Microbial Biotechnology - 2020 - Xu - The Gut Microbiota and Its Interactions With Cardiovascular Disease

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The gut microbiota and its interactions with

cardiovascular disease
Hui Xu,1,2 Xiang Wang,1 Wenke Feng,3,4 Qi Liu,3,4,5 health and disease via numerous pathways. Thus,
Shanshan Zhou1,* Quan Liu1,** and Lu Cai2,3 the gut microbiota and its metabolic pathways have
1
Cardiovascular Center, the First Hospital of Jilin attracted growing attention as a therapeutic target
University, Changchun, 130021, China. for CVD treatment. The fundamental purpose of this
2
Pediatric Research Institute, Department of Pediatrics, review was to summarize recent studies that have
the University of Louisville, Louisville, KY 40202, USA. illustrated the complex interactions between the gut
3
Department of Pharmacology and Toxicology, the microbiota, their metabolites and the development of
University of Louisville School of Medicine, Louisville, common CVD, as well as the effects of gut dysbiosis
KY 40202, USA. on CVD risk factors. Moreover, we systematically
4
Division of Gastroenterology, Hepatology and Nutrition, discuss the normal physiology of gut microbiota and
Department of Medicine, the University of Louisville potential therapeutic strategies targeting gut micro-
School of Medicine, Louisville, KY 40202, USA. biota to prevent and treat CVD.
5
The Second Affiliated Hospital of Wenzhou Medical
University, Wenzhou, 325035, China.
Introduction
Cardiovascular disease (CVD), including hypertension,
Summary
atherosclerosis, cardiomyopathy and heart failure, is a
The intestine is colonized by a considerable commu- leading cause of high morbidity and mortality, producing
nity of microorganisms that cohabits within the host immense health and economic burdens globally (Mozaf-
and plays a critical role in maintaining host home- farian, et al., 2016). Inflammation, dyslipidaemia and dia-
ostasis. Recently, accumulating evidence has betes mellitus are common pathological processes and
revealed that the gut microbial ecology plays a piv- risk factors, both of which can affect the initiation and
otal role in the occurrence and development of car- progression of CVD (Zoungas, et al., 2014; Haybar,
diovascular disease (CVD). Moreover, the effects of et al., 2019). Other widely known CVD risk factors
imbalances in microbe–host interactions on home- include obesity, insulin resistance and unhealthy lifestyle
ostasis can lead to the progression of CVD. Alter- choices, such as smoking, lack of exercise and poor
ations in the composition of gut flora and dietary habits (GBD, 2013; Mozaffarian, et al., 2016).
disruptions in gut microbial metabolism are impli- However, these risk factors cannot fully explain all of the
cated in the pathogenesis of CVD. Furthermore, the consequences of CVD.
gut microbiota functions like an endocrine organ that Recently, there has been growing interest in studies
produces bioactive metabolites, including trimethy- primarily focused on interactions between the gut micro-
lamine/trimethylamine N-oxide, short-chain fatty biota and CVD. Genome sequencing and metagenomic
acids and bile acids, which are also involved in host analyses show that the presence of the gut microbiota
has potential effects on CVD (Karlsson, et al., 2012;
Vinje, et al., 2014). Accumulating evidence demonstrates
Received 25 July, 2019; revised 22 November, 2019; accepted 23 that manipulation of the composition of the gut micro-
November, 2019.
biota affects host cardiovascular phenotypes (Kootte,
For correspondence. *E-mail [email protected]; Tel. +86 135787
37282; Fax 011 86 431 88782217. **E-mail [email protected]; et al., 2012; Sirisinha, 2016). Furthermore, the gastroin-
Tel +86 13756661271; Fax 011 86 431 88782222. testinal tract can be viewed as a diverse and enormous
Microbial Biotechnology (2020) 13(3), 637–656
ecosystem that produces a considerable amount of
doi:10.1111/1751-7915.13524
Funding information microbial metabolites (Eckburg, et al., 2005), which can
The current study was supported by grants from the National Natu- be absorbed into the circulation and serve as mediators
ral Science Foundation of China (No. 81770372 to S.Z. and No.
of gut microbial effects on the host (Furusawa et al.,
81570338 to Q.L.).
ª 2020 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits
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638 H. Xu et al.
2013; Seldin, et al., 2016; Krautkramer, et al., 2017). peptidoglycan, can directly interact with host intestinal
Thus, the gut microbiota contributes directly or indirectly cells via Toll-like receptors (TLRs) (Larsson, et al.,
to our health status. In this review, we describe the nor- 2012). Furthermore, gut microbes also affect the
mal composition and physiological role of the gut micro- bioavailability and absorption of many oral drugs and
biota and highlight emerging discoveries about the gut can contribute to the production of pharmacologically
microbiota and its associated metabolites that are active metabolites that can enhance toxicities or have
involved in several common CVDs. We focus on experi- other adverse effects on the host (Wallace, et al.,
mental studies and potential molecular pathways, as well 2015; Spanogiannopoulos, et al., 2016). Among the
as clinical evidence. Moreover, we summarize findings myriad of physiological functions, the most significant
on the association of the gut microbiota with inflamma- function of the gut microbiota is supporting the diges-
tion, lipid metabolism disorders and diabetes, which tion of food components to allow the metabolites to
underlie increased cardiovascular risk. Finally, we dis- interact with our human biology (Cani, et al., 2016). For
cuss therapeutic strategies for the improvement of example, vitamin synthesis and metabolic regulation in
human cardiovascular health via modulation of the gut the intestine or distal organs occur via several meta-
microbial ecology. bolic molecules, including bile acids (BAs), short-chain
fatty acids (SCFAs), trimethylamine N-oxide (TMAO),
peptide YY (PYY) and glucagon-like peptide 1 (GLP-1)
Components and physiological roles of the gut
(Tremaroli, et al., 2015), indicating that gut microbiota
microbiota
functions as a pseudo-organ with unparalleled endo-
The term ‘microbiota’ describes a collection of microor- crine potential. Different from host endocrine organs
ganisms defined as ‘the ecological community of com- which produce only a few hormones, the gut microbiota
mensal, symbiotic and pathogenic microorganisms that performed as a high-yield endocrine organ to produce
literally share our body space’ (Grice and Segre, 2012). hundreds of humoral molecules through metabolism-de-
As we are abruptly and continuously exposed to the pendent or metabolism-independent pathways. Such
environment after birth, the gut is rapidly colonized by gut microbial-derived hormones are recognized by host
trillions (1013–1015) of normally non-pathogenic bacteria receptors to elicit diverse biological effects (Brown and
(Human Microbiome Project Consortium, 2012; Sender, Hazen, 2015). Overall, emerging evidence supports the
et al., 2016). Age is the major driver of functional taxa concept that the composition of the gut microbiota and
and metabolic performance reconstruction. Although the its fundamental functions alters physiological responses
composition and metabolism functions of gut microbiota relevant to the cardiometabolic health of the host.
are more similar during early life, the divergence of gut
microbial succession will increase with time (Cerdo, Interactions between the gut microbiota and CVD
et al., 2018). In healthy individuals, the composition of
Hypertension
the gut microbiota remains relatively stable, dominated
mainly by a few phyla, for example Firmicutes, Bac- Hypertension is the most prevalent risk factor associated
teroidetes, Proteobacteria, Actinobacteria and Verru- with CVD and is the leading cause of disability and
comicrobia (Human Microbiome Project Consortium, death in developed countries, affecting 594 million in
2012). These organisms inhabit different ecological 1975 and as many as 1.13 billion in 2015 worldwide
niches on mucosal surfaces and in the gut lumen, form- (NCD Risk Factor Collaboration, 2017). Gut dysbiosis
ing complex biochemical interaction networks between and microbial functions affect pathological effects
themselves and their host (Shkoporov and Hill, 2019). beyond the gastrointestinal system. Emerging evidence
However, there is considerable variation in bacterial implicates the gut microbiota in blood pressure (BP) reg-
diversity between individuals that is caused by differ- ulation, and abnormal bacterial communities are associ-
ences in the host genome and also by lifestyle factors, ated with hypertension (Li et al., 2017a,2017b; Wilck,
such as diet, drug use and environmental exposure et al., 2017).
