The key role of the intestines and microbiota in the development of cardiovascular disease

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A high-fat diet disrupts the biology of the gut’s inner lining and its microbial communities – and promotes the production of a metabolite that may contribute to heart disease.

The discoveries in animal models support a key role for the intestines and microbiota in the development of cardiovascular disease, said Mariana Byndloss, DVM, Ph.D., assistant professor of Pathology, Microbiology and Immunology at Vanderbilt University Medical Center.

The intestines, she noted, have been relatively understudied by scientists seeking to understand the impact of obesity.

“Before COVID, obesity and metabolic syndrome were considered the pandemic of the 21st century. Right now, roughly 40% of the U.S. population is obese, and that percentage is predicted to climb,” Byndloss said.

“Our research has revealed a previously unexplored mechanism for how diet and obesity can increase risk of cardiovascular disease – by affecting the relationship between our intestines and the microbes that live in our gut.”

In previous studies, Byndloss and Andreas Bäumler, Ph.D., at the University of California at Davis, found that the epithelial cells lining the intestines and gut microbes share a mutually beneficial relationship that promotes a healthy gut environment. They wondered if diseases like obesity affect this relationship.

The collaborating research teams found that a high-fat diet causes inflammation and damages intestinal epithelial cells in animal models. The high-fat diet impairs the function of energy-generating mitochondria, Byndloss explained, causing the intestinal cells to produce more oxygen and nitrate.

These factors, in turn, stimulate the growth of harmful Enterobacteriaceae microbes, such as E. coli, and boost bacterial production of a metabolite called TMA (trimethylamine).

The liver converts TMA to TMAO (trimethylamine-N-oxide), which has been implicated in promoting atherosclerosis and increasing the relative risk for all-cause mortality in patients.

“It was known that exposure to a high-fat diet causes dysbiosis – an imbalance in the microbiota favoring harmful microbes, but we didn’t know why or how this was happening,” Byndloss said. “We show one way that diet directly affects the host and promotes the growth of bad microbes.”

The researchers demonstrated that a drug currently approved for treatment of inflammatory bowel disease restored the function of intestinal epithelial cells and blunted the increase in TMAO in the animal models. The drug, called 5-aminosalicylic acid, activates mitochondrial bioenergetics in the intestinal epithelium.

“This is evidence that it’s possible to prevent the negative outcomes associated with a high-fat diet,” Byndloss said. A drug such as 5-aminosalicylic acid might be used in conjunction with a probiotic to both restore a healthy intestinal environment and boost beneficial microbe levels, she added.

“Only by fully understanding the relationship between the host—us—and gut microbes during health and disease are we going to be able to design therapies that will be effective in controlling obesity and obesity-associated outcomes like cardiovascular disease.”

Byndloss and her team plan to extend their studies into animal models of cardiovascular disease. They also are exploring the role of the host-microbe relationship in the development of other diseases including colorectal cancer.


ROLE GUT MICROBIOTA IN CARDIOVASCULAR DISEASES

Atherosclerosis is an inflammatory disease with a growing body of evidence supporting a potential autoimmune background[45]. Infection is one of the major contributors to inflammation in the body and is a proposed mechanism of atherosclerosis. A large number of microorganisms such as Chlamydophila pneumoniae, Porphyromonas gingivalis, Helicobacter pylori, Influenza A virus, Hepatitis C virus, cytomegalovirus, and human immunodeficiency virus have been associated with an increased risk of cardiovascular diseases[46].

Infections contribute towards atherosclerosis via two predominant mechanisms: direct infection of the blood vessel wall (making it prone to plaque formation), or indirectly with an infection at a distant site by promoting proinflammatory mediators from a systemic immune response affect plaque growth (Figure ​3)[47]. Additionally, dysbiosis also contributes to the production of atherosclerotic metabolites in the gut like trimethylamine N-oxide (TMAO) and can alter bile acid metabolism[48]. In this section, we will discuss the role and the evidence for each of the proposed mechanisms.

