Accumulating evidence supports a relationship between the complexity and diversity of the gut microbiota and host diseases. In addition to alterations in the gut microbial composition, the metabolic potential of gut microbiota has been identified as a contributing factor in the development of diseases. Recent technological developments of molecular and biochemical analyses enable us to detect and characterize the gut microbiota via assessment and classification of its genomes and corresponding metabolites. These advances have provided emerging data supporting the role of gut microbiota in various physiological activities including host metabolism, neurological development, energy homeostasis, and immune regulation. Although few human studies have looked into the causative associations and underlying pathophysiology of the gut microbiota and host disease, a growing body of preclinical and clinical evidence supports the theory that the gut microbiota and its metabolites have the potential to be a novel therapeutic and preventative target for cardiovascular and metabolic diseases. In this review, we highlight the interplay between the gut microbiota and its metabolites, and the development and progression of hypertension, heart failure, and chronic kidney disease.

Introduction

The human gut harbors more than 100 trillion microbial cells, and majority of them being classified into the phyla Firmicutes and Bacteroidetes. Additionally, these microbes are responsible for various physiological activities including host metabolism, neurological development, energy homeostasis and immune regulation, and vitamin synthesis and digestion [1], and are capable of regulating the normal function of intestinal epithelial mucosal barriers [2,3]. Disruption of intestinal epithelial barrier function can lead to increased gut permeability, increased bacterial translocation, and increased circulating endotoxins that can contribute to the underlying inflammation related to the progression of cardiovascular disease. Furthermore, accumulating evidence suggests that quantitative and qualitative alterations of the gut microbiota (so-called ‘dysbiosis’) can also play an important role in the pathogenesis of various cardiovascular and metabolic diseases [47]. Gut dysbiosis can induce significant changes in the gut immune system, leading to altered signals derived from the gut to the systemic immune system. Indeed, direct modulation of the gut microbiota has been associated with alterations in host metabolism, mainly through immune systems and hormone secretion [810]. Furthermore, the metabolic potential of the gut microbiota has been identified as a contributing factor in the development of diseases, with metabolites acting on distant target organs in a manner similar to the human host’s endocrine organ [1115]. In addition to gut microbiota, many bacteriophages have been found in human gut [16]. Prokaryotic viruses, which are currently thought to be the most abundant in the gut, are associated with human health by affecting bacterial community structure and function [1719]. However, the precise mechanisms of these pathways are yet to be fully clarified. In this review, we highlight the interplay between the gut microbiota and its metabolites, and cardiovascular diseases, including hypertension and heart failure, and chronic kidney disease (CKD) (Figure 1).

Interplay between the gut and the brain, the heart and the kidneys

Gut–brain axis and blood pressure regulation

The homeostatic regulation of blood pressure is a complex process, which is regulated by several factors such as genes, environment, and endocrine hormone secretion. Recent studies have revealed that the human gut has a significant connection with the central nervous system via complex signaling pathways, including bidirectional neuroendocrine signals and immunological factors [20]. This, so-called ‘gut–brain axis’ consists of the gut microbiota, central nervous system, enteric nervous system, and parasympathetic and sympathetic nervous systems [21]. It has also been recognized that altered gut microbial composition is associated with the development of neurodegeneration [22,23]. Besides regulating the microglia, manipulation of the gut microbiota has been thought to be able to modulate neuroimmune activation through the production of microbial derived bioactive metabolites, such as short-chain fatty acids (SCFAs) [2325].

Several studies have suggested a potential role of the gut microbiota in blood pressure regulation and the pathogenesis of hypertension [2629]. A recent case report demonstrated a potent antihypertensive effect of the gut microbiota in a patient with resistant hypertension that was treated with minocycline [30]. This effect was thought to be mainly due to the production of SCFAs, which are important signals generated by the gut microbiota [3134]. Gut dysbiosis was observed in patients with hypertension [3134], which was characterized by a reduction in SCFA production and a change in the Firmicutes to Bacteroidetes ratio [26,27,29]. An animal study of spontaneous hypertensive rats also demonstrated an increase in the Firmicutes to Bacteroidetes ratio, while chronic administration of SCFA reversed this ratio and attenuated the hypertension [27]. Mechanistically, SCFAs can function to stimulate G-protein-coupled receptors 41 (GPR41) and 43 (GPR43), and these are expressed in the renal vasculature [35]. The SCFA olfactory receptor 78 (Olf78) is also expressed in the kidneys, where it regulates blood pressure [32]. However, the balance across these G-protein-coupled receptor activities is complex and likely to be dynamic. In a study using GPR41-deficient mice, administration of the SCFA propionate was associated with a significant increase in blood pressure, which suggested that GPR41 can negate a pressor response to SCFA [32].