(Tamburini, et al., 2016). Relatively few studies have examined the roles of the
The gut microbiota remains in a symbiotic relation- microbiota in hypertensive patients. A small study
ship within us, its human host, and it makes crucial showed that hypertensive patients exhibited significantly
contributions that shape our health. Interactions lower diversity in their microbial communities and distinct
between the gut microbiota and intestinal cells regulate clustering between normotensive individuals and hyper-
barrier functions, continually stimulating the immune tensive patients (Yang, et al., 2015). Patients with prehy-
system to defend against pathogens (De Santis et al., pertension and patients with hypertension had not only
2015). For instance, structural components of the lower gene richness and a-diversity than healthy con-
microbiota, such as lipopolysaccharide (LPS) and trols, but also a higher percentage of bacteria from the
ª 2020 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology., Microbial
Biotechnology, 13, 637–656
Gut microbiota and cardiovascular disease 639
genus Prevotella (Li, et al., 2017a). Although these dif- bacteria, the HGT rate of microbes in human gut is 25-
ferences between the disease groups do not prove cau- fold higher than that in other ecosystems (Smillie, et al.,
sation, they do suggest that the metabolic profile 2011), which foster HGT to be a key consideration for
associated with hypertension is linked to the composition translating gut microbial genome into host hypertensive
of the gut microbiota in humans (Table 1). A study con- pathogenesis.
ducted in mice reported that maternal gut microbial mod- A growing body of literature reporting animal experi-
ulation protected the adult male offspring against ments supports the presence of interactions between the
hypertension when they were fed a high-fat diet and that gut microbiota and hypertension. In a proof-of-concept
a maternal high-fat diet had long-term programming study, ablation of the entire gut microbiota via an antibi-
effects on the adult offspring’s gut microbiota (Hsu et al., otic cocktail significantly reduced the incidence of hyper-
2018). It has been postulated that the epigenome and tension-related aneurysms (Shikata, et al., 2019).
microbiome might be inherited from the parents and that Another study reported that germ-free mice were pro-
they might have more robust effects than previously tected from aortic vascular inflammation and endothelial
believed. If this idea is true, then these factors might dysfunction, as well as cardiac fibrosis and systolic dys-
play more important roles than the host genome alone in function, and from angiotensin II (Ang II)-induced hyper-
the development of hypertension. Consistent with this tension (Karbach, et al., 2016). These experiments were
idea, the gut microbiomes of monozygotic twins are not designed to test whether the gut microbiota had ben-
more similar than those of dizygotic twins, and several eficial or harmful roles in the context of hypertension, but
taxa were recently shown to be heritable and stable for rather to reveal the contributions of the gut microbiota to
more than 3 years (Marques, 2018). The collection of the pathophysiology of hypertension and its related dis-
faecal samples from families with well-characterized eases. Evidence for a causative role of gut dysbiosis in
hypertensive histories could help to address the contri- the genesis of hypertension came from faecal microbiota
bution of the microbiota to essential hypertension related transplantation experiments, in which dysbiotic faecal
to the contributions of genetic, epigenetic and environ- samples transferred from hypertensive patients and rat
mental factors; however, for now, this approach suffers donors elevated the BP in normotensive mice and rat
from significant limitations. Horizontal gene transfer recipients respectively (Durgan, 2017; Li, et al., 2017a;
(HGT) refers to the genes transfer between organisms in Toral, et al., 2018; Toral, et al., 2019). These findings
a reproduction-independent manner. HGT was first point to a strong correlation between hypertension and
described in antibiotic resistance that could be trans- gut microbiota dysbiosis, revealing a possible contribu-
ferred from one microbial strain to another laterally tion or even a cause–effect relationship between ele-
(Ochiai, et al., 1959). Although HGT is common among vated BP and altered gut microbiota.
Table 1. The association between gut microbiota and the development and progression of CVD.
Hypertension Atherosclerosis Heart failure
Participation of gut a diversity↓, Prevotella↑, the Streptococcus↑, Enterobacteriaceae↑, Campylobacter↑, Candida↑, Shigella↑,
microbiota F/B ratios↑, Erwinia↑, Lactobacillales↑, Clostridium subcluster Salmonella↑, Yersinia
Corynebacteriac-eae↑, XIVa↑, Bacteroides↓ enterocolitica↑, Escherichia/
Anaerostipes↓, Shigella↑
Lactobacillus murinus↓
Participation of gut SCFAs TMAO↑ TMAO↑
microbial metabolites 4-ethylphenylsulfate BAs, butyrate, NAPEs Plasma primary BAs↓,
specific secondary BAs↑
Propionate, PAG, PCS
Summary of potential GPCRs (GPR42, Olfr78 and Intestinal permeability↑ Intestinal perfusion↓ and congestion↑
mechanisms Gper1) related signalling Endothelial cell–cell conjunctions↓ and cell Intestinal permeability↑
to elicit biological effects permeability↑ Prolong the effect of angiotensin↑
TLR activation↑ NLRP3 inflammasome-associated
Macrophage scavenger receptors and TGF-b/Smad3 signalling activation↑
CD36↑
NF-jB and inflammasome activation↑
Cyp7a1 and Cyp27a1↓
Intracellular Ca2+ release↑
Medications Captopril: Allobaculum↑ Statins: Firmicutes↓, Proteobacteria↑, BAs Digoxin: Eggerthella lenta could
Candesartan and alteration, butyrate↓ inactivate digoxin
Irbesartan: normalize the Aspirin:Prevotella, Bacteroides,
F/B ratio, preserve Ruminococcaceae and Barnesiella
Lactobacillus levels alterations, TMAO-mediated platelet
hyper-responsiveness↓
640 H. Xu et al.
Short-chain fatty acids are a major class of bacterial linked to benzoate metabolism, is closely related to
metabolites that are mainly generated in the colon via sodium intake and increases upon sodium restriction
bacterial fermentation of dietary fibres (Cummings, et al., (Derkach, et al., 2017) (Table 1). HSD-fed rats displayed
1987). SCFAs, such as acetate and propionate, are pro- higher faecal levels of acetate and propionate than did
duced mainly by Bacteroidetes, while butyrate is typically the control (Bier, et al., 2018). In the Dahl salt-sensitive
produced by Firmicutes (Kasselman, et al., 2018). There- rat hypertensive model, Gper1 deletion via CRISPR/
fore, the ratio of the levels of faecal Firmicutes to Bac- Cas9 gene editing significantly reduced the F/B ratio and
teroidetes (the F/B ratio) is a useful proxy for classifying BP (Waghulde, et al., 2018). These observations indi-
the metabolic composition of the microbiome of an indicate that gut microbiota-targeted therapies could serve
vidual. Changes in bacteria composition associated with as a novel strategy for salt-sensitive hypertension pre-
hypertension are followed by alterations in the levels of vention and treatment and highlight a specific gene that
bacterial metabolic products (Kim, et al., 2018). This could have a strong influence on the cross-talk between
concept is corroborated by data from several studies in the gut microbiota and BP regulation, and the underlying
hypertensive models that demonstrated higher F/B ratio mechanisms are an intriguing target for further investiga-
in affected hosts (Yang, et al., 2015; Marques, et al., tion.
