Defining what is “normal” in healthy microbiota communities is an ongoing process. Currently, there are key players that have already come to light with regards to many diseases. This chapter serves to identify which microorganisms and related mechanisms play a role in cardiovascular disease.

The gut microbiome regulates and influences many metabolic processes in the body. Research clearly indicates that it has a profound impact on the pathogenesis of cardiovascular disease. The gut microbiota is the collection of 40 trillion microorganisms living in the gastrointestinal tract, whereas the gut microbiome is the collection of total genes of these microorganisms. The cells of the human body are outnumbered by microbial cells 10 to 1 and the genes 150 to 1.¹ These genes are so influential in many biological processes that there has been a major shift in the realm of research to examine these microorganisms as they relate to every function and dysfunction of the body. So far, there is not one chronic disease wherein an imbalance of this ecosystem has not been observed.

The term “gut microbiome” was coined only in 2001,² but it was not until 2007 that the science and understanding of the gut microbiome really progressed. Using technology developed for the Human Genome Project, scientists began to realize that the gut microbiome is essential to human health. This resulted in the National Institute of Health’s Human Microbiome Project, which set out to catalog the microorganisms living across the various human body’s “ecosystems.” The differences in diversity of the strains found in the human body are so vast³ that they dwarf the differences in biodiversity found between a tropical rainforest and a savanna when you combine all their respective flora and fauna.

A unique characteristic of the gut microbiome is that it appears to shift and adapt rapidly depending on what resources are present to meet the metabolic needs of the host. This means it is more important that we map the metabolic pathways (the means of obtaining a by-product) and functions (the by-products themselves) of these organisms, rather than focus on specific strains, because their behavior is dependent on their resources and the presence of other organisms.

It is worth mentioning that some of the language used to describe microorganisms needs to change. Because strains once labeled “pathogenic” are proving to play vital roles in human health when they are in the appropriate numbers and location within the body, the more appropriate term is now considered “opportunistic.” Some bacteria are able to be either symbiotic or parasitic depending on the context, which is also called amphibiosis. An example of this is Helicobacter pylori⁴, which is generally associated with acute gastritis but has been found to also be protective against acid reflux. Another concern is the translocation of particular strains, which can sometimes cause issues. An example of this would be a condition called small intestinal bacterial overgrowth (SIBO), where colonic-type bacteria proliferate in large numbers in the small intestine.

The intricate role of these microorganisms in human biology is so profound, it is appropriate to consider this complex ecosystem as an organ of multiple systems, including:

The endocrine system-The gut microbiota is arguably the largest endocrine organ⁵ and capable of producing a wide range of biologically active compounds that may be carried via circulation to distant sites within the host.

The nervous system-The gut microbiota directly influences the development, function, and activity of the enteric nervous system⁶ through neurotransmitter synthesis and the physical and chemical stimuli on intrinsic primary afferent neurons⁷ throughout the gut lining.

The immune system-The gut microbiota is also integral to maintaining homeostasis in the immune system⁸ of the host. It plays an important metabolic role through maintaining cross-talk with the immune system.

Important metabolic functions of the gut microbiome include:

Similar to an ecological ecosystem, the best indicators of the overall health of the gut microbiome are richness and diversity. Richness is the number of species within the community, and diversity refers to the richness combined with how evenly distributed the species are. The gut microbiota includes bacteria, viruses, fungi, archaea, and phages. Bacteria are by far the most prominent microorganisms, comprising almost 90% of this ecosystem.⁹

Greater microbial diversity is associated with the body’s ability to deal with stressors, such as opportunistic pathogens, dietary, and environmental perturbations. Individuals with disease are more likely¹⁰ to have alterations in their gut microbiome compared with healthy controls. There are strong associations between reduced microbial diversity and illness.

Bacterial colonization during birth plays a major role in the formation and resilience of the gut microbiota. Babies born vaginally colonize with a gut microbiome similar to their mothers’ vaginal microbiota, whereas cesarean section-born infants are colonized by bacteria found on the mothers’ skin surface. It is well established that cesarean sections are associated with a higher risk of numerous diseases including asthma, food allergy, type 1 diabetes, and obesity¹¹, and it appears that an altered microbiota is a likely mechanism. Factors that affect diversity throughout life include:

The importance of the gut microbiome and its various roles across human biology makes having an understanding of this “organ” essential for anyone in the medical field. Furthermore, it is critical that medical professionals remain vigilant in continuously educating themselves on the most current research.

Dysbiosis is the imbalance or maladaptation of the gut microbiome. Low diversity and richness can present as dysbiosis and are associated with higher levels of inflammation¹², higher adiposity, insulin resistance, and dyslipidemia. A 2013 study¹³ published in the journal Nature studied participants (n = 292) in two characterized groups, delineated by the number of gut microbial genes (gut bacterial richness) with an average 40% difference between low gene count individuals and high gene count individuals. Individuals with low bacterial gene richness (23% of the study population) were characterized by an increase in adiposity, insulin resistance, and dyslipidemia. Additionally, low bacterial richness individuals showed a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. Various metabolic diseases, including type 2 diabetes and obesity, are associated with dysbiosis that is distinguishable by a unique microbiota profile.

