Gut Microbiota for Atherosclerosis Disease: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Raffaele Palmirotta.

The increasing number of studies on the relationship between the gut microbiota and atherosclerosis have led to significant interest in this subject. The gut microbiota, its metabolites (metabolome), such as TMAO, and gut dysbiosis play an important role in the development of atherosclerosis. Furthermore, inflammation, originating from the intestinal tract, adds yet another mechanism by which the human ecosystem is disrupted, resulting in the manifestation of metabolic diseases and, by extension, cardiovascular diseases. 

  • microbiota
  • cardiovascular diseases
  • atherosclerosis

1. Development of the Gut Microbiota

The assumption that the development of the gut microbiota begins at birth has been challenged by a limited number of studies in which the microbiome could be detected even in the placenta of pregnant women. After birth, the gastrointestinal tract is rapidly colonized by the intestinal microbiota. Some life events such as various diseases, antibiotics, and dietary changes cause chaotic changes in the newborn microbiota [35][1]. Furthermore, the microbiota is transferred from the cervix during normal childbirth, with a greater presence of the Lactobacillaceae family, which abounds in the cervical microbiota. In contrast, in newborns born by caesarean section, the microbiota is weakened and slow to be colonized by the genus Bacteroides; instead, mainly opportunistic pathogens such as those from Clostridiaceae family are found [28][2]. Newborns born by normal delivery carry 72% of their mother’s microbiota, while those born by C-section carry 41%. In the early stages, the gut microbiota has lower diversity, consisting mainly of Acinetobacteria and Proteobacteria [34,35,36][1][3][4]. During the second year of life, diversity increases and begins to take on an adult configuration, with some unique individual patterns [37][5]. Although in adulthood the composition of the microbiota is relatively stable, it is still vulnerable to various life events that may modify it. In people over age 65, the composition changes, with a predominance of Bacteroides and Clostridiaceae family (such as Clostridia class IV); in contrast, in younger individuals, class XIVa is predominant [38][6]. Overall, the ability of the microbiota to carry out metabolic processes such as the production of SCFAs and the lysis of amyloid decreases; instead, the proteolytic activity increases. Given the increased importance of SCFAs as metabolic and immune mediators, it appears that their depletion may enhance the age-related inflammatory process in the intestinal tract of elderly humans [39][7].

2. Gut Microbiota as an Endocrine Organ

Unlike other endocrine organs or systems that secrete one or a small number of chemical compounds, the gut microbiota has the advantage of producing hundreds of such compounds and products. From a morphological and biochemical point of view, it is vastly larger and more biochemically heterogeneous than any other endocrine organ in the human body. In fact, the biochemical complexity of the gut microbiota exceeds even that of the human brain, and many of the hormones produced by the gut microbiota are also neurotransmitters in the central nervous system (CNS) [40][8]. For example, γ-aminobutyric acid (GABA), which is one of the most important inhibitory neurotransmitters in the CNS, is produced by various species of the Lactobacillaceae family, while various monoamines, such as noradrenaline, dopamine, and serotonin, are produced by various bacterial strains within the microbiota [41][9]. This biochemical prowess of the microbiome comes from the large content and diversity of microbial cells, with an estimated mass of 1–2 kg in an average adult. The number of cells is much greater than the number of host cells, and it is estimated that 90% of the cells found in the human body are essentially prokaryotic cells that comprise over 35,000 bacterial species from approximately 1800 genera. Therefore, the diversity of this endocrine system is enormous, and, in adults, about 8 million genes correspond to a small number of genera of microorganisms.

