Biomedicine & Pharmacotherapy 134 (2021) 111156

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

A cross-talk between gut microbiome, salt and hypertension

Salma Naqvi a, Turky Omar Asar b, h, Vikas Kumar c, *, Fahad A. Al-Abbasi b, Sultan Alhayyani d,
Mohammad Amjad Kamal e, f, g, Firoz Anwar b, *
a
Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, United Arab Emirates
b
Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
c
Natural Product Discovery Laboratory, Department of Pharmaceutical Sciences, Shalom Institute of Health and Allied Sciences. Sam Higginbottom University of
Agriculture, Technology and Sciences, Naini, Prayagraj, 211007, India
d
Department of Chemistry. College of Sciences & Arts, Rabigh King Abdulaziz University, Jeddah, Saudi Arabia
e
Novel Global Community Educational Foundation, Australia
f
King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia
g
Enzymoics, 7 Peterlee Place, Hebersham, NSW, 27707, Australia
h
Department of Biology, College of Science and Arts at Alkamil, University of Jeddah, Jeddah, Saudi Arabia

A R T I C L E I N F O A B S T R A C T

Keywords: Cardiac disorders contribute to one of the major causes of fatality across the world. Hypertensive patients, even
Gut microbiota well maintained on drugs, possess a high risk to cardiovascular diseases. It is, therefore, highly important to
Hypertension identify different factors and pathways that lead to risk and progression of cardiovascular disorders. Several
Salt
animals and human studies suggest that taxonomical alterations in the gut are involved in the cardiovascular
TMAO
Cardiovascular disease
physiology. In this article, with the help of various experimental evidences, we suggest that the host gut-
microbiota plays an important in this pathway. Short chain fatty acids (SCFAs) and Trimethyl Amine -n-Oxide
(TMAO) are the two major products of gut microbiome. SCFAs present a crucial role in regulating the blood
pressure, while TMAO is involved in pathogenesis of atherosclerosis and other coronary artery diseases,
including hypertension. We prove that there exists a triangular bridge connecting the gap between dietary salt,
hypertension and gut microbiome. We also present some of the dietary interventions which can regulate and
control microbiota that can prevent cardiovascular complications.We strongly believe that this article would
improve the understanding the role of gut microbiota in hypertension, and will be helpful in the development of
novel therapeutic strategies for prevention of hypertension through restoring gut microbiome homeostasis in the
near future

1. Introduction 24 -h urinary sodium excretion and blood pressure [5]. It is established

Cardiovascular diseases (CVD) account for one of the major causes of
death across the globe. Every fourth death in USA is due to some cardiac
disorder [1]. Several factors have been known for ages which may
impair the cardiac function. These include diabetes, dyslipidemia,
drugs, hypertension and life-style factors like smoking, drinking, lack of
exercises and inadequate diet to name few [2]. Hypertension is one of
the major risk factors that contribute to the cardiovascular and kidney
diseases, and is a leading cause of premature deaths [3]. Salt intake is
considered to be one of the most prevalent environmental factors for
onset of hypertension [4]. There exists a positive relationship between a
that the dietary salt consumption affects the blood pressure in hyper­
tensives more than that in normotensives [6].
Recently, gut microbiota has hit the interest of researchers for its
contribution to CVD [7]. Microbiota is a colony of indefinite number of
micro-organisms, collectively known as Microbiome, hosted by human
body. The microbiota resides mainly in the GIT and especially colon,
where they get an anaerobic, nutrient rich environment, suitable for
their growth and colonization [8]. These contribute to various host
metabolic functions [9] and react to the circulating signaling molecules
within the human body. They are capable to generate certain bioactive
metabolites like amino acids, bile acids and peptide, which can enhance

Abbreviations: CVD, Cardiovascular diseases; SCFAs, Shortchain fatty acids; NF-κB, Nuclearfactor kappa B; TLR, Toll-likereceptors; TMAO, Trimethylamine N-
oxide; GPCRs, G-Proteincoupled receptors; NHE, Sodium-protonexchanger-3; CAD, Coronaryartery disease; DASH, Dietaryapproaches to stop hypertension.
* Corresponding authors.
E-mail addresses: phvikas@gmail.com, vikas.kumar@shiats.edu.in (V. Kumar), fanwar1@kau.edu.sa (F. Anwar).

