Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 6  |  Issue : 1  |  Page : 41-47

Gut microbiota, metabolites, and cardiovascular diseases


1 Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education; Key Laboratory of Molecular Cardiology, Xi'an, Shaanxi Province, China
2 Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University; Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi Province, China
3 Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education; Global Health Institute, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi Province, China

Date of Submission22-Oct-2020
Date of Acceptance17-Jan-2021
Date of Web Publication30-Mar-2021

Correspondence Address:
Lu Ma
Global Health Institute, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi Province
China
Yue Wu
Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xifan 710061, Shaanxi Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2470-7511.312593

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  Abstract 


Numerous studies unveiled the interactions between intestinal flora and the host and how these affect human health and disease. The gut microbiota and its metabolites, such as trimethylamine N-oxide (TMAO), short-chain fatty acids, and secondary bile acids, are related to human metabolism, immunity, and diseases. An increasing number of studies has indicated that intestinal flora and its metabolites contribute to cardiovascular diseases (CVDs) development. Revealing the role of intestinal flora and its metabolites in cardiovascular pathogenesis may provide novel strategies for preventing and treating CVDs. However, the specific mechanisms are unclear, and more research is warranted. Here, we reviewed the most recent research progress on the relationship between intestinal flora, its metabolites, and CVDs.

Keywords: Bile acids; Cardiovascular diseases; Gut microbiome; Short-chain fatty acids; Trimethylamine


How to cite this article:
Zhang YQ, Hua YM, Li CX, Lan BD, Wang XK, Wang Q, Yuan ZY, Ma L, Wu Y. Gut microbiota, metabolites, and cardiovascular diseases. Cardiol Plus 2021;6:41-7

How to cite this URL:
Zhang YQ, Hua YM, Li CX, Lan BD, Wang XK, Wang Q, Yuan ZY, Ma L, Wu Y. Gut microbiota, metabolites, and cardiovascular diseases. Cardiol Plus [serial online] 2021 [cited 2021 Apr 16];6:41-7. Available from: https://www.cardiologyplus.org/text.asp?2021/6/1/41/312593




  Introduction Top


Cardiovascular diseases (CVDs, e.g., hypertension, atherosclerosis, and heart failure [HF]) currently are the leading cause of mortality and morbidity worldwide,[1] accounting for approximately one-third of all death globally. The global death related to CVDs has increased during the past decade by 12.5%. Several researchers have been devoted to exploring the pathogenesis and treatment of CVDs.

Recently, significant interest has been dedicated to the gut microbiota–host interaction as accumulating evidence revealed that gut microbiota plays a key role in the development and progression of CVDs.[2] The gut microbiota contributes to multiple functions, including the intestinal mucosal barrier, participates in food digestion, and controls nutrient intake and metabolism.[3],[4],[5] Noteworthy, the gut microbiome could generate bioactive metabolites, such as trimethylamine-N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFA), and enterogenous sterols, which could enter the blood circulation, interacting with distant organs, affecting their pathophysiological functions.[2] Metabolomics makes it possible to identify bioactive metabolites involved in regulating host pathophysiology. However, the mechanisms underlying the dysbiosis effects mediated by these bacterial metabolites and the associated risk of CVDs have not yet been summarized. Advances in microbial sequencing analysis have enabled us to identify the composition of gut microbiota and its potential effects on the pathogenesis of CVDs. Nowadays, considerable interest has been dedicated to the relationships between gut microbial metabolites and CVDs.[6],[7],[8],[9] Here, we reviewed the latest research progress on the relationship between intestinal flora, its metabolites, and CVDs.


  Gut Microbiota and the Risk of Cardiovascular Diseases Top


As a part of the human body, the intestinal flora can promote the digestion and absorption of food and maintain normal intestinal movement. The gut microbiome can produce hydrogen peroxide, SCFAs, and other substances to shelter the human body from potentially harmful, invading pathogens, and stimulate and aid immune responses.[10] It can also regulate cholesterol absorption, reduce the concentration of endotoxin in the blood, and exert antiaging effects.[11],[12]