Gut microbial composition was found to be significantly different between spontaneously hypertensive rats and Wistar–Kyoto control rats, with hypertensive rats having reduced taxa richness and altered microbial composition compared with the control rats [27]. At the phylum level, the Firmicutes to Bacteroidetes ratio was significantly higher in the hypertensive rats than in the control rats. In addition, angiotensin II-treated rats showed a reduction in microbial species richness and an increased Firmicutes to Bacteroidetes ratio compared with control rats [27]. Another study has reported that the microbiota of Dahl S (salt sensitive) rats was significantly different from that of Dahl R (salt resistant) rats. The phylum Bacteroidetes and family Veillonellaceae were reported to be more abundant in Dahl S rats than in Dahl R rats [29]. Moreover, Dahl S rats showed a significant increase in blood pressure with a high-salt diet, whereas the Dahl R rats did not respond to a high-salt diet [22,29]. Furthermore, administration of an antibiotic to Dahl S rats did not affect their hypertensive responses to the high-salt diet. Although fecal transplantation from Dahl R rats to Dahl S rats exacerbated the hypertensive responses of Dahl S rats and was associated with significantly elevated plasma levels of the SCFAs, fecal transplantation from Dahl S rats to Dahl R rats could not change the hypertensive phenotype of the Dahl R rats [29]. These findings imply that the physiologic differences reside in the differences of gut microbial compositions and corresponding functions between the two rats.

Gut microbial interaction with heart failure and atherosclerosis

Heart failure is a growing health problem and a main cause of mortality and morbidity worldwide. The gut has also been implicated in the pathophysiology and progression of heart failure, largely attributed to impaired perfusion to the intestines leading to intestinal barrier dysfunction. The intestinal endothelial barrier is maintained by several mechanisms of a well-balanced gut microbiota [36,37]. In patients with heart failure, reduced blood flow into the intestinal endothelium due to reduced cardiac output leads to intestinal wall ischemia, leading to increased permeability due to structural disruption of the intestinal epithelial barrier function [38]. Furthermore, systemic congestion in patients with heart failure can cause intestinal wall edema, which also results in increased intestinal permeability. This ‘leaky gut’ is associated with translocation of endotoxins, microbial components, and microbial metabolites, such as lipopolysaccharides (LPS) produced by Gram-negative bacteria, to enter the systemic circulation [39,40]. This process can further activate cytokines and generate systemic inflammation that, in turn, contributes to the progression of heart failure [4143]. Indeed, gut microbial DNA has been detectable in the peripheral blood of patients with advanced kidney diseases, suggesting the leaky gut may serve as the primary source [44].

In addition to hemodynamic deterioration in patients with heart failure, evidence showed that gut dysbiosis was associated with the production of several gut microbiota derived metabolites, as well as promoting the disruption of gut endothelial barrier function [7]. In patients with heart failure, a significant interaction was observed between the amount of fecal gut microbiota and the intensity of intestinal permeability [45]. Furthermore, patients who had bacterial DNA in the peripheral blood had significantly higher plasma levels of inflammatory markers, including high-sensitive C-reactive protein and interleukin-6 levels, than those who did not have bacterial DNA in their peripheral blood [46]. A recent study has shown that heart failure patients had a significantly decreased diversity of gut microbiota and a depletion of core gut microbial groups [47]. These observations suggested that better understanding of the regulation of intestinal barrier function has the potential to develop intestinal barrier directed heart failure therapy.