2017; Toral, et al., 2018). Furthermore, fibre-rich diets or Several studies have suggested that antihypertensive
magnesium acetate and oral minocycline supplementa- medications may lower BP via effects on the gut micro-
tion could restore gut microbiota homeostasis, reduce biota. Captopril (CAP) is an angiotensin-converting
the F/B ratio and attenuate BP levels (Yang, et al., 2015; enzyme inhibitor used clinically in antihypertensive appli-
Marques, et al., 2017). In addition, treatment with propi- cations, and increased Allobaculum levels can maintain a
onate or butyrate could protect the host from cardiac sustained antihypertensive effect even after CAP with-
damage in experimental hypertension models (Wang, drawal (Yang, et al., 2019). Ang II receptor blockers, such
et al., 2017; Bartolomaeus, et al., 2019). In summary, as candesartan and irbesartan, are also commonly used
solid data clearly demonstrate the involvement and ther- as antihypertensive medications, and they have been
apeutic potential of SCFAs in hypertension. One way reported to normalize the F/B ratio, preserve Lactobacillus
that SCFAs influence host cells is by interacting with levels and prevent gut microbial disruption (Yisireyili,
host G protein-coupled receptors (GPCRs), including et al., 2018; Wu et al., 2019a, 2019b) (Table 1).
Gpr41 and Olfr78, among others. Activation of Gpr41 Collectively, these studies support the concept that the
leads to hypotension, whereas Olfr78 stimulation favours gut microbiota and its metabolites are involved in the
elevated BP (Pluznick, 2013). Notably, the SCFA EC50 development and treatment of hypertension and that gut
values (i.e. the concentration required to reach 50% of dysbiosis is not merely a consequence of high BP, but
the maximal effect) for Gpr41 and Olfr78 vary signifi- also a direct causal factor. The interactions between the
cantly over a wide range, which perhaps at least partly gut microbiota, the environment and the host genome
explains why similar SCFAs can target both receptors to remain to be explored.
promote opposite BP trends. The complex effects of
metabolite-sensing GPCRs in the gut require further
Atherosclerosis and thrombosis
exploration (Table 1).
High salt intake promotes the development of hyper- Recent studies established a link between the gut
tension. Since sodium absorption mainly occurs in intes- microbiota and CVD by describing a case of bacterial
tine, the gut microbiota is likely involved in the salt translocation from the gut to the heart (Mitra, et al.,
sensitivity associated with hypertension. In high salt 2015) and the detection of gut bacterial DNA in the pla-
diet (HSD)-induced hypertensive rats, the levels of taxa ques (Jonsson and Backhed, 2017), indicating that the
of the Erwinia genus and the Corynebacteriaceae intestine is a potential reservoir of pathogenic microor-
families are increased. By contrast, taxa of the ganisms and that the gut microbiota is involved in the
Anaerostipes genus exhibited decreased abundance development of atherosclerosis. A metagenomic analy-
versus their levels in the control (Bier, et al., 2018). HSD sis showed that the gut microbiome of atherosclerotic
affects the rodent gut microbiota specifically by decreas- cardiovascular patients differed from those of healthy
ing the abundance of Lactobacillus murinus as well as individuals as they contained elevated levels of Strepto-
by inducing T helper 17 cells and salt-sensitive hyperten- coccus and Enterobacteriaceae species (Jie, et al.,
sion, which are ameliorated via daily L. murinus supple- 2017). Another study used the terminal restriction frag-
mentation (Wilck, et al., 2017). Moreover, several ment length polymorphism method to identify the gut
observations revealed that HSD is also related to microbiota profiles of patients with coronary artery dis-
changes in the levels of gut microbial metabolites. The eases revealed an increase in the Lactobacillales and
level of 4-ethylphenylsulfate, a gut microbial metabolite Clostridium subcluster XIVa and a reduction in the
Bacteroides in faecal samples (Emoto, et al., 2017). markedly decrease the necrotic core area within
The above observations indicate that the gut microbiota atherosclerotic lesions (May-Zhang, et al., 2019). These
is a potential source of plaque bacteria and that its observations suggest the potential involvement of gut
composition is related to the development of atheroscle- microbiota metabolism in the development of atheroscle-
rosis (Table 1). rosis. Statins, common cholesterol-lowering drugs used
Gut dysbiosis can also exert pro-atherosclerotic effects as first-line agents for coronary disease prevention, have
via metabolism-dependent pathways by altering the gen- been reported to alter the BA pool and to reduce buty-
eration of various metabolites. Among the various gut rate production in the intestine (Caparros-Martin, et al.,
microbiota-derived metabolites, TMAO is a major contrib- 2017). HFD-fed rats treated with atorvastatin showed
utor to the development of atherosclerosis. TMA, a reduced levels of Firmicutes and relatively increased
TMAO precursor, is produced by two distinct types of levels of Proteobacteria, as well as reversion of the
bacterial enzymes, that is carnitine-specific and choline- levels of some dominant taxa towards their levels in the
specific lyases, which cleave specific carbon–nitrogen normal chow diet-fed control rats (Khan et al.,
bonds to generate TMA (Koeth, et al., 2013). Once 2018a,2018b). These studies highlight that CVD inter-
absorbed into the blood, TMA is metabolized into TMAO ventions can exert gut microbiota-modifying effects and
in the liver by the flavin-containing monooxygenase fam- may have implications for the host pathophysiology
ily of enzymes (Tang and Hazen, 2014) (Fig. 1). Inhibi- (Table 1).
tion of microbial TMA production attenuated intermittent Currently, some potential mechanisms for the pro-
hypoxia (IH)-induced pulmonary artery atherosclerosis in atherosclerotic effects of gut microbiota have been
an obstructive sleep apnoea-associated mouse model proposed. Dysbiosis-associated changes in bacterial
(Xue, et al., 2017). Another study reported that inhibition composition can lead to increased intestinal permeability,
of the microbial TMA lyases could reduce atherosclerotic leading to an elevation in circulating LPS levels. Circulat-
lesion formation in ApoE-/- mice (Wang, et al., 2015). ing LPS can be sensed by Toll-like receptor 4 (TLR4)
Notably, a growing body of clinical evidence related to and the downstream signals can be transduced by mye-
the prognostic value of TMAO shows that elevated circu- loid differentiation primary response 88 (MYD88) to pro-
lating TMAO levels are associated with the presence of mote inflammation and foam cell formation (Lau, et al.,
coronary plaque vulnerability and that circulating TMAO 2017). Additionally, signals sensed by TLRs cause B2
can directly contribute to enhanced risk for CVD-related cell activation in the spleen, thus modifying IgG produc-
consequences (Li, et al., 2017a; Qi, et al., 2018) tion to promote the development of atherosclerosis
(Table 2). Other gut microbiota-generated metabolites, (Chen, et al., 2016). TMAO-dependent upregulation of
such as BAs and butyrate, exhibit atheroprotective macrophage scavenger receptors and CD36 expression
effects (Jones, et al., 2012; Brown and Hazen, 2015), impair cholesterol metabolism in macrophages, thus pro-
whereas N-acyl phosphatidylethanolamines (NAPEs) moting foam cell generation (Wang, et al., 2011). TMAO
have no significant effects on aortic lesion size but can also inhibits the hepatic bile acid synthetic rate-limiting
Fig. 1. Schematic illustration of the links between the gut microbiota, TMAO and CVD. Dietary trimethylammonium (e.g. phosphatidylcholine,
choline and L-carnitine) can be metabolized into trimethylamine (TMA) by the gut microbiota. In the liver, TMA is converted into trimethylamine
N-oxide (TMAO) by flavin-containing monooxygenases (FMOs). The effects of TMAO are associated with foam cell formation, alterations in choles-
terol metabolism, platelet hyper-responsiveness, vascular inflammation and adverse cardiac remodelling, all of which can contribute to CVD.