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Figure 3
Proposed mechanisms of micro pathogen mediated atherosclerotic cardiovascular diseases. ASCVD: Atherosclerotic cardiovascular diseases.

Direct infection

Over 50 species of bacterial DNA have been observed in atherosclerotic plaques[49]. Proteobacteria phylum (Chryseomonas and Helicobacter genera) is found to be most abundant in atherosclerotic plaques[49]. Firmicutes phylum (Anaeroglobus, Clostridium, Eubacterium, Lactobacillales and Roseburia genera) is predominantly found in the oral and gut cavity and is also present in atherosclerotic plaques[49].

Other bacteria that have been shown to be altered in the gut among patients with atherosclerotic cardiovascular disease includes Lactobacillales, Collinsella (stenotic atherosclerotic plaques in the carotid artery leading to cerebrovascular events), Enterobacteriaceae and Streptococcus spp (Table ​(Table11)[50,51]. In fact, it has been suggested that gut microbiota, especially Bacteroides, Clostridium and Lactobacillales could be considered as diagnostic markers in patients suffering from coronary artery disease[52].

Table 1

Microorganisms associated with cardiovascular disease

Microorganisms associated with cardiovascular disease
C. pneumoniae
P. gingivalis
H. pylori
Lactobacillales
Influenza A
Cytomegalovirus
Human immunodeficiency virus
Enterobacteriaceae
Streptococcus parasanguinis
Collinsella
Veillonella
Aggregatibacter
Firmicutes
Bacteroidetes
Actinobacteria
Fusobacteria
Proteobacteria
Candidate division TM7 single-cell isolate TM7c
Spirochaetes
SR1
Tenericutes
Deinococcus-Thermus
Gemmatimonadetes
Chloroflexi
Neisseria polysaccharea
Neisseria subflava
Waddlia chondrophila
Prevotella
Beggiatoa sp. P5
Alloprevotella rava
Megasphaera micronuciformis
Acidovorax sp. CF316
Atopobium parvulum
Solobacterium moorei
Clostridium difficile

Indirect infection

Microorganisms, through inflammatory cytokine production and stimulation of acute-phase reactants, contribute to the development of atherosclerosis by further adding to the chronic inflammation within the atheromatous plaques[46]. In murine models, the use of antibiotics has shown an alteration in the gut microbiome, which affects carbohydrate and lipid metabolism.

Initial studies investigating the role of pathogens in the development of atherosclerotic plaques had accounted for single microorganisms and not the overall microbiome, more recently it is being recognized that the aggregate number of microorganisms which an individual is colonized or infected with correlates more with atherogenesis, a concept referred to as “pathogen burden” or “infectious burden”[53].

Another possible mechanism for increased inflammation is cross-reactivity or molecular mimicry between self-antigens and bacterial antigens like heat-shock proteins and oxidized low-density lipoproteins[54]. Human heat-shock protein 60 (hHSP60) is expressed on the arterial endothelium in response to stress such as acute hypertension, hypercholesterolemia and in reperfusion injury. Also, a major antigenic component of bacteria during infection is the bacterial heat-shock protein 60s (HSP60s).

Due to the high degree of homology between human and bacterial HSP, it is suggested that the antibodies formed against bacteria can target host cells expressing hHSP60. Indeed, high titres of serum antibody to mycobacterial HSP-65 were found in subjects with coronary or carotid atherosclerosis and post-myocardial infarction state[55].

As mentioned before, dysbiosis also leads to alteration in the immune system, which causes increased inflammation and atherogenesis. TLRs have been known to play a crucial role in bacterial infection and activation of the innate immune response. Once activated by ligands such as LPS, TLR dimerizes with the interleukin-1 receptor (IL-1R) forming a complex that binds myeloid differentiation primary response protein, MyD88, leading to downstream signalling cascade ultimately activating NF-κB.