Trimethylamine N-oxide (TMAO), which is derived from metabolites of gut microbiota from specific dietary nutrients, is clearly linked to atherosclerotic cardiovascular risk [44,4850]. Circulating TMAO levels are elevated and associated with disease severity in patients with atherosclerosis, CKD, and peripheral artery diseases [5052]. We found that elevated TMAO concentrations in animal models were associated with corresponding increases in renal tubulointerstitial fibrosis [51]. A previous study has shown that microbial taxa belonging to the Clostridiaceae and Peptostreptococcaceae families were positively associated with blood levels of TMAO in humans [53]. Interestingly, patients with heart failure had significantly higher levels of TMAO than age-matched and sex-matched subjects without heart failure, irrespective of heart failure etiology [50]. Moreover, plasma TMAO levels were associated with adverse outcomes, and elevated plasma TMAO levels had a strong adverse prognostic value in addition to the traditional risk factors, cardiorenal indices, and markers of systemic inflammation [50]. In a recent animal study using a transaortic constriction model of heart failure, mice fed on a high-choline diet had higher TMAO levels than those with standard choline diet [54]. In addition, high-choline diet fed mice showed adverse ventricular dilatation and wall thinning with a marked increase in fibrosis [54]. The profibrotic transforming growth factor (TGF)-β p-Smad3 pathway has been shown to be enhanced in the choline diet fed mice [51]. However, the causative effects of TMAO and the underlying mechanistic link that explains how TMAO might directly or indirectly promote heart failure are not well understood. In fact, although elevated TMAO levels have shown equivalent adverse prognostic value in patients with ischemic and non-ischemic etiologies [50], a recent report has reported a conflicting result that TMAO levels were elevated in ischemic heart failure compared with non-ischemic dilated cardiomyopathy [55]. Furthermore, there is a lack of understanding of the relationship between TMAO or other gut microbial metabolites in altered intestinal permeability and hemodynamic status in the context of heart failure. Additional studies are needed to investigate whether manipulation of the gut microbial TMAO pathway can attenuate the progression of heart failure, and improve outcomes, even though early animal studies have shown promise with direct microbial enzyme inhibitors of TMA/TMAO synthesis in attenuating cardiac dysfunction [49].

Gut renal axis and uremic toxins

A complex interplay between the kidney and the gut microbiota has long been observed [37]. Several mechanisms were suggested to underlie the interaction between the gut microbiota and pathogenesis of CKD [56]. Gut microbiota has been shown to contribute to the generation of several uremic toxins such as advanced glycation end products (AGEs), phenols, and indoles [57]. These are absorbed into the systemic circulation and are normally cleared by the kidneys. However, in states of impaired renal function, they accumulate and become toxic and induce an inflammatory response in the host, resulting in the progression of CKD [38,56]. The presence of uremic toxins has justified a wide range of innovative and/or obscure colonic cleansing practices or resection procedures to remove colonic uremic toxins over the past century. Nevertheless, several contemporary studies have suggested that blood levels of uremic toxins have been associated with mortality and cardiovascular risks [5860]. Circulating LPS levels increase with the stages of CKD and were an independent predictor of mortality [61]. Elevated indoxyl sulphate levels (microbial product of tryptophan metabolism) were associated with aortic calcification, increased vascular stiffness, and the risk of cardiovascular mortality in patients with CKD [62]. In uremic rats, the administration of indoxyl sulphate mediates the renal gene expression of TGF-β1, which is related to tubulointerstitial fibrosis [60]. Indoxyl sulphate has been suggested to be responsible for vascular disease through an induction of oxidative stress. Indoxyl sulphate induced the production of reactive oxygen species in human umbilical vein endothelial cells [58]. Treatment with the oral adsorbent AST-120 resulted in a significant decrease in indoxyl sulphate with a corresponding increase in flow-mediated, endothelium-dependent vasodilatation [63]. Meanwhile, another tryptophan metabolite, p-cresyl sulphate, may cause inflammation in blood vessels in experimental models [64]. Elevated p-cresyl sulphate levels were also associated with all-cause mortality [65]. Furthermore, in a partial nephrectomized mice model, indoxyl sulphate or p-cresyl sulphate activated the intrarenal renin–angiotensin–aldosterone system and interstitial fibrosis and glomerulosclerosis [65].

In humans and animals with advanced CKD, extensive change in the structure and function of the gut microbiota has been reported [66]. Gut dysbiosis in patients with CKD has been implicated in an increased production of indoxyl sulphate and p-cresyl sulphate, and as a promoter for increasing inflammation and contributing to the progression of their disease [38]. Patients with CKD also showed significant changes in SCFA-producing microbiota, which are known to have beneficial effects. These observations suggested that gut dysbiosis and uremic toxins can cause endothelial dysfunction, aggravate inflammation and oxidative stress, and impair the normal physiological repair process of the endothelium [58].