642 H. Xu et al.
Table 2. Clinical studies investigated links between TMAO and cardiometabolic diseases.
Article Study populations Measurements TMAO alterations Summary of findings
(Zhu, et al., Eight vegans/vegetarians Given oral choline TMAO↑ >10-fold in all Striking association between change
2017) and 10 omnivores (40% supplementation for subjects at both (compared to baseline) in TMAO
male, age 46 5 years, 2 months with monthly 1- and 2-month time level and change (compared to
non-smokers without blood examination points (P < 0.01 each) baseline) in platelet aggregation
diabetes or CVD, no after overnight fast (Spearman rho = 0.38, P = 0.03)
preceding (1-month)
history of antibiotics or
probiotics)
(Li et al., 530 sequential subjects Quantify plasma TMAO TMAO↑ Patients in the highest quartile of
2017a,2017b) presenting to the levels TMAO levels demonstrated adjusted
emergency department Reviews of medical incident MACE at 30 days (OR 6.30,
with suspected cardiac records and follow-up 95% CI, 1.89–21.00, P < 0.01),
origin-related chest pain for the 30-day, 6- 6 months (OR 5.65, 95% CI, 1.91–
within 24 h of onset month outcomes 16.74, P < 0.01) and all-cause
Annually followed for all- mortality at 7 years (HR 1.81, 95%
cause mortality CI, 1.04–3.15, P < 0.05)
(Hayashi, et al., 22 HF patients, 11 control Gut flora evaluation by TMAO↑ in both The genus Escherichial/Shigella is
2018) subjects 16S rRNA compensated and positively correlated with TMAO
Plasma microbes-related decompensated HF levels (r = 0.62, P = 0.002) and is
metabolites evaluation patients more abundant in decompensated
by capillary than in compensated HF (P = 0.030)
electrophoresis time-
of-flight mass
spectrometry
(Tang, et al., 720 stable cardiac disease Quantify fasting plasma TMAO↑ (median level of TMAO is predictive of 5-year mortality
2014) patients with a history of TMAO levels HF: 5.0 lM; median risk (adjusted HR 2.2, 95% CI, 1.42–
HF and undergoing Tracking for all-cause level of control: 3.43, P < 0.001)
elective coronary mortality for 5 years 3.5 lM; P < 0.001)
angiographic evaluation
(Winther, et al., 1159 individuals with Quantify plasma TMAO TMAO↑ Negative correlation between TMAO
2019) T1DM (58% male, age levels and eGFR (R2 = 0.29, P < 0.0001)
46 13 years) Follow-up for all-cause Elevated TMAO levels were
and cardiovascular associated with higher risk of all-
mortality, as well as cause mortality (adjusted HR 1.19,
CVD 95% CI 1.09–1.29, P < 0.001),
cardiovascular mortality (adjusted
HR 1.21, 95% CI 1.05–1.39,
P = 0.008), and combination CVD
(adjusted HR 1.17, 95% CI 1.07–
1.27, P < 0.001) in T1DM patients
(Tang, et al., 1216 stable T2DM Quantify fasting plasma TMAO↑ [4.4 lM (IQR 2.8 Elevated TMAO levels were associated
2017a) patients undergoing TMAO levels –7.7 lM) vs 3.6 lM with higher risk of MACE (adjusted
elective coronary Follow-up for 3-year (2.3–5.7 lM), HR 2.05, 95% CI 1.31–3.20,
angiography MACE risk and 5-year P < 0.001] P < 0.001), and 5-year mortality
mortality (adjusted HR 2.07, 95% CI .37–3.14,
P < 0.001) in T2DM patients
CI, confidence intervals; eGFR, estimated glomerular filtration rate; HR, hazard ratio; IQR, interquartile range coefficient; MACE, major adverse
cardiovascular events; OR, odds ratio; r, correlation of R2: coefficient of determination.
enzymes Cyp7a1 and Cyp27a1, which results in provide new targets for the treatment or prevention of
decreased cholesterol elimination and reverse choles- atherosclerosis (Table 1).
terol transport (RCT) (Koeth, et al., 2013). Furthermore, Trimethylamine N-oxide exerts its pro-atherosclerotic
TMAO induces vascular endothelial dysfunction via NF- effects not only by increasing macrophage foam cell for-
jB and inflammasome activation, thus elevating the mation and suppressing RCT, but also by enhancing pla-
expression of vascular endothelial inflammation factors telet hyper-reactivity (Tang and Hazen, 2014), which is
(Ma, et al., 2017). Another study reported that TMAO-in- associated with platelet aggregation and intra-arterial
duced endothelial dysfunction, including disruption of thrombi generation. A large prospective cohort of patients
cell–cell junctions and alterations in cell permeability via undergoing elective coronary angiography showed that
activation of high-mobility group box protein 1, is associ- TMAO plasma levels were correlated with the incidence
ated with TLR4 upregulation (Singh, et al., 2019). These of arterial thrombotic events (Zhu, et al., 2017) (Table 2).
data support the view that inflammatory mediators are The caecal microbial taxa are related to TMAO levels and
critical in TMAO-induced endothelial dysfunction and thrombogenesis. TMAO promotes platelet hyper-
2+
responsiveness by stimulating intracellular Ca release Campylobacter and Shigella were positively correlated
(Table 1). In addition, caecal microbial transplantation with HF severity (Pasini, et al., 2016). Furthermore,
experiments demonstrated that thrombogenetic potential Escherichia/Shigella were more abundant in decompen-
is a transmissible trait (Zhu, et al., 2016). Consistent with sated HF than in compensated HF over a relatively short
these observations, deletion of the choline utilization C/D period (Yoshihisa, 2018). Digoxin, a cardenolide used for
(CutC/D) gene, which encodes a rate-limiting catalyser HF treatment, could be inactivated by the human gut
that converts TMA to TMAO in the host, could reduce actinobacterium Eggerthella lenta (Haiser, et al., 2013;
thrombosis potential (Skye, et al., 2018). A low dose of Koppel, et al., 2018) (Table 1). Individual differences in
aspirin could alter the gut microbial composition (Rogers the human gut microbiota lead to metabolic differences
and Aronoff, 2016) and attenuate the TMAO-mediated that alter the effects of drugs used for HF management
platelet hyper-responsiveness (Zhu, et al., 2016). (Zhernakova, et al., 2016). These observations empha-
Although the molecular mechanisms of how gut micro- size the potential relationships between the pharmacol-
biota-derived TMAO can increase the incidence of ogy of CVD drugs and our microbial genomes.
atherosclerosis- and thrombosis-related cardiovascular Moreover, the development of personalized HF treatment
events are not entirely understood, the above observa- approaches should be considered.
tions suggest that TMAO could serve as a rational poten- Metabolic derangements resulting from altered gut
tial therapeutic target to decrease the risk for the microbial composition and function may also influence HF
development and progression of atherosclerotic disease development. HF patients had higher TMAO serum levels
and to attenuate pro-thrombotic tendencies without bleed- than control subjects (Table 2). Additionally, decompen-
ing complications. Furthermore, the clinical use of TMAO sated HF patients tended to exhibit a higher CutC/D gene
levels to identify subjects potentially suffering from expression level compared with that of compensated HF
atherosclerosis or thrombosis and who might benefit from patients (Hayashi, et al., 2018). In HF patients, higher
CVD therapy is also an interesting area to explore. TMAO levels were associated with 1.18- to 1.79-fold
higher mortality and cardiac transplantation rates respec-
tively (Kanitsoraphan, et al., 2018). Elevated plasma
Heart failure and cardiomyopathy
TMAO level is a remarkably strong adverse prognostic
Heart failure (HF) includes a large body of complex clinical marker and provides a basis for HF risk stratification.
