Role of bacteria in vascular health and endothelial dysfunction
In a healthy vascular system, the endothelium, which lines the inside of blood vessels, plays an essential role in maintaining vascular dilation, regulating blood flow, and inhibiting the adhesion of inflammatory cells and platelets. Bacteria play a crucial role in maintaining the body’s homeostasis, but some species are also implicated in pathological processes that can negatively affect vascular health, contributing to endothelial dysfunction and the formation of atheromatous plaques, which are hallmarks of atherosclerosis. This process occurs primarily through the induction of systemic inflammation, the production of endotoxins, and the activation of the immune response, all of which promote plaque formation. Confirmation that bacterial species may be the cause or at least a contributory cause of the phenomenon occurred about a decade ago, when lipidomic analysis of plaque material found lipids containing both fatty acids with an odd number of carbon atoms (humans metabolize them with an even number) and with lateral methyl branches, which is an exclusive biochemical characteristic of prokaryotes but not eukaryotes.
Bacteria associated with atherosclerosis
Porphyromonas gingivalis
This bacterium, common in periodontal infections, has been shown to be associated with endothelial dysfunction and atherosclerosis. In recent years, increasing evidence has accumulated suggesting an association between P. gingivalis infection and atherosclerosis, a disease characterized by the formation of atheromatous plaques in the arteries. P. gingivalis can enter the bloodstream through inflamed gingival tissue, spreading throughout the circulatory system and negatively affecting the vascular endothelium. It can also invade deep periodontal tissues and enter the bloodstream through inflamed gingiva, a process called transient bacteremia. Once in the blood, the bacterium can colonize blood vessels and arterial walls, directly contributing to the formation of atherosclerotic plaques.
Porphyromonas gingivalis infection can stimulate LDL oxidation, which is a key process in the development of atherosclerosis. Oxidized LDL is highly atherogenic and promotes the recruitment of immune cells that, once in the vascular tissue, amplify inflammation and plaque growth. It also produces lipopolysaccharides (LPS) that induce systemic inflammation and proteases known as gingipains, which can degrade extracellular matrix proteins and damage the vascular endothelium. In addition, LPS from P. gingivalis activate Toll-like receptor 4 (TLR4) present in endothelial and immune cells, triggering a further inflammatory cascade. This systemic inflammatory response damages the vascular endothelium, facilitating lipid accumulation and infiltration of inflammatory cells into the arterial walls, resulting in the formation of atherosclerotic plaques.
Streptococcus mutans
It is a facultative anaerobic gram-positive bacterium known primarily for its role in dental caries. However, recent studies have suggested that S. mutans may also play a role in the development of atherosclerosis and other cardiovascular diseases. Although its link with oral health is well established, the association with muscle diseases is gaining attention in medical research, as chronic inflammation caused by oral infections has been linked to systemic effects. The hypothesis of the contribution of S. mutans to the development of atherosclerosis is based on several pathogenetic mechanisms, which include both direct and indirect effects on the arteries and endothelium:
- Transient bacteremia and adhesion to blood vessels: When there is oral inflammation, such as in the case of advanced caries or gingivitis, S. mutans can enter the bloodstream, causing transient bacteremia. During this process, the bacterium can adhere to the walls of blood vessels, particularly at sites that are already damaged, where it can facilitate the accumulation of lipids and the recruitment of inflammatory cells.
- Exposure of the Cnm antigen and colonization of arteries: A particular subpopulation of S. mutans expresses a protein called collagen-binding protein (Cnm), which facilitates the adhesion of the bacterium to collagen present in human tissues. This protein particularly makes S. mutans suitable for colonizing damaged vascular walls and atherosclerotic lesions, contributing to the stabilization and expansion of plaques.
- Induction of the inflammatory response: S. mutans can trigger a strong immune response, which leads to the release of pro-inflammatory cytokines such as IL-6 and TNF-α. These cytokines promote the recruitment of immune cells to vascular sites, a process that favors the formation and growth of atherosclerotic plaques.
- 4. Platelet activation: S. mutans has been shown to activate platelets, causing them to aggregate and form microthrombi. This process promotes the formation of atherosclerotic plaques and may contribute to the progression of atherosclerosis, increasing the risk of acute muscle events such as heart attacks and strokes.
- Formation of reactive oxygen species (ROS): S. mutans infection can stimulate the production of reactive oxygen species, which are involved in the oxidation of LDL, a process that is critical for the initiation of atherosclerotic plaque formation. Oxidized LDL is easily phagocytosed by macrophages, leading to the formation of foam cells, which are a key component of plaques.
Chlamydia pneumoniae
This species has been frequently associated with atherosclerosis. Some studies have shown a correlation between high levels of antibodies against C. pneumoniae in the blood and an increased risk of cardiovascular disease. This suggests a possible association between chronic infection and atherosclerosis. Some studies have attempted to use antibiotics specific to C. pneumoniae in patients with atherosclerosis, but the results have been inconclusive. This may be due to the difficulty of eradicating chronic infection or the multifactorial complexity of atherosclerosis, where the presence of C. pneumoniae is only one of many risk factors. The involvement of Chlamydia in atherosclerosis appears to result from a combination of direct and indirect effects. C. pneumoniae can infect endothelial cells, which line the inside of blood vessels, as well as smooth muscle cells in the arteries.