Patients with CKD have consistently high TMAO levels that are associated with higher mortality, accelerated atherosclerosis, and progressive loss of kidney function in patients with CKD [50,51,67,68]. Dietary induced elevation of TMAO concentrations in mouse models has been associated with greater degree of tubulointerstitial fibrosis [51]. Animals with increased TMAO levels also had increased fibrosis and phosphorylation of Smad3, an important regulator of fibrosis [65]. However, there was only a modest correlation between TMAO levels and the estimated glomerular filtration ratio [51,69]. Since TMAO is predominately excreted in urine and its clearance is largely dependent on renal function [49,70], decreased renal function in patients with CKD can confound the association of high TMAO levels in CKD [71]. A recent meta-analysis clearly showed that TMAO and its precursors were associated with an increased risk of mortality and major adverse cardiac event independently of traditional risk factors such as diabetes mellitus, obesity, and CKD [72]. Further studies exploring the physiology of TMAO generation and metabolism are warranted to more thoroughly define the etiology of TMAO elevations in CKD.

Diet intervention

Several studies have shown that dietary interventions were effective strategies in reducing cardiovascular risks [73,74]. It has been reported that adherence to the Mediterranean diet leads to a decrease in all the causes of mortality and in the incidence of cardiovascular diseases [75]. Moreover, dietary interventions can modify the microbiota composition by inducing rapid changes in certain nutrients [76,77]. A high level of variability in the microbiota significantly correlated with dietary habits, confirming the shaping effect of long-term dietary patterns on the gut microbiota [78]. A previous study has shown that fiber-rich diets promote the growth of beneficial commensal bacteria and limit the growth of known opportunistic pathogens [79]. Thus, modulation of the gut microbiota composition through dietary intervention represents a promising therapeutic target. However, little is known about the mechanistic interplay between the diet intervention and the relevant gut microbial metabolism.

Conclusion and future perspective

The gut microbiota is an exciting new research field with enormous possibilities for human health, and holds great promises for novel diagnostic and therapeutic approaches with lasting and preventive impact. Nevertheless, few human studies have looked into causative associations of the gut microbiota and its metabolites to host disease, and their putative mechanisms. Recent novel molecular biochemical analyses are expected to enable the detection and classification of the diverse microorganisms, and to assess all genomes of these microbiota and their metabolites. In particular, since the diversity of the gut microbiota in different individuals may lead to different responses to treatment and ultimately different outcomes, genome-scale metabolic models have the potential to be used as a key in understanding the role of individual species in the gut microbiota as well as the role of the microbiota as a whole. Genome-scale metabolic models are mathematical representations of the knowledge of a microbiota’s metabolic capacity and can predict how metabolic system functions differently in different species by integrating knowledge of the metabolism of the gut microbiota. These technological developments are expected to facilitate the move from correlation studies to a gain in mechanistic insights, and to result in new diagnostic tests and therapeutics in the near future. Additional studies are needed to investigate the exact mechanisms underlying interactions between the host and microbiota to better understand the impact of direct or indirect manipulations of the gut microbiota on their biological functions.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the National Institute of Health (NIH)/ Office of Dietary Supplements [grant numbers P20HL113452, R01DK106000, R01HL126827 (to W.H.W.T)]. W.H.W.T. and T.K. have no relationships to disclose.