https://doi.org/10.1016/j.biopha.2020.111156
Received 10 October 2020; Received in revised form 14 December 2020; Accepted 15 December 2020
Available online 2 January 2021
0753-3322/© 2020 Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Naqvi et al.
host-receptor activation, signaling and immunomodulatory functions
[10,11].
This article would improve the understanding the role of gut
microbiota in hypertension, and will be helpful in the development of
novel therapeutic strategies for prevention of hypertension through
restoring gut microbiome homeostasis in the near future.
2. Healthy gut microbiome
Human microbiota represents a large community of micro-organisms
invading the host body [12]. This community includes a group of bac­
teria, archaea, viruses and other eukaryotes [9], and play vital roles in
an individual’s metabolic profile including nutrient metabolism, main­
taining integrity and strength of gut mucosal epithelium barrier,
immunomodulation and other functions [13]. The human gut is the
residence of more than 2900 commensal and opportunistic bacterial
species, with 102 bacteria per gram content present in the stomach,
which increase upto1011 per gram content in the colon [14–16]. The
abundance of bacterial genome occupying the human body is approxi­
mately 150 times greater than that of human genome. Among the
several bacterial species forming a healthy gut microbiome, Bacter­
oidetes (majorly Bacteroides or Prevotella) that are gram negative, and
Firmicutes (majorly Clostridium and Lactobacillus), which are gram
positive, constitute >90 % of the total composition [17]. Other phyla
include Proteobacteria (8%), Actinobacteria (3%) and others Fusobac­
teria, Verrucomicrobia and TM7 (2%). Fungi and archaea constitute
<1% of total gut microflora [18,19]. Researchers have reported various
important roles played by the gut microbiota. They are able to metab­
olize indigestible carbohydrates and proteins into short chain fatty acids
(SCFAs), including acetic, propionic and butyric acid, which can easily
be absorbed and digested in the distal gut [20,21]. These SCFAs provide
energy to the intestinal epithelial cells, and thus strengthen the mucosal
barrier. Propionate, majorly produced by bacteroidetes, andbutyrates
produced by Firmicutesdegrade the indigestible polysaccharides.As
these microorganisms aid digestion of the residual substrates, they
contribute in the synthesis of vitamin K, vitamin B12, riboflavin, thia­
mine and folate and essential amino acids [22,23].
Other than digestion, the gut microbiota is also involved in the
regulation of endocrinesystem, mental health and the immune system.
These SCFAs are the potent anti-inflammatory compounds which reduce
cytokine production by inhibiting nuclear factor kappa B (NF-κB) [24].
Gut microbiome is known to enhance immune system via intestinal
epithelial cells consisting of toll-like receptors (TLR) [25]. These re­
ceptors are activated through their recognition site for bacteria, and
in-turn, activate the immune response. While intestinal epithelium
performs the immune function, its metabolic functions are reduced,
thereby resulting in reduced leptin levels and fat absorption. Thus, gut
biome has a significant role in maintaining the balance between meta­
bolic and immune functions of the gut epithelium [26].
Colonic bacteria can also alter the bile acid composition and affect
host metabolism. They convert unabsorbed primary bile acids into sec­
ondary bile acids. The secondary bile acid further enters the circulation
and affects signaling pathways associated with energy expenditure,
inflammation and metabolism [27].
3. Gut microbiome and cardiovascular diseases
While the dietary and host derived molecules utilized by gut
microbiome are beneficial in significant physiological functions of GIT,
at the same time, they may hamper the functions of other organs like
heart [28]. The patients with CHF are reported to have altered
morphological and functional physiology of small intestine. CHF and
cardiac cachexia increase bowel permeability and reduce intestinal
resorption. Bowel wall edema and altered microcirculation in the gut
cause malabsorption of the nutrients. Disintegration of intestinal mu­
cosa increases the gut permeability for lactulose and sucralose sugars.
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Biomedicine & Pharmacotherapy 134 (2021) 111156
Celik et al. proposed that this altered gut barrier function is the result of
bacterial translocation [29]. Any disruption in this microbial ecosystem
may have severe consequences on the host’s cardiovascular system
(CVS) [30]. Alteration in composition of gut microbiota is reported to be
associated with several metabolic disorders like diabetes, obesity and
cardiovascular disorders [31] including heart failure, dyslipidemia [32],
atherosclerosis [33,34], hypertension and chronic kidney diseases [35].
This microbial relation to the diseases may be via direct pathways
through the metabolites formed by bacteria like toxins, bile acids,
SCFAs, trimethyl amine N-oxide (TMAO), vitamin K, vitamin B, gut
hormones etc., or via indirect pathways through immune system [36].
Recently, it has been discovered that alteration in gut microbiome is
also associated with emergence of hypertension, vascular dysfunction
and chronic renal disorders [37–39]. This is attributed to the gut
microbiota’s communication with nervous, endocrine as well as immune
system to regulate blood pressure, kidney functions and other homeo­
stasis processes. Chronic kidney disorders are generally accompanied by
several metabolic disorders, hyper-sympathetic activation and immune
dysregulation, which in turn are all associated with gut dysbiosis [40].
Also, kidney plays a major role in regulating the blood pressure. Thus, a
healthy microbiome environment may have a significant therapeutic
outcome in treatment of renal diseases and hypertension [40].
There are evidences that gut microbiome can also be affected by
steroid hormones and vice versa. The microflora composition may vary
with gender. It has been observed that males have higher levels of
Bacteroidetes and Prevotella as compared to females. Also there occurs a
shift in microbiome diversity with proliferation of Proteo- and Actino-
bacteria during pregnancy which may render metabolic changes. It
may be attributed to change in estrogen and progestin levels. Further,
gut microbiota can also modulate androgens and glucocorticoids
through oxidation and reduction reactions [165]. Besides, studies have
shown that there exists a relation between sex steroids hormones and
hypertension. Estrogen level was found to be decreased in hypertensive
males, while estradiol was higher in hypertensive males and females
[166]. These findings suggest a possible relation between hypertension
and gut-associated steroid metabolism. However, further studies are
needed to prove this.
4. Association between gut microbiota and hypertension
Hypertension, a very common and a profound cardiovascular disease
worldwide, affects more than a billion people across the globe [41].
Especially in high class societies, blood pressure level increases with age
in both males and females, owing to different factors, with high salt diet
being the major the contributor to the prevalence of the disease [42]. It
is well established in last few years that there is a strong co-relation
between gut microbiota and blood pressure [43]. Bacterial metabolites
have an influencing role in regulation of blood pressure [44]. This as­
sociation of gut microbiome with hypertension has been studied by
various researchers in different animal and human models. Emerging
literature on both animal and human experiments are suggestive of in­
crease in blood pressure with disruption of gut microbial composition
[45]. Gut dysbiosis indicates reduced abundance, richness and diversity
of microbial genome with taxonomical distinction. The alteration in
abundance of bacterial taxonomy in hypertension are shown in Tables 1
and 2, as observed in the studies conducted respectively on rodents and
human subjects. Clostridiales have been found to be in abundance in
both, hypertensive human as well as rodents [46–48]. Additionally,
Bacterodiales population also increases in hypertensive human, but are
negatively associated with blood pressure in rodents [49]. Researchers
have investigated influence of microbiome on blood pressure through
bacterial DNA in fecal matter of two animal models of hypertension, i.e.
spontaneously hypertensive and angiotensin-II induced hypertensive
rats [38]. They induced hypertension in germ-free and microbiota-intact
groups of mice by injecting angiotensin-II. The former showed low BP,
reduced free oxygen radicals and circulatory IL-17, as compared to latter
S. Naqvi et al. Biomedicine & Pharmacotherapy 134 (2021) 111156