When the intestinal flora is imbalanced, and the mucosal barrier is destroyed, it adversely affects the body, increasing the risk of CVDs. Reportedly, significant differences exist between the flora of healthy people and patients with prehypertension and hypertension. The flora of the latter two was expectedly imbalanced, with a marked reduction of probiotics and excessive abundances of genera Preto and Klebsiella. Transplanting the flora of hypertensive patients into sterile mice can increase blood pressure.[13] Another study reported that after the ST-elevation myocardial infarction, intestinal flora products' blood concentration increased significantly, along with systemic inflammation and widespread cardiovascular adverse events. However, antibiotic administration to treat myocardial infarction could alleviate systemic inflammation and myocardial damage in mice.[14] Similarly, in patients with HF, researchers found significant changes in the flora compared to healthy people. Of note, Eubacterium rectale and Dorea longicatena were less abundant in the gut microbiota of HF patients than in healthy control participants.[15] Therefore, the flora plays a critical role in maintaining the physiological function of the body. Once it changes, it can affect disease occurrence and development, not being limited to CVD but including glucose metabolism disorders[16],[17] and cancer.[18]

The increased permeability of the intestinal mucosal barrier can promote the occurrence of CVDs. In Kawasaki disease patients, intestinal permeability and circulating secretion of immunoglobulin A increased. Targeted correction of intestinal permeability can prevent IgA deposition and alleviate the cardiovascular pathological changes in a murine model.[19]

In addition to the above mechanisms, the intestinal flora can also regulate the immune system, increasing the risk of CVDs. For instance, interleukin 17, a key regulator of the mucosal interface, was reported to couple gut microbes with the body's immune system. Similarly, Th17 cells have also been confirmed as the intermediary between gut microbes and autoimmunity, ultimately regulating autoimmune myocarditis.[20] Bacteria can improve myocardial injury by reducing inflammation and infiltration. In myocarditis model mice after bacterial transplantation, the expression of the interferon-gamma (IFN-γ) gene in the heart tissue and the expression of CD4+IFN-γ+ cells in the spleen were reduced. The researchers also found that microbiota transplantation can rebalance the intestinal flora by restoring the Bacteroides population and reshaping the flora composition. Therefore, the exploration of intestinal flora may yield potential therapeutic strategies to treat myocarditis. However, how the intestinal flora affects the immune system and the entire body remains largely elusive. Notably, the intestinal flora could affect vascular aging through immune cells.[21] Furthermore, the TwinsUK cohort showed that the intestinal flora only partly accounted for arterial stiffness changes.[22]


  Trimethylamine-N-oxide Contributes to Cardiovascular Disease Development Top


It has recently been extensively proven that TMAO contributes to the development of CVDs, such as atherosclerosis and major cardiovascular events.[9],[23],[24],[25],[26],[27] TMA is an amine synthesized from dietary components (e.g., L-carnitine, lecithin, choline, and betaine) by microbial enzymes and is further oxidized into TMAO by hepatic flavin monooxygenases [Figure 1].[9]
Figure 1: Gut microbiota and TMAO pathways involved in CVDs.
TMA: Trimethylamine, FMO: Flavin monooxygenases, TMAO: Trimethylamine N-oxide


Click here to view


Elevated circulating levels of TMAO are closely associated with increased risk of CVDs and major cardiovascular events. For instance, in a human study of 1876 patients who underwent an elective cardiac evaluation, it was demonstrated that TMAO-associated metabolites-choline, betaine, and L-carnitine were associated with increased risk of CVDs.[8] In a 3-year follow-up study of 4,007 patients who underwent elective coronary angiography, plasma levels of TMAO were associated with an increased risk of major adverse cardiovascular events (e.g., death, myocardial infarction, and stroke).[23] Circulating TMAOs ability to predict the short-and long-term risk of major cardiovascular events in patients with chest pain was also confirmed by subsequent studies.[28],[29] Higher TMAO levels were observed in patients with HF and portended higher long-term mortality risk independently of conventional risk factors and cardiorenal indexes.[24] Animal studies revealed similar findings. For example, transverse aortic constriction mice model studies found that pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly worse in mice fed either TMAO or choline-supplemented diets compared to mice fed a control diet.[30] These findings suggested that HF severity was significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO.[30] These studies collectively suggest that targeting the intestinal flora TMAO pathway may improve the prognosis or delay the progression of HF.

In terms of thrombotic disease, animal model studies revealed that TMAO contributed to platelet hyperreactivity and enhanced thrombosis potential.[31] Plasma TMAO levels in participants independently predicted incident thrombosis (heart attack and stroke) risk and direct exposure of platelets to TMAO enhanced submaximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores.[8],[31] Wang[27] used 3,3-Dimethyl-1-butanol to suppress TMA and TMAO formation in apolipoprotein e-/-mice models and found that macrophage foam cell formation and atherosclerosis were reduced. TMAO also promotes age-related endothelial dysfunction through oxidative stress, as TMAO supplementation can damage the carotid endothelium-dependent expansion of acetylcholine.[21] These studies reveal that targeting the TMAO pathway may reduce the risk of human CVDs, which could be an important direction for future CVD prevention research.