Some causes of dysbiosis include:

The gut microbiota is an important player in atherogenesis.¹⁴ Specifically, higher levels of Lactobacillales and decreased levels in Bacteroides have been associated with coronary artery disease.¹⁵ Metabolism by certain intestinal flora has been linked to the deleterious association between the development of atherosclerotic plaque and egg yolk consumption, due to its choline content. Certain gut microbiota can metabolize choline, phosphatidylcholine¹⁶, and L-carnitine¹⁷ to produce trimethylamine (TMA), which can be oxidized in the liver into trimethylamine N-oxide (TMAO), a proatherogenic metabolite. Inhibiting TMAO production through the gut microbiota has been found to be a promising treatment of atherosclerosis.¹⁸ Owing to the inherent complexity of the gut microbiome and its differences among individuals, this pathway
is not the same for everyone. The complex ecology of the gut microbiota and its role in metabolic behavior must be considered. For example, many types of fish are still considered beneficial for cardiovascular patients¹⁹ despite their trimethylamine content. Additionally, L-carnitine may ameliorate metabolic diseases²⁰ by increasing insulin sensitivity of the skeletal muscle and may reduce ischemic heart disease in some people.

Another major mechanism that causes systemic inflammation in the body and is largely modulated by the gut microbiota and gastrointestinal lining is the development of metabolic endotoxemia²¹ brought on by intestinal permeability and lipopolysaccharides (LPS). There is a strong correlation between metabolic endotoxemia and an increased risk of cardiovascular disease, diabetes, and obesity. Metabolic endotoxemia is characterized by insulin resistance and low-grade inflammation.

Intestinal permeability can cause systemic inflammation through translocation of LPS. Intestinal permeability is also known as “leaky gut” and is a reinforcing process that can result in intestinal inflammation, damage to the gut lining, dysregulation of the immune system response, nutrient malabsorption (especially vitamins B12, magnesium, and iron), gastrointestinal issues, multiple food intolerances, and, eventually, autoimmune disease.

LPS are a major component of the outer membrane of gram-negative bacteria and considered endotoxins. If they are absorbed through the gastrointestinal lining, they can elicit systemic inflammation and a strong immune system response. The detection of antibodies against LPS can reveal macromolecule endotoxin infiltration through the intestinal barrier into the systemic circulation. Other indicators of a compromised gastrointestinal lining include occludin, the main component of the proteins that hold together the tight junctions, and zonulin, which is a protein that regulates permeability of the intestine. Detection of antibodies for occludin and zonulin can indicate that tight junctions are breaking down or that normal regulation of tight junctions is compromised, respectively. An assessment of gut barrier damage can be done by measuring these barrier protein antibodies. This detects damage long before there is a dysregulation of the immune system response. This process can be a major driver of inflammation in the body.

Clinical indications that would warrant testing for LPS endotoxemia include:

Causes of increased intestinal permeability include:

Biomarkers of intestinal permeability:

Metabolic endotoxemia is characterized by:

This mechanism suggests that lowering plasma LPS concentration is a potential strategy for controlling metabolic diseases.

The gut microbiota and its metabolites have been implicated in the regulation of host physiological functions that can contribute to hypertension, a precursor to cardiovascular disease. As in cardiovascular disease, Firmicutes, Bacteroides, Actinobacteria, and Proteobacteria are the microorganisms
that play a major role in the pathogenesis of hypertension. Toxic products produced by the gut microbiome, such as TMAO, p-cresol sulfate, and indoxyl sulfate, can contribute to salt sensitivity and affect blood pressure regulation and related epigenetic changes. SCFA receptors are expressed in the kidney and blood vessels and have been reported to function as a regulator of blood pressure (BP).

Specific and observed gut microbiome contributors to hypertension²²:

These interactions provide novel therapeutic pathways for BP regulation. The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. Other hypertension intervention methods via the gut microbiome worth considering include²³:

When the brain-gut microbiome axis and the gastrorenal reflex are affected, psychological symptoms may be observed. The absence of some gut microbiota may increase anxiety and decrease dopamine in the frontal cortex, hippocampus, and striatum. There can also be alterations in renal dopamine with salt intake. Finally, changes to the gut microbiome can induce changes in microRNAs, DNA methylation, and acetylation, which can contribute to inflammatory diseases including hypertension and cardiovascular disease.

The connection between periodontal microbes and cardiovascular disease has long been observed with no definitive mechanisms identified. LPS-mediated mitochondrial dysfunction²⁴ is a potential origin of oxidative stress in periodontal patients, as is intestinal permeability. Research indicates that inflammatory responses evoked by the LPS of Porphyromonas gingivalis is one key factor in this process. The influence of LPS on fibroblast and peripheral blood mononuclear cells appears to increase reactive oxygen species production while reducing CoQ10 levels and citrate synthase activity. Mitochondrial dysfunction promoted by Porphyromonas gingivalis LPS on these cells may also promote oxidative stress and alter cytokine homeostasis.

Certain organisms and gut microbiota composition patterns have been associated with cardiovascular disease and metabolic syndrome. Low bacterial richness is associated with a reduction in beneficial butyrate-producing bacteria. Butyrate is an SCFA with potent anti-inflammatory potential. Low bacterial richness is also associated with mucus degradation, potential gut barrier impairment, and an increase in oxidative stress (Table 27.1).

Species and patterns associated with atherosclerosis:

Species associated with cardiovascular disease (Table 27.2):