This cascade results in stimulation of the synthesis of proinflammatory cytokines, chemokines and costimulatory molecules[56]. TLR’s expression is found in most cardiovascular cells like endothelial cells, cardiomyocytes, adventitial fibroblasts, and macrophages. Among TLRs, TLR4 is best understood. Studies have described activation of TLR4 by saturated fatty acids, acting as a ligand through the same downstream pathways as for LPS resulting in the production of proinflammatory cytokines and chemokines[57,58].

Additionally, saturated fatty acids contribute to the induction of the inflammation by alternating gut microbiota in favour of Gram-negative bacteria, thus, increasing LPS levels. These processes promote translocation of bacteria and endotoxins into the bloodstream from the intestinal lumen due to an increase in intestinal permeability, further adding to the activation of TLR4[59]. In the animal models with a genetic deficiency of TLR4 and MyD88 genes, reduced proinflammatory cytokines and decreased plaque lipid content and aortic atherosclerosis were observed[60]. Human studies have also shown increased expression of TLR1, TLR2 and TLR4 in atherosclerotic plaques, suggesting a potential role in pathogenesis[61].

Production of proatherogenic metabolites

TMAO is an intestinal microbiota metabolite of choline and phosphatidylcholine. Dietary components such as choline, phosphatidylcholine, and carnitine, found in various animal-based products and energy drinks, are metabolized by gut microbiota to trimethylamine (TMA), and then oxidized by flavin monooxidases 3 in the liver to TMAO[62,63]. Flavin monooxidases 3 is an important regulator of TMAO synthesis and is regulated by farnesoid X receptor (FXR) whose expression can be upregulated by bile acids.

TMAO can lead to atherogenesis via multiple mechanisms, though the underlying pathway is not completely understood. It inhibits reverse cholesterol transport causing reduced cholesterol removal from peripheral macrophages, and also affects atheroprotective effects of high-density lipoprotein thus promotes atherosclerosis[64]. TMAO also acts on platelets and increases platelet hyperre-sponsiveness by enhancing the stimulus-dependent release of Ca2+ from intracellular Ca2+ stores leading to increased thrombotic risk[63].

The effects of TMAO have also been observed in vascular cells promoting proinflammatory protein activation such as interleukin-6, cyclooxygenase-2, intercellular adhesion molecule-1 and E-cadherin – through the NF-κB signalling pathway[65]. Tang et al[62] showed elevated TMAO levels were associated with increased risk of major adverse cardiovascular events, including death, myocardial infarction and stroke over a 3-year follow-up period involving more than 4000 human subjects. A strong correlation between TMAO levels and CVD was noted even after adjustments of traditional risk factors. Also, an increased risk was associated with a graded increase in TMAO levels with a significant risk of major adverse cardiovascular events seen in the highest quartile.

There are an increasing number of studies explaining the complex interplay between intestinal microflora, bile acids and metabolic disease. Bile acids affect cardiac function and play a significant, yet poorly understood, role in CVD[66]. Direct and indirect pathways have been proposed to explain their effects in CVD.

In the direct pathway, bile acids have been shown to interact with cardiac myocytes affecting muscle contractility and electrical excitation. In the indirect pathway, bile acids play a significant role in lipid metabolism, plaque formation, endothelial vasodilation and neovascularization of injured organs[66]. Having been metabolized by intestinal microflora, bile acid metabolites affect different metabolic pathways through FXR-induced signalling[67]. FXR is an endogenous bile acid sensor, a member of the nuclear receptor family with chenodeoxycholic acid being its most potent ligand.

FXR acts as a receptor-transcription factor which, after being bound by ligand, regulates promoter activity in a coordinated manner. In adult human tissues, FXR expression has been found in adrenal glands, colon, liver, small intestine, kidneys and heart whereas no expression detected in brain, lung and skeletal muscles[68]. In vitro studies have recognized the prevention of vascular inflammation and neointimal proliferation as the potential roles FXR activation in the vascular smooth muscle cells[69].

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215967/


More information: High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine-N-oxide, Science (2021). DOI: 10.1126/science.aba3683

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