Indian Journal of Clinical Anatomy and Physiology

Infection and Inflammation

Development of atherosclerosis can be affected via two different mechanisms direct infection of vessel wall cells, which creates a point prone to lesion development, or a circular infection at a point distant from the atherosclerotic atheromatous plaque, which activates the vulnerable system that in turn increases the systemic inflammatory status.^[3]

Inflammation plays a crucial part in the development and progression of atherosclerosis. When the inner lining of endothelium is damaged by factors such as high blood pressure, smoking, or high situations of LDL cholesterol, white blood cells called monocytes and macrophages travel to the area and phagocytose the damaged cells.

These vulnerable cells release chemicals such as cytokines and growth factors that initiate inflammation, leading to chain of events that can eventually affect in the formation of atherosclerotic plaque. Over time, the plaque can become unstable and rupture, leading to blood clots that can block blood inflow to the heart or brain, causing a heart attack or stroke.

In addition to these vulnerable cells, other factors such as high levels of C- reactive protein (CRP), a marker of inflammation, have also been linked to an increased threat of atherosclerosis and cardiovascular impact. One way that infection is linked with atherosclerosis is through inflammation. Infection leads to inflammation which begin damage to inner linings of endothelium, which can make it easier for atheromatous plaque to form. Certain bacterial species in the gut microbiome have been linked to increased atherosclerosis risk. For example, infections with periodontal bacteria such as Porphyromonas gingivalis have been associated with systemic inflammation and atherosclerosis. These bacteria may translocate into the bloodstream, triggering an immune response and endothelial dysfunction resulting in atherosclerosis.

In addition to Porphyromonas gingivalis, many other gut bacteria contribute in atherosclerosis. For example, Escherichia coli (E. coli)- Certain strains of E. coli can produce lipopolysaccharides (LPS), which are potent inflammatory molecules. Elevated levels of LPS in the bloodstream have been linked to inflammation, endothelial dysfunction, and atherosclerosis. Enterococcus faecalis: This bacterium has been associated with the production of trimethylamine (TMA), a precursor to trimethylamine-N-oxide (TMAO), which is linked to atherosclerosis. TMAO has been shown to promote the development of atherosclerotic plaques by affecting cholesterol metabolism and promoting inflammation.

Metabolism of lipid and cholesterol

Cholesterol is a type of lipid molecule that is essential for many important physiological functions in the human body, including the formation of cell membranes, the production of hormones, and the synthesis of bile acids. However, high levels of cholesterol in the blood can contribute to the development of atherosclerosis, a condition in which fatty plaques build up inside the arteries, restricting blood flow and increasing the risk of heart attack and stroke.^[8]

The gut microbiome plays an important role in regulating lipid metabolism and cholesterol levels in the body. Certain types of bacteria in the gut are able to produce enzymes that can break down bile acids, which are produced by the liver to help digest fats in the diet. This process leads to the production of secondary bile acids, which have been shown to lower cholesterol levels in animal studies.

In addition, some types of gut bacteria have been shown to produce short-chain fatty acids (SCFAs), which have been linked to lower cholesterol levels and a reduced risk of cardiovascular disease. SCFAs are produced when certain types of bacteria ferment dietary fiber in the colon, and they have been shown to inhibit the synthesis of cholesterol in the liver.

Patient with atherosclerosis have altered lipid metabolism and bacterial flora in gut and oral cavity which correlate with plasma cholesterol levels. bacterial richness (that is, the number of bacterial taxa identified) and specific taxa were associated with BMI and levels of triglycerides and HDL, whereas no such clear association was found with levels of total cholesterol or LDL. Compared with germ-free mice, the levels of cholesterol and triglycerides in the plasma of conventionally raised mice are reduced, whereas they are increased in adipose tissue and liver. These findings support a relationship between the composition of the gut microbiota and plasma levels of cholesterol and lipids.^[2]

TMAO metabolism

Large proportion of humans now consume a diet with cholesterol, fats and sugar. Dietary components are also involved in the atherogenic process. One such example is the proatherogenic metabolite trimethylamine (TMA) generated from microbial metabolism of phosphatidylcholine, which is common in red meat, shellfish, and eggs. TMA is later converted by liver into trimethylamine N-oxide (TMAO). ^[9]

TMAO may promote inflammation, impair cholesterol metabolism, and alter endothelial cell function.^[10], ^[11] Inflammation plays a key role in the development of atherosclerosis, and TMAO has been shown to increase the expression of inflammatory markers such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). TMAO also upregulates the expression of macrophage CD-36 and SR-A1. It results in increase in formation of macrophage foam cells, which are a key component of atherosclerotic plaques. TMAO also increases the instability of atherosclerotic plaque resulting in plaque rupture. The rupture of plaque might cause diseases like myocardial infarction and stroke.^[12] Additionally, TMAO has been shown to alter endothelial cell function, which can lead to endothelial dysfunction and impaired vascular function.^[8], ^[11]

As a result, high TMAO levels causes reduction in removal of bad cholesterol from arteries and make blood more likely to clot. If you have high TMAO, one should consider changing the diet to alter the gut bacteria. Eating a Mediterranean style diet rich in green leafy vegetables and reducing the intake of red meat will help reduce TMAO production. This will lower the risk of atherosclerosis and its related diseases.

Remedial strategy to target gut microbiota and lower the risks of atherosclerosis

Studies that suggest microbiome as a risk factor for atherosclerosis also raise hope for novel therapeutic and remedial strategies for the same. One of such potential remedial strategy to alter the gut microbiota and reduce the risk of atherosclerosis is through dietary modification. Studies have shown that certain plant-based diets like eating green leafy vegetables, fruits and whole grain can promoted a diversified and beneficial gut microbiome thus results in reduction in chances of atherosclerosis.^[2], ^[13] Plant based food also contain phytochemicals in them, which have anti-inflammatory effect.^[13] Another novel therapeutic strategy might be using prebiotics & probiotics.

A further prospective therapeutic approach for atherosclerosis is fecal microbiota transplantation (FMT). FMT restores microbial diversity and function by transferring the microbiota of a healthy donor to a recipient. FMT has a lot of potential for changing the gut microbiome and reducing inflammation associated with atherosclerosis, despite the fact that its safety and effectiveness in treating cardiovascular disease still need to be thoroughly investigated.^[14], ^[15]