted to trimethylamine by the TMA-generating lyase (CutC/D) of gut microbiota, especially Firmicutes and Proteobacteria, then host flavin-containing monoamine oxidases (FMO) are responsible for the conversion to TMAO (Rath, Heidrich, Pieper, & Vital, 2017;Velasquez, Ramezani, Manal, & Raj, 2016). Plasma TMAO concentration is positively correlated to the mortality risk in patients with stable coronary artery disease, carotid intima-media thickness in obese individuals or patients with thrombosis risk (Kiouptsi & Reinhardt, 2018;Randrianarisoa et al, 2016;Senthong et al, 2016;Wang et al, 2011;Zhu et al, 2016). TMAO has been shown to exacerbate atherosclerosis in apolipoprotein E (ApoE) knockout mouse model (Wang et al, 2011) while Jonsson et al found no correlation between plasmaTMAO concentrations and atherosclerotic lesion size (Lindskog Jonsson et al, 2018).…”

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

“…69 Dependent on diet, numerous mouse studies demonstrated that this gut-resident microbial ecosystem affects atherogenesis. 70 Atherosclerotic lesion formation can be driven by gut microbial metabolites, such as the choline-metabolite trimethylamine, but also by microbiota-derived microbial-associated molecular patterns that reach the circulation and affect endothelial cell activation and organspecific immunity. 69,70 We and others could show a reduced thrombus growth in germ-free mice in various carotid artery injury models, implicating the gut microbiota in arterial thrombosis.…”

“…70 Atherosclerotic lesion formation can be driven by gut microbial metabolites, such as the choline-metabolite trimethylamine, but also by microbiota-derived microbial-associated molecular patterns that reach the circulation and affect endothelial cell activation and organspecific immunity. 69,70 We and others could show a reduced thrombus growth in germ-free mice in various carotid artery injury models, implicating the gut microbiota in arterial thrombosis. 66,67 The deposition of platelets to the vascular injury site of germ-free mice was diminished due to reduced von Willebrand factor plasma levels and impaired platelet integrin function.…”

When pharmacology meets the microbiome: new targets for therapeutics?

“…However, such approaches are not limited to psychiatric illness. For example, bacterial‐derived trimethylamine is a substrate for host flavin monooxygenases that gives rise to trimethylamine N‐oxide, which has been implicated in cardiovascular disease (Kiouptsi and Reinhardt, ). As in psychiatric illness, the underlying pathophysiology of cardiovascular disease is unlikely to involve a single microbial‐associated mechanism, and in this regard, microbial‐associated molecular patterns and their recognition systems have also been implicated in the development of atherosclerosis (Kiouptsi and Reinhardt, ).…”

“…For example, bacterial‐derived trimethylamine is a substrate for host flavin monooxygenases that gives rise to trimethylamine N‐oxide, which has been implicated in cardiovascular disease (Kiouptsi and Reinhardt, ). As in psychiatric illness, the underlying pathophysiology of cardiovascular disease is unlikely to involve a single microbial‐associated mechanism, and in this regard, microbial‐associated molecular patterns and their recognition systems have also been implicated in the development of atherosclerosis (Kiouptsi and Reinhardt, ). Kiouptsi and Reinhardt () therefore propose that pattern recognition receptors, such as , may not be the only prospective microbial‐associated therapeutic targets, but also suggest that targeting bacterial enzymatic pathways implicated in the pathophysiology of cardiovascular disease and atherosclerosis may be equally valid with proof‐of‐concept studies demonstrating that non‐lethal inhibition of trimethylamine may be therapeutically relevant (Wang et al ., ).…”