complications that result in damage to the function or struc- Researchers found that elevated plasma TMAO levels in
ture of the heart, and it represents the end stage of many combination with proBNP were better biomarkers for eval-
CVDs. Our knowledge of the pathogenic mechanisms uating the long-term mortality risk in patients suffering
underlying HF has considerably improved in recent years. from not only chronic HF, but also from acute HF (Tang,
The main concept has shifted from haemodynamic changes et al., 2014; Suzuki, et al., 2018). Some other gut-derived
to neuro-humoral modulation. Most recently, the link metabolites also have effects on HF. Microbial metabolism
between the gut microbiota and HF has drawn more atten- has a pivotal impact on BA metabolism. BA composition
tion (Dantzer, et al., 2018; Moshkelgosha, et al., 2018). and size were altered in HF patients. In a cohort study,
There is considerable evidence supporting the role of decreased plasma primary BA levels and increased speci-
the gut microbiota in the development and progression fic secondary BA levels have been observed in patients
of HF, and the ‘gut hypothesis’ has been proposed. The with chronic HF (Mayerhofer, et al., 2017). The SCFA pro-
gut hypothesis suggests that intestinal hypoperfusion pionate significantly attenuated cardiac hypertrophy, fibro-
and congestion due to reduced cardiac output could sis and vascular dysfunction, mainly via regulatory T cells
induce bowel wall oedema and impaired barrier function, (Bartolomaeus, et al., 2019). Besides the gut metabolites
thus leading to increased bacterial translocation-related mentioned above, phenyl-acetyl-glutamine (PAG) is a
inflammatory responses and alterations in the gut micro- strong and independent risk factor for CVD and mortality
biota that could further exacerbate HF (Sandek, et al., (Poesen, et al., 2016), and p-cresyl sulfate (PCS) might
2007; Nagatomo and Tang, 2015; Organ, et al., 2016) function as a predictor of cardiovascular events and all-
(Fig. 2). HF patients with lower intestinal blood flow had cause mortality (Lin, et al., 2013) (Table 1).
higher anti-LPS IgA serum levels, which were associated In animal experiments, the aforementioned gut micro-
with enhanced growth of bacteria obtained from biopsies biota-derived metabolite TMAO has also been studied.
of the colonic mucosa (Sandek, et al., 2014). Compar- Both choline supplementation (a precursor for TMAO
ison of the faecal bacteria of HF patients with those of production) and direct dietary TMAO supplementation
healthy individuals revealed that the chronic HF patients resulted in higher systemic TMAO levels, increased
were colonized by more pathogenic bacteria, including myocardial fibrosis and worsened functional parameters
Campylobacter, Shigella, Salmonella and Yersinia ente- in transaortic constriction-induced HF (Organ, et al.,
rocolitica (Lim, 2016), and species as Candida, 2016). Consumption of a Western diet leads to elevated
644 H. Xu et al.
Fig. 2. Diagram of the cardiovascular risks associated with inflammation, lipid metabolism disorders and diabetes related to gut microbial ecol-
ogy. The gut microbiota interacts with the host immune system to maintain gut–barrier functions. Pathological disorders, including ischaemia
and oedema, are associated with alterations in gut–barrier functions. A leaky intestinal barrier allows for increased flux of pro-inflammatory bac-
terial products into the circulation, causing chronic low-grade inflammation mainly via TLR activation. Consequently, elevated levels of inflamma-
tory cytokines in the bloodstream are potent inducers of intestinal permeability, thus resulting in the formation of a vicious cycle that promotes
toxic molecule translocation and inflammation. Furthermore, TLR activation also contributes to insulin resistance. Changes in the gut microbial
composition are related to abnormal serum lipid levels and other adverse metabolic effects, whereas some species shifts result in beneficial
effects on metabolism. As for gut microbial metabolites, TMAO induces diabetes-related metabolic effects and disrupts cholesterol metabolism,
whereas urolithin A, urolithin B, NAPEs and SCFAs have protective properties. Molecules such as DPP-4, SGLT2, GLP-1 and MyD88 are
potential mediators that link the gut microbiota to CVD risk. Diabetes and lipid metabolism disorders, together with inflammation, are risk factors
that contribute to CVD development and progression. The brown arrows with single arrowhead indicate the effects of promotion, whereas the
horizontal T shape indicates the effects of inhibition; the brown arrows with double arrowhead indicate the interactions with each other; the
brown arrow in dash line indicates the feedback; the black arrows indicate the elevation and reduction.
circulating TMAO levels, subsequently contributing to These observations imply that an assessment of
cardiac fibrosis and dysfunction. Multiple studies indicate intestinal barrier function and reliable and reproducible
that TMAO can affect HF susceptibility and development, biomarkers may bring greater mechanistic understanding
partially via increased myocardial fibrosis, ventricular of the impacts of gut-HF therapy and lead to the devel-
remodelling and the accompanying cardiac dysfunction opment of HF diagnostic strategies. However, the link
(Fig. 2). The underlying mechanism by which TMAO between increased TMAO levels and HF progression is
aggravates myocardial fibrosis is not fully understood. not fully understood and remains to be determined.
TMAO prolongs the effect of angiotensin, eventually Future studies should examine the potential roles of the
leading to adverse cardiac remodelling (Ufnal, et al., intestinal microbial composition and metabolism to
2014). Another mechanistic link is that TMAO promotes design novel therapeutic targets in order to tailor treat-
myocardial fibrosis via activation of NLRP3 inflamma- ment strategies to the wide inter-individual variation for
some-associated TGF-b/Smad3 signalling; in addition, the management of HF.
the finding that NLRP3 silencing can abolish the
increases in the levels of IL-1b, TGF-b and other profi- The link between the gut microbiota and CVD-related
brotic markers induced by TMAO in cardiac fibroblasts risk factors
(Li, et al., 2019) suggests that TMAO could be a new
Inflammation
potential target for retarding the development of myocar-
dial remodelling and the progression of myocardial func- Epidemiologic studies show a correlation between the
tional impairment (Table 1). mediators of inflammation and the risk of cardiovascular
events (Kaptoge, et al., 2014). Intestinal barrier impair- activation, and these effects subsequently result in cardio-
ment disrupts host immune homeostasis and is associ- vascular comorbidities (Kristoff, et al., 2014; Spadaro,
ated with diverse inflammatory diseases (Shreiner, et al., et al., 2017) (Fig. 2). Thus, the gut microbiota might be a
2015), including CVD. Multiple factors can lead to intesti- new target for improving the prognosis of HIV patients
nal barrier function disruption, for example, decreased and limiting non-infectious AIDS-related comorbidities.
