**1. Introduction**

*Cardiovascular disease* or *CVD* is a term for disorders affecting the heart or blood vessels. Except in Africa, cardiovascular illnesses are the main cause of mortality globally, resulting in 17.9 million deaths (32.1%) in 2015, an increase from 12.3 million (25.8%) in 1990 [1]. CVD deaths are more widespread and have been growing in most developing countries, whereas rates in most developed countries have declined since the 1970s [2]. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% in females. The majority of cardiovascular disease affects older people. In the United States, 11% of adults between the ages of 20 y and 40 y have CVD, 37% between the ages of 40 y and 60 y, 71% between the ages of 60 y and 80 y, and 85% above the age of 80 y have CVD. In developed countries, the average age of death from coronary artery disease is over 80 y, while it is roughly 68 y in the developing world [2]. Diagnosis of diseases typically occurs seven to ten years earlier in men than in women.

The underlying processes differ according to the illness. Dietary risk factors are responsible for 53% of CVD fatalities [3]. Atherosclerosis is a common factor in coronary artery disease, stroke, and peripheral artery disease [4]. High blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor food, excessive alcohol consumption, and poor sleep, among other factors, may contribute to this [5]. High blood pressure contributes around 13% of CVD fatalities, whereas tobacco accounts for 9%, diabetes accounts for 6%, lack of exercise factors for 6%, and obesity accounts for 5%. Untreated strep throat can potentially cause rheumatic heart disease. Up to 90% of cardiovascular disease is thought to be preventable [6]. Lowering risk factors through good food, exercise, avoiding cigarette smoke, and limiting alcohol use are all part of CVD prevention. It also treats risk factors such as high blood pressure, lipids, and diabetes. In those with strep throat, antibiotics can lower the risk of rheumatic heart disease [7].

The microbiome plays a beneficial role in the homeostatic regulation of different body tissues of the host [8]. The overall relationship between humans and their microbiota can be described as a mutualistic symbiosis, also known as eubiosis [9]. This healthy balance of gut bacteria can be disrupted, leading to the onset of a variety of chronic diseases with an underlying inflammatory condition [10]. A large population of microbiota, predominantly bacteria, that populate the human gut have a symbiotic connection with the host, and imbalances in host-microbial interaction (dysbiosis) hamper these homeostatic systems that govern health and activate numerous pathways that contribute to advancing CVD risk factors [11]. Dysbiosis is related to intestinal inflammation and decreased gut barrier integrity, which raises circulating levels of bacterial structural components and microbial metabolites such as trimethylamine-N-oxide and short-chain fatty acids, which may aid in the development of CVDs [11].

Trimethylamine-N- oxide (TMAO) is a type of osmolyte found in the tissues of marine crustaceans and fish, where it prevents protein distortion and, therefore, the animal's death [12]. The concentration of TMAO increases as the animal's depth in the seas increases [13]. It is a protein stabilizer that counteracts the protein-destabilizing effects of pressure. In general, the bodies of animals living at great depths are adapted to high-pressure environments by having pressure-resistant biomolecules and small organic molecules present in their cells, known as piezolytes, of which TMAO is the most abundant. These piezolytes give the proteins the flexibility to function properly under great pressure [13–15]. However, more importantly, TMAO has emerged not only as an important metabolite in the human diet but also as a major cardiometabolic risk factor. It has been associated with many cardiovascular complications including foam cell formation [16], endothelial dysfunction [17], acute heart failure [18], infracted coronary artery [19], inflammation [20] and vascular aging [21].

## **2. Role of gut microbes in regulating cardiovascular health and disease**

The gut microbiome has emerged as a critical factor in human health and disease [22, 23] and cardio-metabolic diseases are no exception. Obesity and insulin resistance are serious cardiometabolic risk factors [24–27], and gut microbial composition is a major regulator of these conditions. Changes in fecal microbial community composition have been linked to the development of obesity and insulin resistance, and microbial transplantation has been shown to transmit increased adiposity in