3. Gut Microbiota Dysbiosis and Atherosclerosis

The intestinal microbiota plays an important role in the human immune system and takes part in its development. Intestinal dysbiosis may promote atherosclerosis by modulating the immune system. Mediators of the microbiome in this direction are NOD-like receptors (NLR), myeloid differentiation factor 88 (MyD88), and Toll-like receptors (TLRs), including TLR4, TLR3, and TLR2. The latter are directly linked to the development of atherosclerosis [43][10]. Platelets are activated by downstream signaling pathways of these receptors (myeloid differentiation factor 88 (MyD88) and Toll-like receptors (TLRs), including TLR4, TLR3 and TLR2), specifically as damage-associated molecular patterns (DAMPs). Receptors involved in platelet activation have been found before [44][11]. Thus, this process may highlight a key role of the gut microbiota in underlying platelet activation in patients with CAD. A high-calorie diet with increased SCFAs affects the permeability of the intestinal wall, modifying the composition of the intestinal microbiota and the “tight” junctions (ZO-1) between the cells of the intestinal wall. This results in bacterial fragments and uremic toxins being transported into the bloodstream, either through extracellular leakage between junctions or through transport by a chylomicron-mediated mechanism [45,46][12][13]. In particular, the connections between the cells of the intestinal wall are affected by the production of nitrite components (ammonia and ammonium hydroxide) which come from intestinal dysbiosis (the microbiota hydrolyses urea and, thus, these chemicals are produced) [47][14]. Some of these fragments are lipopolysaccharides (LPS) and glycolipids that lead to endotoxemia, thereby activating macrophages and NK cells [48][15]. In addition, saturated SCFAs are associated with the differentiated composition of the intestinal microbiome and are ligands for TLR4 receptors [49][16]. When binding to the TLR4/CD14 receptors in macrophages, they induce a cascade of pro-inflammatory cytokines (mainly IL-6 and TNF-a), thereby initiating an immune response. As previously mentioned, inflammation is a key risk factor for atherosclerosis. Studies have found DNA from the microbiota in the arterial plaque, mainly in combination with the overexpression of the genus Proteobacteria [50,51][17][18]. DNA levels correlated with leukocyte and B2 cell levels in atherosclerotic plaque and appeared to influence plaque stability [52][19]. Furthermore, it has been reported that metabolic products from the intestinal microbiota activate B2 cells and their production of IgG, which affects the promotion of atherosclerosis. This has been demonstrated, as atheromatous plaque generation was considerably decreased in patients receiving antibiotics that reduced these metabolic products [53,54,55][20][21][22]. Diet is the main factor that determines the composition of the microbiota. The diversity of the composition of different microbial colonies contributes to and is associated with various metabolic disorders such as atherosclerosis. Low levels of Bacteroidota and intestinal dysbiosis of opportunistic pathogens such as Enterobacter, Collinsella, Desulfovibrio, and Klebsiella genera are factors associated with atherogenesis and atherosclerotic plaques [29,46,56][13][23][24] Furthermore, apart from their absolute number, the relative ratio between them is also of great importance, which also plays a role in metabolic diseases. It has been reported that Bacteroidota play an important role in regulating the actions of T cells and, by extension, the body′s immune system [46,56,57,58,59][13][24][25][26][27]. In addition, infections by Helicobacter pylori are associated with an increased atherogenic profile, due to lipopolysaccharide (LPS), which characterizes this genus of microbes and their ability to cause vascular inflammation. This occurs when LPS passes into systemic circulation through the intestinal wall. As mentioned above, variations in the composition of the intestinal microbiome enhance the production of TMA, the precursor to TMAO. Finally, there are many studies linking intestinal dysbiosis to specific classes of lipids only, such as HDL and VLDL. In the intestinal tract, trimethylamine N-oxide (TMAO) is produced by the metabolism of L-carnitine, choline, betaine, and phosphatidylcholine. Initially, trimethylamine (TMA) is produced by the intestinal microbiome. In the liver, trimethylamine (TMA) is converted to trimethylamine N-oxide (TMAO) by flavonoid-containing monooxygenase type 3 (FOM-3). Choline is converted to trimethylamine (TMA) via CutC and CutD, which are the genes responsible for the formation of trimethylamine (TMA) from choline via choline TMA-lyase [60][28]. Also, trimethylamine N-oxide (TMAO) is produced, as mentioned above, from L-carnitine, through two different pathways. The exact relationship of how TMAO is associated with atherosclerosis is not yet known. Several studies remain to be carried out in this direction. The first pathway is through the direct conversion of L-carnitine to TMAO