Table 1
Rodent taxa alteration in abundance in hypertension.
Phylum Class Order Family Genus Increase/ decrease References

Barnesiellaceae Increased [46]

Bacteroidetes Bacteroidia Bacteroidales
S24− 7 S24− 7_g (unclassified) Decrease [49]
Christensenellaceae Increased
Eubacteriaceae Anaerofustis Increased [46]
Lachnospiraceae Anaerostipes Decrease
Clostridia Clostridiales Peptococcaceae Anaerofustis Increased [48]
Clostridiaceae Decrease [47]
Coprococcus (butyrate producing) Decrease
Firmicutes [35]
Pseudobutyrivibrio (butyrate producing) Decrease
Lactobacillaceae Lactobacillus Increased [47]
Bacilli Lactobacillales
Streptococcaceae Streptococcus (Lactate producing) Increased [35]
Coprobacillus Decrease
[47]
Erysipelotrichia Erysipelotrichales Erysipelotrichaceae Holdemania Decrease
Turicibacter (Lactate producing) Increased [35]
Enterobacteriales Enterobacteriaceae Erwinia Increased
Proteobacteria Gammaproteobacteria [46]
Pseudomonadales Increased

Table 2
Human taxa alteration in abundance in hypertension.
Phylum Class Order Family Genus Species Increase/ decrease References