intestinal perfusion in HF patients particularly affects the Elevated concentrations of circulating bacterial DNA in
structure of the villi (and microvilli), which are susceptible heart disease patients (Dinakaran, et al., 2014), as well
to ischaemia (Jodal and Lundgren, 1986). Bowel wall as higher LPS levels in the hepatic veins than those
oedema is associated with the congestion that results detected via direct sampling in the left ventricle, further
from decreased cardiac output (Romano, et al., 2015). confirmed that gut bacteria and their related products can
Furthermore, increased collagen content in mucosal be translocated from the gut (Peschel, et al., 2003). LPS
walls corresponds to HF (Arutyunov, et al., 2008). Due induces the expression of a wide array of downstream
to constant exposure to trillions of microbial antigens, inflammatory products, mainly via TLR4 signalling, which
the intestine is constantly at high risk of barrier dysfunc- occurs in multiple cell types, such as dendritic cells,
tion. The gut microbes could maintain and modify the macrophages, cardiac fibroblasts and cardiomyocytes
gut barrier directly (Jakobsson, et al., 2015). Commensal (Frangogiannis, 2014). Increase in LPS plasma concen-
bacteria can regulate the differentiation and function of tration over three times the normal threshold is referred to
host T cells, thus triggering the participation of T cells in as ‘metabolic endotoxaemia’ because it is prevalent in
the maintenance of mucosal homeostasis. The MATE many metabolic diseases (Kasselman, et al., 2018),
(microbial adhesion-triggered endocytosis) process rep- which alters CVD risk potentially. Bacteriophages, the
resents a novel communication pathway that contributes most abundant members of the microbiota, activate IFN-
to commensal antigen recognition (Ladinsky, et al., c-mediated immune responses via TLR9. Consistently,
2019). SCFAs are also involved in the maintenance of TLR9/IFN-c blockade abrogates phage-mediated inflam-
the gut barrier by reducing luminal pH and inhibiting mation (Gogokhia, et al., 2019). Elevated levels of circu-
pathogenic microorganisms. Furthermore, such gut lating inflammatory cytokines, such as TNFa, IL-6 and
microbe-derived molecules are used as a source of CRP (C-reactive protein), are potent inducers of intestinal
energy by intestinal bacteria and host colonocytes (Tang permeability (Sandek, et al., 2007; Al-Sadi, et al., 2013;
and Hazen, 2017). Interestingly, colonic IL-10-producing Al-Sadi, et al., 2014), which can promote a vicious feed-
macrophages are regulated by the gut microbiota and forward cycle of heightened endotoxin translocation and
play a role in impaired epithelial recovery in the colon; inflammatory cytokine accumulation in the circulation
by contrast, the gut microbiota is dispensable for epithe- (Fig. 2). Furthermore, targeted inhibition of this inflamma-
lial recovery in the small intestine (SI), and depletion of tory pathway reduces the risk of incident adverse cardio-
the gut microbiota does not alter IL-10 production by SI vascular events (Ridker, et al., 2017). SCFAs, such as
macrophages or SI barrier restoration (Morhardt, et al., butyrate, have received increasing interest in relation to
2019). Activation of the NLRP3 inflammasome plays a hypertension, and their main effects are modulation of the
protective role in the maintenance of intestinal epithelium microbial composition and inflammation reduction (Wang,
homeostasis. However, once the epithelial barrier is dis- et al., 2017; Kim, et al., 2018). Propionate also exhibits
rupted, NLRP3 inflammasome activation exerts a delete- hypotensive effects, possibly via expansion of the splenic
rious effect (Zhen and Zhang, 2019) (Fig. 2). Treg cell population (Bartolomaeus, et al., 2019).
Impaired intestinal barrier function leads to enhanced As described above, the gut microbiota and intestinal
levels of circulating gut microbiota-derived toxins and homeostasis affect CVD, in which inflammation plays
LPS, which is accompanied by increased inflammation pivotal roles in determining the severity and progression
and suppressed myocardial function (Romano, et al., of the disease. The above studies could generate further
2015). For example, translocation of Weissella spp. from interest in the roles of the gut microbiota and endotoxin-
the gut (Kamboj, et al., 2015) and commensal Entero- induced inflammation in the pathophysiologic mecha-
cocci-associated biofilm formation (Ch’ng, et al., 2019) nisms of CVD. Indeed, the range of investigations indi-
contributed to infective endocarditis. Intestinal Strepto- cates that gut microbiota-driven inflammatory pathways
cocci were implicated in the onset of Kawasaki disease, are potential therapeutic targets for novel pharmacologi-
although the precise aetiology remains unclear (Kinumaki, cal strategies.
et al., 2015). Human immunodeficiency virus (HIV) and
simian immunodeficiency virus (SIV) inflict gut mucosal
Lipid metabolism disorders
damage, leading to microbial translocation and persistent
low-grade chronic inflammation associated with the contri- Lipid metabolism disorders, such as dyslipidaemia and
bution of phospholipase to monocyte or macrophage hyperlipidaemia, are major risk factors and driving forces
646 H. Xu et al.
for the development of CVD. In recent decades, the term metabolism in relation to CVD and show how the effects
‘cardiometabolic syndrome’ has been mentioned in the of host metabolism dysregulation can significantly impact
context of various conditions (Yang et al., 2018a,2018b). the intestinal microbiome, which in turn likely impacts the
A study of a population cohort identified metabolic risks overall host metabolic physiology, including car-
related to microbiome functional parameters, such as diometabolic phenotypes. However, we have not yet pro-
lipoprotein particle composition, fatty acid saturation, and ven whether gut microbiome perturbation is a driver or a
carbohydrate and sugar derivative metabolism that could parallel event in lipid metabolism disorders. To date, the
predict the probability of CVD consequences (Kurilshikov, underlying biological mechanisms through which the gut
et al., 2019). A growing body of studies suggests that the microbiota or its metabolites impact host lipid metabolism
gut microbiota can mechanistically impact host lipid are poorly understood. Although previous studies provide
levels. For example, a high-fat diet alone was not suffi- a basis for cardiometabolic disease prevention and treat-
cient to restore lipid absorption in germ-free mice, indicat- ment, there is still a long way to go in understanding
ing that the gut microbiota is required for adequate lipid how the gut microbiota regulates host diseases.
absorption in the gut (Martinez-Guryn, et al., 2018). Sev-
eral microbes, including Turicibacter, Roseburia, Lach-
Diabetes
nospira and Romboutsia, showed positive relationships
with abnormal serum triglyceride, total cholesterol and Accumulating data from human and animals suggest that
low-density lipoprotein (LDL) levels, and a negatively cor- shifts in the gut microbiota play a fundamental role in
related relationship with the serum high-density lipopro- diabetes, which is an important risk factor for CVD. For
tein (HDL) levels. By contrast, the abundance of instance, Akkermansia muciniphila, a single species of
Ruminococcus_1, Rikenella, Bacteroides, Butyrivibrio the human gut microbiota, has gained considerable
and Alistipes was negatively correlated with serum triglyc- attention since reductions in its abundance are closely
eride, total cholesterol and LDL levels but were positively linked to insulin resistance, diabetes and other car-
correlated with HDL levels (Wan, et al., 2018). Gut colo- diometabolic comorbidities (Ha€nninen, et al., 2018; Cani,
nization with bacteria of the phylum Bacteroidetes altered et al., 2019). Other genera found in the human gut
bile salt hydrolase features, leading to changes in the gut microbiota, including Acidaminococcus, Aggregatibacter,
bile acid composition that affected host metabolism and Anaerostipes, Bifidobacterium, Blautia, Desulfovibrio,
gene expression (Yao, et al., 2018) (Fig. 2). Dorea and Faecalibacterium, are also associated with
Bioactive products generated by the host or commen- type 2 diabetes mellitus (T2DM) (Yang, et al., 2018a). In
sal microbes modulate metabolic factors involved in coronary artery disease patients with T2DM, significant
CVD. Urolithin B, which is derived from ellagitannins by decreases in the abundance of commensal or beneficial
components of the gut microbiota, modulates gene bacteria and increases in the abundance of opportunistic
expression levels involved in RCT and increases choles- pathogens were detected (Sanchez-Alcoholado, et al.,
terol efflux from macrophages into HDL particles, thus 2017).