Once infected, these cells suffer damage that compromises their functionality, promoting inflammation and the recruitment of immune cells into the arterial wall. This phenomenon contributes to the initiation and progression of atherosclerosis. The bacterium stimulates a chronic inflammatory response, which induces the release of inflammatory cytokines such as IL-6, IL-1β and TNF-α. This stimulates the recruitment of macrophages and lymphocytes into the arterial walls. Macrophages, in particular, phagocytose low-density lipoproteins (LDL), forming foam cells, which are key components of atheromatous plaque. Finally, C. pneumoniae is able to metabolize and use cholesterol for its intracellular growth, which could stimulate the accumulation of oxidized LDL in the arteries. This factor favors the accumulation of lipoproteins and promotes plaque growth.
Helicobacter pylori
Helicobacter pylori is a gram-negative bacterium that colonizes the gastrointestinal tract and is primarily known for its association with gastritis, peptic ulcers, and gastric cancer. Some epidemiological studies have suggested an association between H. pylori infection and an increased risk of cardiovascular disease. However, the results have not always been conclusive, with some studies showing a significant link and others not finding one. However, recent research has suggested that H. pylori may also be involved in some cardiovascular diseases, particularly atherosclerosis, the buildup of atherosclerotic plaque in the arteries, which is a major risk factor for cardiovascular events such as heart attacks and strokes. Evidence suggests that H. pylori may contribute to vascular dysfunction and atherosclerosis through a number of indirect mechanisms:
- Systemic inflammation: H. pylori is known to cause chronic inflammation in the stomach, which can have systemic repercussions. Chronic Helicobacter infection leads to the release of inflammatory cytokines, such as IL-6, IL-1β, and TNF-α, which are associated with a systemic inflammatory state. Persistent inflammation promotes damage to the vascular endothelium, increasing the likelihood of atherosclerotic plaque formation.
- Stimulation of the immune response and endothelial activation: The bacterium induces a sustained immune response that can lead to the production of autoantibodies and activation of endothelial cells. This stimulates the release of adhesion molecules (such as ICAM-1 and VCAM-1) that promote the recruitment of inflammatory cells to arterial sites and increase the risk of endothelial damage and lipid deposition in arterial walls.
- Increased homocysteine levels: Some studies have observed that patients infected with H. pylori may have elevated levels of homocysteine, an aminoacid associated with an increased risk of atherosclerosis. Hyperhomocysteinemia promotes endothelial dysfunction and contributes to plaque formation, increasing the risk of cardiovascular events.
Role of the microbiota in cardiovascular stability
Bacteria in the gut microbiota produce metabolites, such as short-chain fatty acids (SCFAs), which exert anti-inflammatory effects and modulate the immune response. SCFAs, including acetate, propionate, and butyrate, help maintain the integrity of the intestinal barrier, preventing pathogenic bacteria and pro-inflammatory molecules from entering the bloodstream, a process that can lead to systemic inflammation and vascular damage. In addition to SCFAs, the gut microbiota produces other compounds that can influence cardiovascular health. For example, some bacteria produce antioxidants, vitamin K, and B vitamins, which are essential for cardiovascular metabolism and protection against oxidative stress, a risk factor for cardiovascular disease.
When the microbiota is in balance, it helps maintain a robust intestinal barrier. A compromised intestinal barrier allows lipopolysaccharides to enter the blood. Some gut bacteria influence lipid metabolism, helping to maintain healthy levels of cholesterol and lipoproteins in the blood. In conditions of dysbiosis, there may be an alteration in the production of bile acids and an increased synthesis of LDL cholesterol (“bad” cholesterol), which is associated with an increased risk of atherosclerotic plaque formation. Finally, the gut microbiota is involved in the metabolism of some bioactive compounds present in foods, such as polyphenols, which have protective effects on the cardiovascular system. These compounds help reduce inflammation and improve endothelial function, helping to maintain healthy blood vessels.
Dysbiosis and cardiovascular risk
When dysbiosis occurs – that is, an alteration in the balance between beneficial and potentially pathogenic bacteria – an environment is created that is favorable to inflammation and the development of chronic diseases. Some effects of dysbiosis associated with an increase in cardiovascular risk include:
Increased pro-atherogenic metabolites: in conditions of dysbiosis, some bacteria produce compounds such as trimethylamine (TMA), which is subsequently transformed in the liver into trimethylamine-N-oxide (TMAO). TMAO is a compound that promotes the accumulation of cholesterol in the foam cells of the arteries, favoring the formation of atherosclerotic plaques.
Increased systemic inflammation: dysbiosis leads to an increase in intestinal permeability and, consequently, to a passage of endotoxins into the blood. This can contribute to a condition of chronic low-grade inflammation that damages the vascular walls and favors the development of atherosclerosis.
Alteration of lipid and carbohydrate metabolism: some bacteria directly influence the metabolism of lipids and carbohydrates. Dysbiosis is associated with disorders of lipid metabolism, manifested as hyperlipidemia and obesity, two well-known risk factors for cardiovascular disease.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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