Abbreviations

     
  • GPR41

    G-protein-coupled receptor 41

  •  
  • CKD

    chronic kidney disease

  •  
  • LPS

    lipopolysaccharide

  •  
  • SCFA

    short-chain fatty acid

  •  
  • TGF

    transforming growth factor

  •  
  • TMAO

    trimethylamine N-oxide

  •  
  • TMA

    trimethylamine

References

References
1
Everard
A.
and
Cani
P.D.
(
2014
)
Gut microbiota and GLP-1
.
Rev. Endocr. Metab. Disord.
15
,
189
196
2
Power
S.E.
,
O’Toole
P.W.
,
Stanton
C.
,
Ross
R.P.
and
Fitzgerald
G.F.
(
2014
)
Intestinal microbiota, diet and health
.
Br. J. Nutr.
111
,
387
402
3
Vitetta
L.
and
Gobe
G.
(
2013
)
Uremia and chronic kidney disease: the role of the gut microflora and therapies with pro- and prebiotics
.
Mol. Nutr. Food Res.
57
,
824
832
4
Festi
D.
,
Schiumerini
R.
,
Eusebi
L.H.
,
Marasco
G.
,
Taddia
M.
and
Colecchia
A.
(
2014
)
Gut microbiota and metabolic syndrome
.
World J. Gastroenterol.
20
,
16079
16094
5
Gomez-Hurtado
I.
,
Such
J.
,
Sanz
Y.
and
Frances
R.
(
2014
)
Gut microbiota-related complications in cirrhosis
.
World J. Gastroenterol.
20
,
15624
15631
6
Ilan
Y.
(
2012
)
Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis
.
World J. Gastroenterol.
18
,
2609
2618
7
Winslow
M.M.
,
Gallo
E.M.
,
Neilson
J.R.
and
Crabtree
G.R.
(
2006
)
The calcineurin phosphatase complex modulates immunogenic B cell responses
.
Immunity
24
,
141
152
8
Burcelin
R.
(
2016
)
Gut microbiota and immune crosstalk in metabolic disease
.
Mol. Metab.
5
,
771
781
9
Perry
R.J.
,
Peng
L.
,
Barry
N.A.
et al. 
(
2016
)
Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome
.
Nature
534
,
213
217
10
Thaiss
C.A.
,
Zmora
N.
,
Levy
M.
and
Elinav
E.
(
2016
)
The microbiome and innate immunity
.
Nature
535
,
65
74
11
Schroeder
B.O.
and
Backhed
F.
(
2016
)
Signals from the gut microbiota to distant organs in physiology and disease
.
Nat. Med.
22
,
1079
1089
12
Tang
W.H.
,
Kitai
T.
and
Hazen
S.L.
(
2017
)
Gut microbiota in cardiovascular health and disease
.
Circ. Res.
120
,
1183
1196
13
Tang
W.H.
and
Hazen
S.L.
(
2014
)
The contributory role of gut microbiota in cardiovascular disease
.
J. Clin. Invest.
124
,
4204
4211
14
Kitai
T.
and
Tang
W.W.
(
2015
)
Recent advances in treatment of heart failure
.
F1000Res.
4
,
pii: F1000
15
Kitai
T.
and
Tang
W.H.W.
(
2017
)
The role and impact of gut microbiota in cardiovascular disease
.
Rev. Esp. Cardiol.
70
,
799
800
16
Virgin
H.W.
(
2014
)
The virome in mammalian physiology and disease
.
Cell
157
,
142
150
17
Reyes
A.
,
Haynes
M.
,
Hanson
N.
et al. 
(
2010
)
Viruses in the faecal microbiota of monozygotic twins and their mothers
.
Nature
466
,
334
338
18
Cadwell
K.
,
Patel
K.K.
,
Maloney
N.S.
et al. 
(
2010
)
Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine
.
Cell
141
,
1135
1145
19
Minot
S.
,
Bryson
A.
,
Chehoud
C.
,
Wu
G.D.
,
Lewis
J.D.
and
Bushman
F.D.
(
2013
)
Rapid evolution of the human gut virome
.
Proc. Natl. Acad. Sci. U.S.A.
110
,
12450
12455
20
Bauer
K.C.
,
Huus
K.E.
and
Finlay
B.B.
(
2016
)
Microbes and the mind: emerging hallmarks of the gut microbiota-brain axis
.
Cell. Microbiol.
18
,
632
644
21
O’Mahony
S.M.
,
Clarke
G.
,
Borre
Y.E.
,
Dinan
T.G.
and
Cryan
J.F.
(
2015
)
Serotonin, tryptophan metabolism and the brain-gut-microbiome axis