decreasing lipid deposition in plaques (Zhao, et al., With regard to the development of diabetes and its
2019). However, another study reported that the Cori- cardiovascular comorbidities, changes in the levels of
obacteriaceae family, which is involved in urolithin B pro- metabolites produced by organisms in the gut microbiota
duction, is positively associated with total cholesterol should also be emphasized. Excessive TMAO was
and LDL levels and is a potential CVD risk biomarker detected in T2DM patients with coronary artery disease
(Romo-Vaquero, et al., 2019). Other molecules, such as or chronic kidney disease as well as in type 1 diabetes
indoleamine 2,3-dioxygenase, serotonin (5-HT) and mellitus (T1DM) patients, and this elevation in TMAO
NAPEs, are also correlated with gut microbiota changes predicts adverse cardiac outcomes and mortality in dia-
that alter lipid absorption or lipid metabolism, conse- betic patients (Al-Obaide, et al., 2017; Sanchez-Alcoho-
quently linking the gut microbiota to cardiometabolic phe- lado, et al., 2017; Winther, et al., 2019) (Table 2).
notypes (Laurans, et al., 2018; May-Zhang, et al., 2019; Specifically, butyrate has attracted more attention since
Singhal, et al., 2019). Melatonin improves lipid metabo- it is proven to improve insulin sensitivity and to induce
lism, and the potential mechanism is related to gut beneficial metabolic effects via prevention of metabolic
microbiota reprogramming, especially with respect to endotoxaemia, enhancement of mitochondrial activity
Bacteroides- and Alistipes-mediated acetic acid produc- and profound immunometabolic effects (Tilg and
tion (Yin, et al., 2018). Furthermore, sodium butyrate Moschen, 2014; Hartstra, et al., 2015; Tang et al.,
administration limits lipid deposition and HFD accumula- 2017a, 2017b). Urolithin A and urolithin B were reported
tion in mice (Fang, et al., 2019) (Fig. 2). to reduce diabetes-induced microenvironmental changes
These studies demonstrate the roles of the gut micro- in cardiac tissue and to prevent myocardial dysfunction
biota and its associated molecules in regulating lipid (Savi, et al., 2017) (Fig. 2). The above-mentioned gut
microbial metabolites linked to common metabolic disor- gut microbiota to modulate insulin secretion (Grasset,
ders and CVD are promising targets for reducing dia- et al., 2017), diabetes-related metabolic effects (Duparc,
betes-associated cardiovascular abnormalities. et al., 2017; Liao, et al., 2019) and diabetes-induced
Several potential mechanisms have been proposed to vascular dysfunction (Lee, et al., 2018).
link the gut microbiota with diabetes and adverse dia- In summary, these observations reveal that the gut
betes-related cardiovascular events. Gut microbial com- microbiota and microbial products might alter insulin sen-
position shifts are a signature of low-grade inflammation sitivity, the immune system and the metabolic ability of
(Scheithauer, et al., 2016; Allin, et al., 2018), which inter- host, thus linking them to some disease states, such as
acts with reactive oxygen species to promote atheroscle- diabetes and diabetic CVD. Further study of the casual
rosis in diabetic individuals (Yuan, et al., 2019). mechanisms of gut microbial imbalance and diabetic
Translocated LPS binds to TLRs to induce insulin resis- CVD is warranted, as the results of such studies could
tance and PCSK9 transcription, which in turn limit the reveal how specific gut bacteria and their metabolites
clearance of cholesterol and LPS from the blood (Morelli, may be employed as antidiabetic molecules and could
et al., 2019), thus increasing the risk for CVD. SCFAs suggest potential therapeutic strategies for cardiovascu-
could alter the metabolic state via activation of nuclear lar benefits in diabetic patients with CVD.
receptors such as PPARs (Hasan, et al., 2019) or speci-
fic GPRs such as GPR41 and GPR43 that are involved
Gut microbiota interventions for CVD
in the release of the entero hormone PYY (Samuel,
et al., 2008), fat accumulation reduction, energy expendi- The multiple correlations between altered gut microbiota
ture (Kimura, et al., 2013) and insulin secretion (Tolhurst, composition and its metabolites and CVD susceptibility
et al., 2012). Several molecules, including GLP-1, have highlighted the gut microbiota as a novel regulator
MyD88, dipeptidyl peptidase-4 (DPP-4) and sodium glu- of CVD, and these relationships have become potential
cose cotransporter 2 (SGLT2), interact closely with the targets for novel therapeutics (Fig. 3).
Fig. 3. Interventions that target the gut microbiota for improving CVD therapeutics. Increasing evidence has proven the link between the gut
microbiota and CVD, indicating that modification of the intestinal microbiota could help to prevent and manage CVD. Current strategies for
manipulating gut microbes to elicit positive effects on the cardiovascular system include dietary interventions, use of pre- or probiotics and
antibiotics, faecal microbiota transplantation, TMAO reduction and exercise.
648 H. Xu et al.
Dietary interventions Probiotics, prebiotics and antibiotics
Modulation of the gut microbiota via dietary intervention is Probiotics are live microorganisms administered to re-
a powerful approach for CVD prevention and therapy. A establish an intestinal ecological balance. By contrast,
meta-analysis indicated that higher fibre consumption prebiotics are non-microbial and non-digestible entities
was associated with lower risk for coronary diseases involved in microbial community modulation. Some pre-
(Threapleton, et al., 2013) and significantly reduced BP in liminary evidence suggests that such supplements can
hypertensive patients (Aljuraiban, et al., 2015). Feeding be cardioprotective. In one study, Lactobacillus rhamno-
mice with a high-fibre diet increased the abundance of sus GR-1 administration reduced infarct sizes and
acetate-producing gut bacteria, which significantly improved cardiac functions (Gan, et al., 2014). A ran-
decreased myocardial hypertrophy and fibrosis (Marques, domized controlled pilot study reported that Saccha-
et al., 2017). Furthermore, a Mediterranean diet resulted ronyces boulardii had benefits in HF patients as
in low TMAO levels, which can consequently prevent car- indicated by improved left ventricular ejection fraction
diovascular consequences and HF (Papadaki, et al., (Costanza, et al., 2015). Other common probiotics
2017; Estruch, et al., 2018). One study specifically include Bifidobacterium, Enterococcus and Streptococ-
demonstrated that ginger supplementation modulated the cus (Markowiak and Slizewska, 2017). However, in very
gut microbiota community, inducing a significant increase sick patients with weak immunity, clinically applied probi-
in fatty acid metabolism (Wang, et al., 2019). Further- otics might become opportunistic pathogens that can
more, miRNAs contained by ginger-derived exosome-like engender endocarditis (Kothari, et al., 2019), indicating
nanoparticles could alter bacterial gene expression to that careful consideration is required before the adminis-
affect the host (Teng, et al., 2018), representing promis- tration of probiotics to vulnerable populations. Inulin (a
ing precision tools for dietary therapy to manipulate the prebiotic) supplementation significantly decreased
gut microbiota for improved consumer health. atherosclerotic lesions in ApoE / mice (Jin, et al.,
Zinc is a trace element required by organisms, and it 2019). Furthermore, some studies demonstrated that
is a cofactor for some commensal bacterial proteins probiotics and prebiotics can beneficially modify lipid
involved in metabolism (Cerasi, et al., 2013). Zinc defi- metabolism (Korcz, et al., 2018; Lew, et al., 2018). Sev-
ciency can alter the microbial community composition eral cardiovascular experiments have focused on the
and result in higher b-diversity (Gaulke, et al., 2018); elimination of bacterially induced diseases via antibiotics.