Some studies have pointed out the influence of the dietary intervention on circulating TMAO levels and the risk of CVDs. The Mediterranean diet proved to be a dietary intervention that could reduce TMAO levels, further preventing CVDs.[32],[33] However, little is known about the mechanism underlying dietary interventions' effects on the risk of CVDs through regulating circulating TMAO levels. Further investigation is warranted.


  Bile acids Have Advantages and Disadvantages for Cardiovascular Diseases Top


Bile acid is synthesized by the liver from cholesterol and then excreted into the intestine through the bile duct. Bile acids can be divided into primary and secondary bile acids. Cholic acid and chenodeoxycholic acid are the two main primary bile acids in humans. They are first excreted into the bile and then in the small intestine. Under the action of bacteria, bile acids are catabolized by bacterium enzymes, which remove the hydroxyl group to form secondary bile acids, such as ursodeoxycholic acid (UDCA), deoxycholic acid, and lithocholic acid.

Studies have shown that bile acids could have advantages for CVDs through the Farnesoid X receptor (FXR) and osmotic transition pore in the PI3K/Akt-dependent pathway. Bile acids can reduce the content of intestinal emulsified triglycerides and the activity of microsomal triglyceride transfer proteins through FXR to control intestinal fat absorption, thereby reducing postprandial dyslipidemia.[34] However, FXR is not only expressed in the intestine but also cardiomyocytes, smooth muscle cells, and vascular endothelial cells. The pharmacological inhibition of FXR can significantly reduce myocardial cell apoptosis in ischemic/reperfused myocardium and improve cardiac function.[35] In rat experiments, UDCA protected the heart from reperfusion injury by inhibiting the osmotic transition pore in a PI3K/Akt-dependent pathway.[36]

However, bile acids have also been associated with the risk of CVDs. A high level of taurocholic acid was a facilitator of arrhythmia in adults, and atrial fibrillation has also been found to be related to the levels of certain bound bile acids, such as higher serum levels of non-UDCA bile conjugates.[37] Bile acids could also reduce liver paraoxonase-1 expression and plasma high-density lipoprotein levels through FXR-dependent FGFR4 signaling.[38] It has been demonstrated that oral metformin could modulate gut microbiota and bile acid metabolism and inhibit intestinal FXR signaling. Further study found that the abundance of Bacteroides fragilis correlated with changes in bile acid metabolites and FXR signaling in metformin-treated individuals with type 2 diabetes. In addition, glycoursodeoxycholic acid (GUDCA) had therapeutic effects on glucose intolerance and insulin resistance.[39] These findings suggest that metformin acts partly through a B. fragilis-GUDCA-intestinal FXR axis to improve metabolic dysfunction, including hyperglycemia. In conclusion, the current evidence indicates that bile acids have both advantages and disadvantages for the risk of CVDs; however, additional research is needed.


  Short-chain Fatty Acids May Play a Critical Role in the Pathophysiology of Cardiovascular Diseases Top


SCFAs (carbon chain lengths <6) are produced by anerobic gut bacteria in the cecum and the proximal colon, principally through the fermentation of dietary fibers, and to a lesser extent, proteins, and peptides.[3] Butyrate, acetate, and propionate are the primary SCFAs,[40] which have local effects (butyrate and propionate) as primary energy sources for gut mucosal cells or distal effects (acetate and propionate) as transfer to the circulation to generate an important source of calory and energy for the organism and to act as signaling molecules.

Many studies suggested that SCFAs have beneficial effects on the pathophysiological process of CVDs. For instance, after treating C57BL/6J mice with antibiotics, SCFAs (acetic acid, butyric acid, and propionic acid) were reduced, and the host immune composition and repair capacity after the myocardial infraction were impaired.[41] Supplementation of dietary SCFAs improved the physiological state of mice after myocardial infarction.[30] In mice fed a high-fat diet, transplantation of fecal flora rich in SCFAs alleviated intestinal flora imbalance and lipid metabolism disorders and could prevent obesity and ischemic stroke.[42]