#### *Gut Microbial Metabolite Trimethylamine-N-Oxide and Its Role in Cardiovascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.107976*

the host [28–30]. Disruptions to the microbiota early in life have since been identified to induce increased obesity [31]. Koren et al. [32] argued that microbiota could be associated with atherosclerosis since human atherosclerotic plaques were found to contain bacterial DNA, albeit it was unclear if the DNA came from live bacteria within the arterial wall. The initial research into a possible link between the gut microbiome and cardiovascular disease (CVD) focused on trimethylamine N-oxide (TMAO), a metaorganismal metabolite generated after ingestion of food substances plentiful in a Western diet (eg, carnitine, lecithin, choline) [16, 33, 34]. TMAO has swiftly established itself as a biomarker for human CVD risk as well as a promoter of atherothrombotic disease [35, 36]. In fact, a Western-style diet deficient in microbiota-accessible carbohydrates (MACs) may cause irreversible microbial diversity loss and the extinction of particular bacterial species in the digestive system [37]. As a result, the low intake of dietary fiber and increased levels of fat and sugar in our food, which are typical of a westernized lifestyle and diet, may contribute to the depletion of specific bacterial taxa, at least in part [38]. Fiber, fruit, legume and vegetable consumption is linked to an increased microbial richness in the gut microbiota [39, 40], and several recent epidemiological studies have found an inverse relationship between dietary fiber consumption and CVD risk variables [41–45]. Non -digestible carbohydrates present in dietary fiber are converted by intestinal bacteria into Short-Chain fatty acids(SCFAs) like acetate, propionate and butyrate [46, 47]. SCFAs have been shown to have a direct effect on renin release and vasomotor function, resulting in lower blood pressure [48–50]. Butyrate has been shown to have a potential adjuvant effect in the lowering of diastolic blood pressure by reducing inflammation in a recent controlled experiment [51]. Moreover, in early pregnancy, the presence of butyrateproducing bacteria was found to be inversely related to blood pressure and plasminogen activator inhibitor-1 levels [52].

#### **2.1 Gut microbiota dysbiosis and implications in CVD risk**

Most microbiome-related diseases have skyrocketed in the last century, implying that a change in lifestyle could disturb gut microbiota symbiosis by removing helpful, protective bacteria [53]. Patients with a variety of CVD risk factors, such as hypertension, dyslipidemia, insulin resistance, and other metabolic abnormalities, have been found to have variations in microbial composition [36, 37]. Dysbiosis of the gut microbiota can lead to chronic inflammation, which is a major contributor to obesity, cardiovascular disease, and notably atherosclerosis [38, 39]. In symptomatic atherosclerosis patients, metagenome research indicated a higher concentration of triglycerides and a lower level of high-density lipoprotein in the circulation, as well as an increased abundance of *Collinsella* and a decreased abundance of *Roseburia* and *Eubacterium* [54]. Jie et al. [55] discovered an elevated relative abundance of *Enterobacteriaceae* and *Streptococcus* spp. taxa in atherosclerotic CVD patients. In coronary artery disease patients, Emoto et al. discovered a distinct alteration in microbial composition, with a large increase in *Lactobacillales* (Firmicutes) and a decrease in Bacteroidetes [56]. In another study, patients with type 2 diabetes had a lower number of Firmicutes and a non-significant rise in Bacteroidetes and Proteobacteria [57]. Some cross-sectional studies have found evidence that high-protein and high-fat diets (associated with Western lifestyles) are linked to gut microbial populations characterized by the Bacteroides enterotype, while diets heavy in carbohydrates and simple sugars are linked to the Prevotella enterotype [58].

The metabolism-independent pathway and the metabolism-dependent pathway are two key pathways via which gut dysbiosis can contribute to the development and progression of atherosclerosis [59]. In the metabolism -independent pathways, bacterial components located on the outer membrane of Gram-negative bacteria, such as lipopolysaccharides (LPS), can encourage the production of foam cells, which are a primary component of atherosclerotic plaque [60]. To prevent the accumulation of excess cholesterol in peripheral tissues, the body has internal homeostatic systems in place, such as reverse cholesterol transport (RCT). Excess cholesterol is transported to the liver and transformed into bile acids through the RCT process [61–63]. By producing metabolic endotoxemia, gut dysbiosis can overload systems like RCT and encourage the development of foam cells [64–66]. Metabolic endotoxemia is a condition marked by a high level of LPS in the bloodstream [67]. The presence of *Bifidobacteria*, which typically enhance intestinal barrier function and inhibit bacterial translocation, is reduced in high-fat (HF) diet-induced dysbiosis [60].
