The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease

Abstract

Commensal gut microbiota have recently been implicated in cardiovascular disease (CVD) and cerebrovascular disease. Atherosclerotic plaque formation depends on the colonization status of the host. In addition to host nutrition and the related microbiota-dependent metabolic changes, activation of innate immune pathways triggers the development of atherosclerosis and supports arterial thrombosis. Gnotobiotic mouse models have uncovered that activation of Toll-like receptor-2 by gut microbial ligands supports von Willebrand factor-integrin mediated platelet deposition to the site of vascular injury. Depending on nutritional factors, the microbiota-derived choline-metabolite trimethylamine Noxide (TMAO) increases atherosclerotic plaque size, triggers prothrombotic platelet function and promotes arterial thrombus growth. Hence, the composition of the commensal microbiota is an emerging risk factor for CVD. Here, we provide an overview on microbiota-dependent pathomechanisms that drive the development of CVD and arterial thrombosis.Keywords: Arterial thrombosis r Atherosclerosis r Cardiovascular disease r Microbiota r Toll-like receptors IntroductionAt birth, our body surfaces are colonized by microbial communities (microbiota), representing one of the most densely colonized microbial ecosystems [1]. This process is strongly influenced by genetic, nutritional, and environmental factors [2]. The commensal microbiota constitutes a permanent inflammatory stimulus [3], which is kept in check by the host's immune responses [4]. The microbiota can be viewed as an organ that impacts host physiology [5,6]. Changes in gut microbiota composition were associated with intestinal diseases (e.g. inflammatory bowel disease, colon cancer) and cardiometabolic disease states, such as diet-induced obesity, type 2 diabetes, atherosclerosis, and arterial thrombosis [7]. The results from recent experimental and clinical studies have led to the assumption that Correspondence: Christoph Reinhardt e-mail: Christoph.Reinhardt@unimedizin-mainz.de molecules synthesized by the intestinal microbiota are involved in the development of cardiovascular disease (CVD) [8] and may increase the risk of arterial thrombosis [9, 10] as well as the outcome of ischemic stroke [11]. Experimental evidence from germ-free mouse studies and metagenomics analyses have associated the gut microbiota with obesity [12][13][14][15], type 2 diabetes [3, 16, 17], stroke [11, 18], and CVD [8, 9, 19]. Therefore, targeting the composition and metabolic function of the intestinal microbiota may represent a therapeutic option that in the future may allow prevention and treatment of cardiometabolic diseases [20].Here, we provide a comprehensive overview on the emerging link between gut microbiota and CVD. We delineate the contribution of this complex microbial ecosystem to metabolic inflammation and its impact on host metabolism. The main focus of this review is to highlight how gut microbiota may contribute to the development of CVD, cerebrovascular disease and arterial thromb...

Liver X Receptor regulates Th17 and RORγt+ Treg cells by distinct mechanisms

“…In these experiments, we observed significantly higher enrichment of bacteria belonging to the family Ruminococcaceae and Lachnospiraceae in LXRα −/− mice compared to WT littermates in steady state, suggesting that lack of LXRα allows preferential colonization of specific groups of bacteria. Both Ruminococcaceae and Lachnospiraceae belong to the order Clostridiales and phylum Firmicutes and have been associated with multiple human diseases including IBD 22-24 and atherosclerosis 25,26 . While the abundance of both Ruminococcaceae and Lachnospiraceae are decreased in IBD patients, suggesting a protective role, they have been shown to be associated with pro-atherogenic effects.…”

The Gut Microbiota in Cardiovascular Disease and Arterial Thrombosis

“…Next to LPS, trimethylamine N-oxide (TMAO), a choline metabolite, which was associated with inflammation, atherosclerotic lesion progression, and arterial thrombosis, belongs to the group of signaling active metabolites, that are derived from the gut microbiota [7,12]. Red meat, egg yolk, and fat-rich products contain a high amount of L-carnitine and phosphatidylcholine [13,81].…”

“…This densely colonized microbial ecosystem critically influences the host's immune homeostasis via microbial-associated molecular patterns (MAMPs) and through the signaling of active metabolites [3,4]. For example, stimulation with MAMPs increases the phagocytic capacity and the response to cytokines of macrophages and neutrophils and drives atherogenesis [5][6][7][8]. In contrast, metabolites such as short chain fatty acids (SCFAs) inhibit interferon-γ (IFN-γ) production and protect from mucosal inflammation, but also reduce the development of atherosclerotic lesions [5,6].…”

“…The gut microbiota influences the development of vascular inflammation and atherosclerosis [7][8][9]. Various mouse models have shown that intestinal microbial communities have a crucial influence on vascular inflammatory phenotypes, the development of cardiovascular diseases (CVD), and arterial thrombosis [10].…”

“…Various mouse models have shown that intestinal microbial communities have a crucial influence on vascular inflammatory phenotypes, the development of cardiovascular diseases (CVD), and arterial thrombosis [10]. While interfering with host energy metabolism [8], the gut microbiota impacts on the development of atherosclerosis, as demonstrated by the association-based sequencing studies on patient samples [8,[11][12][13] and by the depletion of the gut microbiota with antibiotics or by comparing germ-free (GF) with conventionally raised (CONV-R) mouse atherosclerosis models [7,[13][14][15][16]. Via the activation of pattern recognition receptors (PRRs) on platelets and endothelial cells, MAMPs promote arterial thrombosis and stimulate the synthesis of prothrombotic von Willebrand factor (VWF) in in plasma and 86 metabolites in feces were detected to change under angiotensin II treatment [41].…”