by the gut microbiota, and the second pathway is through the conversion of L-carnitine to γBB (γ-butyrobetaine), a process that takes place in the small intestine, which is then converted to TMA and then to TMAO via FOM-3. In patients with atherosclerotic disease in their carotid arteries, it was found that the levels of γ-butyrobetaine (γ-BB) and L-carnitine were higher than those in the healthy group. Of note, γ-butyrobetaine is also produced from trimethyllysine (TML), independently of L-carnitine. Furthermore, TML and γ-BB have been found to be associated with atherosclerosis, independently of TMAO production (i.e., their indirect involvement in the promotion of atherosclerosis via TMAO) [61,62][29][30]. Regarding the silencing of genes which produce FOM-3, this induces a syndrome in patients, who then emit a fishy odor due to trimethylaminuria production [63,64][31][32]. The reason for this unpleasant odor is that TMA is excreted by the kidneys, sweat, and breath. Foods that are rich in TMAO are mainly red meat, egg yolks, and sea fishes. Nevertheless, fish is a key element in a balanced, cardioprotective diet. This beneficial effect, from eating fish, probably comes from the omega-3 fatty acids. Thus, the intake of TMAO from eating fish is likely to be proportionally negligible in relation to the benefits of eating it [65][33]. It has also been found in studies that vegetarians have lower levels of TMAO than those who also consume meat [66,67,68,69][34][35][36][37]. Elevated L-carnitine levels combined with elevated TMAO levels were found to have a combined role in increased cardiovascular risk (myocardial infarction, stroke, and death). In addition, the content of the intestinal microbiota also contributes to determining the levels of TMAO in the bloodstream. This is because different microbes have varying ability to produce TMAO. For example, Prevotella species are more prone to TMAO production than Bacteroides spp. Also, it has been reported that vulnerability to atherosclerosis can also be promoted by fecal transplantation [70,71][38][39]. Trimethylamine N-oxide (TMAO) suppresses cholesterol efflux by blocking its reverse transport to the liver; this is yet another way by which TMAO promotes atherosclerosis. Bile acid concentration is altered and reduced due to TMAO, as well as its synthesis and secretion (there is reduced activity of FXR (farsenoid X receptor) signaling—this type of signaling has to do with bile acids and affects lipid metabolism) [72,73,74,75][40][41][42][43]. Some other effects are the reduction of cholesterol absorption from the enterocyte, increasing glucose tolerance and promoting adipose tissue inflammation. It is evident that all these effects indirectly affect the development of atherosclerosis [76,77][44][45]. Additionally, TMAO is associated with higher-level syntax levels. Many authors have considered whether TMAO is a clinical marker of atherosclerosis or is the cause of atherosclerosis. For example, if there is atherosclerosis in the renal arteries with concomitant atherosclerosis in the coronary arteries, then TMAO would be a marker for renal dysfunction [78][46]. TMAO also increases macrophage scavenger receptors, which results in macrophage cholesterol accumulation and foamy cell formation [79,80,81,82][47][48][49][50]. Another pathway by which TMAO contributes to the development of atherosclerosis and, by extension, to cardiovascular disease is through inducing platelet hyperreactivity. This is due to the change in the calcium levels in the platelets. This increases the risk of thrombosis [82,83][50][51]. TMAO can increase platelet activation through a direct interaction or it can indirectly affect platelets via the elevation of cytokine/chemokine released from other cells such as leukocytes, which interact with platelets in indirect ways [83,84][51][52]. TMAO is also responsible for the inflammation of vascular endothelial cells because it induces the chemotaxis of leukocytes, increases the expression of pro-inflammatory cytokines, and promotes the secretion of IL-6, E-selectin, and adhesion molecules (in essence, it promotes the transcription of the corresponding genes of such substances) [44,85][11][53]. It also inhibits endothelial nitric oxide synthase (eNOS) and the bioavailability of nitric oxide (NO), instead activating the products of oxidative stress (ROS), which lead to the inflammation of endothelial cells. In turn, ROS can activate platelets, thus enhancing their proinflammatory phenotype, complicating atherosclerosis [85,86,87,88,89][53][54][55][56][57]. High levels of TMAO are associated with hypomethylation conditions and a specific pattern of the lipid profile, in which phospholipids and HDL are detected at low levels. Male gender may also play a role in TMAO production [90][58]. TMAO has been found to be a potential clinical marker in patients with peripheric vasculopathy. In rats, the Slc30a7 gene has been reported to play an important role in TMAO production and levels, but, in humans, the mechanism appears to be much more complex than one specific gene being involved [91][59].