.
Behav. Brain Res.
277
,
32
48
22
Kohler
C.A.
,
Maes
M.
,
Slyepchenko
A.
et al. 
(
2016
)
The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: mechanisms and pathophysiological role in Alzheimer’s disease
.
Curr. Pharm. Des.
22
,
6152
6166
23
Dinan
T.G.
and
Cryan
J.F.
(
2017
)
Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration
.
J. Physiol.
595
,
489
503
24
Sampson
T.R.
,
Debelius
J.W.
,
Thron
T.
et al. 
(
2016
)
Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease
.
Cell
167
,
1469
1480.e12
25
Erny
D.
,
Hrabe de Angelis
A.L.
,
Jaitin
D.
et al. 
(
2015
)
Host microbiota constantly control maturation and function of microglia in the CNS
.
Nat. Neurosci.
18
,
965
977
26
Durgan
D.J.
,
Ganesh
B.P.
,
Cope
J.L.
et al. 
(
2016
)
Role of the gut microbiome in obstructive sleep apnea-induced hypertension
.
Hypertension
67
,
469
474
27
Yang
T.
,
Santisteban
M.M.
,
Rodriguez
V.
et al. 
(
2015
)
Gut dysbiosis is linked to hypertension
.
Hypertension
65
,
1331
1340
28
Holmes
E.
,
Loo
R.L.
,
Stamler
J.
et al. 
(
2008
)
Human metabolic phenotype diversity and its association with diet and blood pressure
.
Nature
453
,
396
400
29
Mell
B.
,
Jala
V.R.
,
Mathew
A.V.
et al. 
(
2015
)
Evidence for a link between gut microbiota and hypertension in the Dahl rat
.
Physiol. Genomics
47
,
187
197
30
Qi
Y.
,
Aranda
J.M.
,
Rodriguez
V.
,
Raizada
M.K.
and
Pepine
C.J.
(
2015
)
Impact of antibiotics on arterial blood pressure in a patient with resistant hypertension - a case report
.
Int. J. Cardiol.
201
,
157
158
31
Nutting
C.W.
,
Islam
S.
and
Daugirdas
J.T.
(
1991
)
Vasorelaxant effects of short chain fatty acid salts in rat caudal artery
.
Am. J. Physiol.
261
,
H561
H567
32
Pluznick
J.L.
(
2013
)
Renal and cardiovascular sensory receptors and blood pressure regulation
.
Am. J. Physiol. Renal Physiol.
305
,
F439
F444
33
Mortensen
F.V.
,
Nielsen
H.
,
Mulvany
M.J.
and
Hessov
I.
(
1990
)
Short chain fatty acids dilate isolated human colonic resistance arteries
.
Gut
31
,
1391
1394
34
Pluznick
J.L.
,
Zou
D.J.
,
Zhang
X.
et al. 
(
2009
)
Functional expression of the olfactory signaling system in the kidney
.
Proc. Natl. Acad. Sci. U.S.A.
106
,
2059
2064
35
Pluznick
J.L.
,
Protzko
R.J.
,
Gevorgyan
H.
et al. 
(
2013
)
Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation
.
Proc. Natl. Acad. Sci. U.S.A.
110
,
4410
4415
36
Vaziri
N.D.
,
Goshtasbi
N.
,
Yuan
J.
et al. 
(
2012
)
Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium
.
Am. J. Nephrol.
36
,
438
443
37
Sabatino
A.
,
Regolisti
G.
,
Brusasco
I.
,
Cabassi
A.
,
Morabito
S.
and
Fiaccadori
E.
(
2015
)
Alterations of intestinal barrier and microbiota in chronic kidney disease
.
Nephrol. Dial. Transplant.
30
,
924
933
38
Ramezani
A.
and
Raj
D.S.
(
2014
)
The gut microbiome, kidney disease, and targeted interventions
.
J. Am. Soc. Nephrol.
25
,
657
670
39
Krack
A.
,
Richartz
B.M.
,
Gastmann
A.
et al. 
(
2004
)
Studies on intragastric PCO2 at rest and during exercise as a marker of intestinal perfusion in patients with chronic heart failure
.
Eur. J. Heart Fail.
6
,
403
407
40
Sandek
A.
,
Bauditz
J.
,
Swidsinski
A.
et al. 
(
2007
)
Altered intestinal function in patients with chronic heart failure
.
J. Am. Coll. Cardiol.
50
,
1561
1569
41
Sandek
A.
,