Actinobacteria Actinobacteria Actinomycetales Actinomycetaceae Actinomyces Increase

Porphyromonadaceae Porphyromonas Increase [53]
Bacteroidetes Bacteroidia Bacteroidales Prevotellaceae Prevotella Increase
Rikenellaceae Alistipes finegoldii Increase
Ruminococcaceae Ruminococcus torques Increase [37]
Firmicutes Clostridia Clostridiales
Eubacteriaceae Eubacterium siraeum Increase
Proteobacteria Gammaproteobacteria Enterobacteriales Enterobacteriaceae Klebsiella Increase
[53]
Actinobacteria Actinobacteria Bifidobacteriales Bifidobacteriaceae Bifidobacterium Decrease
Bacteroidetes Bacteroidia Bacteroidales Bacteroidaceae Bacteroides thetaiotaomicron Decrease [37]
Clostridiaceae Faecalibacterium Decrease [53]
Firmicutes Clostridia Clostridiales Butyrivibrio Decrease
Lachnospiraceae [53]
Roseburia Decrease

[38]. Also, conventional rats with intact microbiome, when subjected to
angiotensin-II induced hypertension, showed reduced microbial rich­
ness as compared to control groups. They reported a significant dis­
balance in microbiota, along with an increase in Fermicutes/
Bacteroidetes ratio in spontaneously hypertensive rats [35]. Several
studies evidence the fact that a high salt diet is greatly responsible for
hypertension and kidney disorders [50,51]. On an average people
consume 9–12 g m of salt per day, which is nearly twice the recom­
mended intake [52]. A study carried on the Dahl salt- sensitive (DSS) rat
model, where there is a prominent increase in blood pressure and kidney
injury due to high-salt induced diet, reported a significant alteration in
the composition of gut microbiome [46]. Similarly, Mell et al. have
demonstrated that there’s a significant difference between the gut bac­
terial composition of salt-sensitive and salt -resistant Dahl rats [51]. In
another study, where germ-free mice were subjected to fecal microbiota
transplantation from hypertensive patients, it resulted in an increase in
systolic and diastolic blood pressure of mice, with decreased microbial
richness and diversity [53]. In a similar experiment performed by Toral
et al., fecal microbiota was transplanted from hypertensive to normal
rats, systolic BP elevated in the receiver group, while systolic BP
ameliorated in hypertensive rats on microbial transplantation from
normotensive to the latter. Not only was BP attenuated, but reduced
oxidative stress and vascular inflammation also improved vascular
inflammation in hypertensive rats [49]. This vascular injury and in­
crease in BP is subjected to the inflammatory IL-17 and oxidative stress
produced by TH17 cells and NADPH respectively [49]. In a study con­
ducted by Shikata et al., [54], entire gut microbiota was ablated using an
antibiotic cocktail, which resulted in significant reduction in the in­
cidences of hypertension-induced aneurysms. All these experiments
suggest that there exists a strong co-relation between hypertension and
the gut microbial composition. Taxa like Ruminococcus torques, Eubac­
teriumsiraeum and Alistipesfinegoldii are all associated with high blood
pressure (BP) and may cause intestinal inflammation [55]. On the other
hand, Bacteroidesthetaiotaomicronis anti-inflammatory, and is associated
with lower BP (Table 2), [37]. Few studies have been conducted to
examine the role of gut microbiome in patients with hypertension. Blood
pressure and bacterial metabolites are strongly associated, as revealed
by certain population based studies conducted on humans [56,57].
Hypertensive patients have relatively lower diversity in their
commensal microbial colony as compared to subjects with normal blood
pressure. Both prehypertensive and hypertensive patients were observed
to have lower gene richness and microbial α-diversity, but a higher
percentage of bacteria of genus Prevotella, when compared to that of
healthy controls. These differences in microbiome clusters between the
disease groups suggest that the metabolic profile related to hypertension
is linked to the gut microbiome concentration in host [58]. Few other
studies, conducted mainly in Chinese, US and Brazilian population, have
explored that the microbiome alterations underlie hypertension, provide
a range of phylogenetic and functional signatures and thus suggest that
the gut microbiota dysbiosis possibly contribute to the pathogenesis of
hypertension [59–62].
5. Major products of gut microbiome
5.1. `Short chain fatty acids (SCFAs)
Commensal gut bacteria carry out the fermentation or degradation of
carbohydrates and proteins, resulting in the formation of SCFAs, which
are crucial in maintaining a healthy intestinal system. Metabolites pro­
duced by Gut microbes comprise of nearly 20 % of small molecules
circulating in human blood [63], are implicated in activation of sym­
pathetic system and maintenance of lymphocyte influx to the intestinal
tissues [64,65]. These SCFAs are either absorbed by the gut and
contribute various physiological processes, or they are excreted in feces.