4. Potential Therapeutic Targets

Nowadays, there are many potential therapeutic approaches that are used to prevent the development and promotion of atherosclerosis through the gut microbiota. Some are used as modifiers of the intestinal microbiota composition, thus preventing intestinal dysbiosis. Such approaches include antibiotics, probiotics, prebiotics, resveratrol, meldonium, antibiotics, dietary modification (e.g., reduced choline intake and high-fiber diet), fecal transplantation, and physical exercise. Another possible treatment is 3,3-dimethyl-1-butanol (DMB), which is promising [92,93,94,95,96][60][61][62][63][64].
Initially, during treatment with antibiotics (mainly ampicillin and azithromycin), the composition of the microbiota improved significantly; however, there were several side effects due to the prolonged use of these drugs [97][65]. Prebiotics have a positive effect on the composition of the intestinal microbiome and promote the growth of symbiotic bacteria in the intestinal lumen. They also cause a reduction in intestinal pathogens that have a negative effect on metabolism and, by extension, a promotion in atherosclerosis. Some prebiotics are oligosaccharides and inulin. Probiotics are known as live microorganisms with a positive effect on the human body in the same way as prebiotics. Some of them are Bifidobacteria, Enterococcus, and Lactobacillus [98,99][66][67]. Archaebiotics, such as Methanomassiliicoccus luminyensis B10, reduce the production of TMA by reducing methanogenesis in the intestinal lumen, which is a therapeutic target for atherosclerosis [97][65]. Regarding dietary food intake, resveratrol (a natural phytoalexin) behaves as a prebiotic and increases the proportion of Bifidobacteria and Lactobacillus [100,101][68][69]. Plant sterol ester (PSE) and β-glucan (OBG) have been reported as dietary interventions that reduce the promotion of atherosclerosis by the gut microbiome through the reduction of TMA levels [102,103][70][71]. Furthermore, SCFAs such as butyric acid and pomegranate have an anti-inflammatory effect, reducing pro-inflammatory cytokines. This results in a reduction in atherosclerotic plaque [104,105][72][73]. In addition to butyric acid, some probiotic products, such as berberine, kefir, and Greek yogurt, are reported in the international literature for their anti-atherosclerotic role by modifying the composition of the microbiota [106,107][74][75]. Meldonium, an analogue of γ-butyrobetaine, was found to reduce TMA production [108][76]. Other dietary habits that may be beneficial are red berries, tea polyphenols, and oligosaccharide mannans [109,110][77][78]. Beyond affecting the composition of the microbiota, many therapeutic approaches interfere with TMAO production. DMB, which is a choline analogue, inhibits TMA lyases and, consequently, the production of TMA by the gut microbiome, thereby reducing TMAO levels [111][79]. DMB is found in virgin olive oil and wine [112][80]. In addition, DMB inhibits the generation of foamy cells and, thus, reduces the promotion of atherosclerosis [113,114,115,116][81][82][83][84]. The FOM-3 enzyme has many positive effects on the human body and, for this reason, its suppression has many side effects such as liver inflammation [117,118][85][86]. In fact, when there is a genetic disorder in the function of FOM-3, patients suffer from fish odor syndrome, which is one of the side effects of suppressing this enzyme [117,118][85][86]. Thus, the above therapeutic path is not an attractive intervention, despite the initial enthusiasm. Finally, bariatric surgery did not appear to decrease TMAO levels, even though some metabolic parameters improved [119][87].

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