meanwhile, microbiota shifts can in turn aggravate the For example, vancomycin and minocycline interventions
zinc-deficient conditions (Reed, et al., 2015). However, decreased systolic BP in spontaneously hypertensive
during the early stage of zinc deficiency, gut microbial rats (Galla, et al., 2018). Furthermore, ampicillin reduced
composition was mildly disrupted, whereas significant atherosclerotic risk factors, such as lipoprotein levels
functional modifications were indicated by decreased (Rune, et al., 2016). However, the general consensus is
choline demethylation efficiency (Mayneris-Perxachs, that non-specific antimicrobial approaches may lead to a
et al., 2016). Zinc transporters, such as ZnT8 and wide range of side-effects and that even probiotics with
ZnuABC, are involved in the maintenance of the cellular excellent safety records could potentially increase the
zinc level, deficiencies in which were reported to risk of probiotic translocation into the circulation (Liong,
reshape the gut microbial pattern (Mao, et al., 2019) and 2008). Although these results suggest that prebiotics,
impact the infectious ability of gut pathogens (Battistoni, probiotics and antibiotics are effective interventions for
et al., 2017); thus, zinc transporters are new targets for altering the function of colonizing microbes associated
the treatment of metabolic dysfunction or infection-re- with cardiovascular health and disease, further investiga-
lated comorbidities. Dietary zinc–curcumin supplementation into how to preserve their beneficial effects while
tion improved the gut dysbiosis associated with zinc minimizing potential safety concerns is required.
dysregulation and the cardiotoxicity induced by doxoru-
bicin in rats (Wu, et al., 2019a), providing a basis for
Faecal microbiota transplantation
future clinical studies to support the development of
novel approaches for cardiotoxicity prevention. However, Faecal microbiota transplantation (FMT) is a possible
zinc supplementation affected the gut microbial composi- therapeutic intervention designed to inhibit intestinal
tion in a dosage-dependent manner (Watson, et al., pathogens via the transfer of functional bacteria from
2018), and excess dietary zinc increased intestinal per- healthy subjects into the gastrointestinal tract of patients,
meability and enriched pathogenic gut microbial species consequently reconstituting the normal functions of the
(Podany, et al., 2019), suggesting that zinc levels have gut microbiota (Gallo, et al., 2016). Numerous studies
critical effects on the susceptibility of individuals to demonstrate that FMT is effective in the treatment of
pathogenic effects and disease severity. refractory and recurrent Clostridium difficile infection (van
Nood, et al., 2013; Youngster, et al., 2014; Khan, et al., aforementioned findings highlight the benefits of gut
2018a), likely via a secondary bile acid-dependent mech- microbiota modulation via physical exercises for the host
anism (Buffie, et al., 2015). In an experimental autoim- beyond the cardiovascular system. However, longer
mune myocarditis mouse model, FMT could rebalance duration and higher intensity aerobic training are
the gut microbiota community and attenuate myocarditis- required to induce significant and long-term benefits.
associated myocardial injury (Hu, et al., 2019). However,
the obvious limitation of FMT is that endotoxins or infec-
Conclusions and future perspectives
tious agents might also be transferred, thus leading to
new complications. The potential of FMT for treating In conclusion, complex correlations exist between the
CVD requires further investigation to reduce the risk of gut microbiota and CVD, as they mutually influence each
adverse effects and to improve the efficiency of its appli- other via microbiota-associated products, the circulatory
cation. system, immune responses and metabolic changes.
Modifications of the gut microbiota via dietary foods,
FMT, pre- or probiotics, molecular inhibitors or binders
TMAO reduction therapeutics
and daily exercise can drastically alter the gut microbiota
Due to the numerous clinical links between TMAO and profile, thus driving the host cardiometabolism in a
adverse CVD consequences as well as its adverse favourable direction. However, current studies do not
effects on cardiometabolic phenotypes, strategies for tar- typically determine how specific constituents of the
geted inhibition of TMAO production and removal of microbiota or their products interact with each other or
TMAO or its precursor (TMA) have attracted attention. with their host nor have they elucidated the relevant
Treatment with DMB (a TMA-lyase inhibitor) reduced underlying molecular players. Future investigations
TMA production and, consequently, limited the conver- should focus on identifying, at a mechanistic level,
sion to TMAO, thus significantly improving haemody- whether the interconnected pathways underlying gut dys-
namic parameters and reduced ventricular remodelling biosis that contribute to CVD are causal, correlational or
(Chen, et al., 2017). Furthermore, DMB also plays a role consequential. Unique genetic factors of the gut micro-
in anti-atherogenesis (Wang, et al., 2015; Xue, et al., biota and host might predispose individuals towards
2017). Oral charcoal adsorbent (AST-120) has been CVD susceptibility. Microbial technologies related to
used clinically to remove uremic toxins to prevent the combination of microbial omics with phenotypes could
progression of cardiac hypertrophy and fibrosis in a help to obtain the desired outcome (De Vrieze, et al.,
model of chronic kidney disease plus HF (Fujii, et al., 2018), which will be promising strategies to compose
2009). These results provide evidence to support the and modulate gut microbiome for CVD prevention and
future development of interventions against car- therapeutics. Moreover, bacteria also produce mem-
diometabolic phenotypes. However, the efficacies of brane vesicles and release their non-coding RNA into
these strategies have not been fully demonstrated. host cells, thus inducing epigenetic changes in the host.
Therefore, future genome association studies should be
combined with analyses of genetic factors associated
Exercise
with microbiota-dependent epigenetic modifications.
Emerging research indicates that exercise modulates the Although TMA/TMAO are potential biomarkers for CVD
gut microbiota to influence cardiac function. Several development, additional gut microbiota components or
studies suggest that exercise elevates the ratio of Firmi- related metabolites should be explored for use as early
cutes to Bacteroidetes (Petriz, et al., 2014; Lambert, CVD markers. Furthermore, clinical studies are required
et al., 2015) and increases the levels of the bacterial to test whether interventions targeting the pathways
metabolite butyrate (Allen, et al., 2018). Alterations in the associated with these biomarkers could reduce adverse
gut microbial structure induced by physical exercise are cardiac consequences. Tailored and personalized thera-
associated with the prevention of cardiac dysfunction in pies could offer benefits by modulating microbiota-car-
myocardial infarction mice (Liu, et al., 2017). Interest- diovascular cross-talk.
ingly, LPS levels are elevated in CVD and some car-
diometabolic disorders (Kallio, et al., 2015), and high-
Acknowledgements
endurance training can decrease plasma LPS levels
(Lira, et al., 2010). Notably, the benefits imparted by the The current study was supported in part by grants from
gut microbiota disappeared after the suspension of the National Natural Science Foundation of China (No.
endurance exercise training (Allen, et al., 2018), indicat- 81770372 to S.Z. and No. 81570338 to Q.L.), and
ing that the effects of exercise on the gut microbiota China-U.S. University of Louisville Pediatric Research
were transient and reversible. Ultimately, the Exchange Training Program. We thank BioEdit for the
650 H. Xu et al.
language editing of the manuscript. Personnel expenses Buffie, C.G., Bucci, V., Stein, R.R., McKenney, P.T., Ling,
and partial research-related expenses for Hi Xu were L., Gobourne, A., et al. (2015) Precision microbiome
provided by Jilin University through a collaborative reconstitution restores bile acid mediated resistance to
Clostridium difficile. Nature 517: 205–208.
research agreement between the University of Louisville
Cani, P.D., Plovier, H., Van Hul, M., Geurts, L., Delzenne,
and Jilin University, Changchun, China. N.M., Druart, C., and Everard, A. (2016) Endocannabi-
noids–at the crossroads between the gut microbiota and
host metabolism. Nat Rev Endocrinol 12: 133–143.
Conflicts of interest
Cani, P.D., Van Hul, M., Lefort, C., Depommier, C., Rastelli,
None declared. M., and Everard, A. (2019) Microbial regulation of organis-
mal energy homeostasis. Nature metabolism 1: 34.
Caparros-Martin, J.A., Lareu, R.R., Ramsay, J.P., Peplies,
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The gut microbiota and its interactions with

Hypertension Atherosclerosis Heart failure

Article Study populations Measurements TMAO alterations Summary of ﬁndings

Dietary interventions Probiotics, prebiotics and antibiotics

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