Bjarnason
I.
,
Volk
H.D.
et al. 
(
2012
)
Studies on bacterial endotoxin and intestinal absorption function in patients with chronic heart failure
.
Int. J. Cardiol.
157
,
80
85
42
Verbrugge
F.H.
,
Dupont
M.
,
Steels
P.
et al. 
(
2013
)
Abdominal contributions to cardiorenal dysfunction in congestive heart failure
.
J. Am. Coll. Cardiol.
62
,
485
495
43
Niebauer
J.
,
Volk
H.D.
,
Kemp
M.
et al. 
(
1999
)
Endotoxin and immune activation in chronic heart failure: a prospective cohort study
.
Lancet
353
,
1838
1842
44
Shi
K.
,
Wang
F.
,
Jiang
H.
et al. 
(
2014
)
Gut bacterial translocation may aggravate microinflammation in hemodialysis patients
.
Dig. Dis. Sci.
59
,
2109
2117
45
Pasini
E.
,
Aquilani
R.
,
Testa
C.
et al. 
(
2016
)
Pathogenic gut flora in patients with chronic heart failure
.
JACC Heart Fail.
4
,
220
227
46
Wang
F.
,
Jiang
H.
,
Shi
K.
,
Ren
Y.
,
Zhang
P.
and
Cheng
S.
(
2012
)
Gut bacterial translocation is associated with microinflammation in end-stage renal disease patients
.
Nephrology
17
,
733
738
47
Luedde
M.
,
Winkler
T.
,
Heinsen
F.A.
et al. 
(
2017
)
Heart failure is associated with depletion of core intestinal microbiota
.
ESC Heart Fail.
4
,
282
290
48
Tang
W.H.
,
Wang
Z.
,
Levison
B.S.
et al. 
(
2013
)
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
.
N. Engl. J. Med.
368
,
1575
1584
49
Wang
Z.
,
Klipfell
E.
,
Bennett
B.J.
et al. 
(
2011
)
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
.
Nature
472
,
57
63
50
Tang
W.H.
,
Wang
Z.
,
Fan
Y.
et al. 
(
2014
)
Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis
.
J. Am. Coll. Cardiol.
64
,
1908
1914
51
Tang
W.H.
,
Wang
Z.
,
Kennedy
D.J.
et al. 
(
2015
)
Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease
.
Circ. Res.
116
,
448
455
52
Senthong
V.
,
Wang
Z.
,
Fan
Y.
,
Wu
Y.
,
Hazen
S.L.
and
Tang
W.H.
(
2016
)
Trimethylamine N-oxide and mortality risk in patients with peripheral artery disease
.
J. Am. Heart Assoc.
5
,
pii: e004237
53
Backhed
F.
(
2013
)
Meat-metabolizing bacteria in atherosclerosis
.
Nat. Med.
19
,
533
534
54
Organ
C.L.
,
Otsuka
H.
,
Bhushan
S.
et al. 
(
2016
)
Choline diet and its gut microbe-derived metabolite, trimethylamine N-oxide, exacerbate pressure overload-induced heart failure
.
Circ. Heart Fail.
9
,
e002314
55
Troseid
M.
,
Ueland
T.
,
Hov
J.R.
et al. 
(
2015
)
Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure
.
J. Intern. Med.
277
,
717
726
56
Goncalves
S.
,
Pecoits-Filho
R.
,
Perreto
S.
et al. 
(
2006
)
Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients
.
Nephrol. Dial. Transplant.
21
,
2788
2794
57
Wikoff
W.R.
,
Anfora
A.T.
,
Liu
J.
et al. 
(
2009
)
Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites
.
Proc. Natl. Acad. Sci. U.S.A.
106
,
3698
3703
58
Yu
M.
,
Kim
Y.J.
and
Kang
D.H.
(
2011
)
Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress
.
Clin. J. Am. Soc. Nephrol.
6
,
30
39
59
Liabeuf
S.
,
Barreto
D.V.
,
Barreto
F.C.
et al. 
(
2010
)
Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease
.
Nephrol. Dial. Transplant.
25
,
1183
1191
60
Miyazaki
T.
,
Ise
M.
,
Seo
H.
and
Niwa
T.
(
1997
)
Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys
.
Kidney Int. Suppl.
62
,
S15
S22
61
Mak
R.H.
and
Cheung
W.
(
2007
)
Adipokines and gut hormones in end-stage renal disease