SCFAs could regulate blood pressure by binding to specific receptors (e.g., Olfr78 and Gpr41) on target cells. So far, the found SCFAs receptors are G protein-coupled receptors (GPRs),[43] including GPR41, GPR42, GPR43, GPR91, GPR109A, GPR164, and olfactory receptor 78 (OLFR78), mediating SCFA-related signaling.[44],[45] It has been reported that SCFAs could modulate blood pressure through Olfr78 and Gpr41,[46] which are expressed in the renal juxtaglomerular apparatus and smooth muscle cells of small vessels. In hypertension mice models, propionate could attenuate cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension.[47] Stimulation of Olfr78 elevated blood pressure, but GPR41 stimulation lowered blood pressure.[48]

SCFAs are also involved in human metabolism by binding to other specific receptors. The combination of SCFAs and Gpr41 can induce enteroendocrine cell-derived hormone peptide YY (PYY) expression in intestinal epithelial cells, increasing the harvest of energy (SCFA) obtained from the diet.[49] SCFAs can also induce the secretion of GLP-1 from intestinal L cells by combining Gpr41 and Gpr43, affecting insulin release by raising cytosolic Ca2+ in L cells and regulating central action appetite by delaying gastric emptying, thereby inducing satiety and reducing nutrients' absorption rate.[50],[51] In a recent study, propionate supplementation significantly increased postprandial GLP-1 and PYY from human colonic cells and reduced calorie intake.[52] Over 24 weeks, 10 g/day inulin-propionate ester supplementation could significantly reduce weight gain and intra-abdominal adipose tissue distribution.[52]

It is noteworthy that a few studies suggest that dietary fiber supplementation could influence the production of SCFAs and further influence the development of type 2 DM, obesity, and atherosclerosis,[34],[53],[54] which may be a novel therapeutic strategy for CVDs.


  The Effects of Enterogenous Sterols on Cardiovascular Diseases Risk Remains Controversial Top


Coprostanol is an enterogenous sterol produced by specific intestinal bacteria through absorbable cholesterol. Coprostanol is nonabsorbable and excreted in feces.[55],[56] Some studies reported that specific gut microbiota belonging to genera Bacteroides and Lactobacillus could convert cholesterol to coprostanol, thus, reducing circulating cholesterol levels.[57],[58] Plasma cholesterol levels were inversely proportional to the coprostanol/cholesterol ratio in the human feces.[59] However, the conversion process, regulatory genes, and required enzymes are unclear.

The relationship between intestinal sterols and salt-sensitive hypertension (SSH) has recently been revealed. In SSH rats, the corticosterone level reportedly increased, whereas the abundance of Bacteroides and arachidonic acid levels was reduced, which tightly correlated with BP. However, intestinal Bacteroides fragilis could inhibit high-salt diet-induced intestinal-derived corticosterone production through its metabolite arachidonic acid.[60] However, studies on intestinal sterols and the risk of CVDs are scarce, and underlying mechanisms remain to be clarified.


  Conclusions Top


There is growing evidence on the role of the intestinal flora and its derived metabolites in the risk of some CVDs. TMAO, SCFAs, secondary bile acids, and enterogenous sterols are associated with CVDs through different mechanisms and pathways [Figure 1] and [Figure 2]. The TMAO pathway and its role in CVDs are widely recognized. Furthermore, the exploration of gut microbiota and its metabolites makes it possible to prevent and treat CVDs through microbial pathways. Several studies have explored the effects of diet inventions, prebiotics, probiotics, and small-molecule inhibitors of defined microbial enzyme pathways on human CVDs. Although the existing circulating probiotics can partially improve some intestinal diseases, the targeted treatment of the flora or the supplementation of probiotic products for specific CVDs remains insufficient.
Figure 2: Gut microbiota and secondary metabolites involved in CVDs.
FXR: Farnesoid X receptor, SCFA: Short-chain fatty acids, Olfr78: Olfactory receptor 78, GPR41: G protein-coupled receptor 41, WAT: White adipose tissue


Click here to view


Effective screening for strains that critically affect CVD development is a research challenge. Additional attempts to break through this crucial link are urgently needed. We need to further reveal how or why these associations exist, and unravel the potential molecular involved. A better understanding of the interactions among microbes, and between bacteria and the hosts, and how these interactions are related to potential molecular susceptibility to CVDs, shall be our future research direction. Targeting the intestinal flora metabolite pathway is still in the early stages of research; further studies are needed.

Financial support and sponsorship

This work was supported by the National Key R and D Program of China (grant numbers 2019YFA0802300, 2018YFC1311505).

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Gut Microbiota a...
Trimethylamine-<...
Bile acids Have ...
Short-chain Fatt...
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