.
Perit. Dial. Int.
27
(
Suppl. 2
),
S298
S302
62
Lin
C.J.
,
Wu
V.
,
Wu
P.C.
and
Wu
C.J.
(
2015
)
Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure
.
PLoS ONE
10
,
e0132589
63
Niwa
T.
,
Nomura
T.
,
Sugiyama
S.
,
Miyazaki
T.
,
Tsukushi
S.
and
Tsutsui
S.
(
1997
)
The protein metabolite hypothesis, a model for the progression of renal failure: an oral adsorbent lowers indoxyl sulfate levels in undialyzed uremic patients
.
Kidney Int. Suppl.
62
,
S23
S28
64
Massy
Z.A.
,
Barreto
D.V.
,
Barreto
F.C.
and
Vanholder
R.
(
2010
)
Uraemic toxins for consideration by the cardiologist-Beyond traditional and non-traditional cardiovascular risk factors
.
Atherosclerosis
211
,
381
383
65
Sun
C.Y.
,
Chang
S.C.
and
Wu
M.S.
(
2012
)
Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition
.
PLoS ONE
7
,
e34026
66
Vaziri
N.D.
,
Wong
J.
,
Pahl
M.
et al. 
(
2013
)
Chronic kidney disease alters intestinal microbial flora
.
Kidney Int.
83
,
308
315
67
Rhee
E.P.
,
Souza
A.
,
Farrell
L.
et al. 
(
2010
)
Metabolite profiling identifies markers of uremia
.
J. Am. Soc. Nephrol.
21
,
1041
1051
68
Tang
W.H.
,
Wang
Z.
,
Shrestha
K.
et al. 
(
2015
)
Intestinal microbiota-dependent phosphatidylcholine metabolites, diastolic dysfunction, and adverse clinical outcomes in chronic systolic heart failure
.
J. Card. Fail.
21
,
91
96
69
Stubbs
J.R.
,
House
J.A.
,
Ocque
A.J.
et al. 
(
2016
)
Serum trimethylamine-N-oxide is elevated in CKD and correlates with coronary atherosclerosis burden
.
J. Am. Soc. Nephrol.
27
,
305
313
70
Al-Waiz
M.
,
Mitchell
S.C.
,
Idle
J.R.
and
Smith
R.L.
(
1987
)
The metabolism of 14C-labelled trimethylamine and its N-oxide in man
.
Xenobiotica
17
,
551
558
71
Mueller
D.M.
,
Allenspach
M.
,
Othman
A.
et al. 
(
2015
)
Plasma levels of trimethylamine-N-oxide are confounded by impaired kidney function and poor metabolic control
.
Atherosclerosis
243
,
638
644
72
Heianza
Y.
,
Ma
W.
,
Manson
J.E.
,
Rexrode
K.M.
and
Qi
L.
(
2017
)
Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies
.
J. Am. Heart Assoc.
6
,
pii: e004947
73
Estruch
R.
,
Ros
E.
,
Salas-Salvado
J.
et al. 
(
2013
)
Primary prevention of cardiovascular disease with a Mediterranean diet
.
N. Engl. J. Med.
368
,
1279
1290
74
Appel
L.J.
,
Moore
T.J.
,
Obarzanek
E.
et al. 
(
1997
)
A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group
.
N. Engl. J. Med.
336
,
1117
1124
75
Mekki
K.
,
Bouzidi-bekada
N.
,
Kaddous
A.
and
Bouchenak
M.
(
2010
)
Mediterranean diet improves dyslipidemia and biomarkers in chronic renal failure patients
.
Food Funct.
1
,
110
115
76
David
L.A.
,
Maurice
C.F.
,
Carmody
R.N.
et al. 
(
2014
)
Diet rapidly and reproducibly alters the human gut microbiome
.
Nature
505
,
559
563
77
Ravussin
Y.
,
Koren
O.
,
Spor
A.
et al. 
(
2012
)
Responses of gut microbiota to diet composition and weight loss in lean and obese mice
.
Obesity
20
,
738
747
78
Almoosawi
S.
,
Winter
J.
,
Prynne
C.J.
,
Hardy
R.
and
Stephen
A.M.
(
2012
)
Daily profiles of energy and nutrient intakes: are eating profiles changing over time?
Eur. J. Clin. Nutr.
66
,
678
686
79
Foye
O.T.
,
Huang
I.F.
,
Chiou
C.C.
,
Walker
W.A.
and
Shi
H.N.
(
2012
)
Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling
.
FEMS Immunol. Med. Microbiol.
65
,
467
480