3
S. Naqvi et al.
The most abundant form of these SCFAs are acetic, propionic and butyric
acids [66,67]. They have shown beneficial outcomes in various rat
models. An obstructive sleep apnea model of hypertension showed
reduction in colonic acetate levels of rats by 48 %. However, successful
reversal in hypertension was seen on infusion with colonic acetate [68].
Administration of corn starch and Clostridium butyricum, which produce
acetate and butyrate, also led to the reversal of hypertension in
sleep-apnea induced hypertensive rats.
Similarly, propionate treatment orally, in angiotensin-II induced
hypertensive mice resulted in reduction in systolic and diastolic blood
pressure along with reduced systemic inflammation and cardiac effects
[69]. Also, vascular functions were improved in the treated rats. Similar
results were obtained with butyrate treatment via intraperitoneal
administration [37].
These data indicate that SCFAs have a positive outcome in rodent
models of hypertension. Furthermore, they are the major source of en­
ergy for colonocytes. They play a vital role in maintaining gut barrier
function. They also strengthen the intestinal barrier and possess an anti-
inflammatory action. Along with this, SCFAs enhance gut and peripheral
immune responses [70] and regulate the appetite function [71]. They
also modulate vasodilation and regulate renin secretion and blood
pressure, majorly acting via G-Protein coupled receptors (GPCRs),
mainly Gpr41, Gpr43, Gpr 109a and Olfr78 [72–74]. Gpr41 is expressed
mainly in vascular endothelium of blood vessels, dendrites and neu­
trophils along with some other tissues like lymph nodes, spleen,
fat-tissues, bone marrow, lungs, small intestine as well assympathetic
ganglia [75]. However, Gpr43 are expressed majorly in intestines and
immune cells including peripheral blood monocytes
polymorpho-nuclear neutrophils, lymphocytes and monocytes. SCFAs
supplementation can lead to significant changes in the expression of Gpr
41 and 43, and are characterized by an increase in adipose tissues and
decrease in colon [76]. Both these receptors are coupled to Gi/o, which
leads to the production of cAMP to SCFA propionate followed by buty­
rate and least to acetate [77,78]. Additionally, Gpr43, also known as
Free Fatty Acid Receptor-2, is also attached to Gq in the intestine and
regulates Glucagon-like Peptide (GLP)-1 secretion [79,80]. These are
expressed majorly in entero-endocrine cells, neutrophils and adipocytes,
and are involved in obesity, type II diabetes and inflammation [81].
Gpr109a or Hydrocarboxylic Acid Receptor-2, coupled to Gi/o and
arrestin-1, is expressed in innate immune cells, intestinal epithelium and
adipocytes [82,83].
Olfr78, activated by mainly by propionate SCFA, is expressed in islets
and intestinal epithelial cells. Research has shown its role in regulation
of GLP-1 secretion from entero-endocrine cells of murine model. Olfr78-
knockdown murine resulted in significantly lesser secretion of propio­
nate induced GLP-1 secretion [84]. It mediates the release of renin in
juxta-glomerulus of kidney, and hence plays a significant role in blood
pressure regulation [85,86].
Changes in gut microbial composition would result in the alteration
of circulating SCFAs in bloodstream [87]. Hence, decreased abundance
of gut bacterial population may affect the immunological, physiological
and metabolic homeostasis of the host, including its influence on blood
pressure [87]. In a study by Cuesta- Zuluaga, it was observed that there
exists a strong association of fatty acids with the composition and di­
versity of gut microbiome, gut permeability and hypertension along
with other cardiac outcomes [88]. A cross talk between the gut intestinal
system and central nervous system has also emerged as a potential link
to blood pressure [89,90]. Metabolites produced by Gut microbes are
implicated in increased sympathetic activity and maintenance of
lymphocyte influx to the intestinal tissues [64,65]. Activation of sym­
pathetic system and renin secretion increases blood pressure, which can
be inhibited by Gpr41, Gpr43, Gpr 109a induced vasodilation.
5.2. Trimethyl amine-N- oxide (TMAO)
Gut microbiota converts choline into trimethyl amine (TMA) and
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Biomedicine & Pharmacotherapy 134 (2021) 111156
trimethyl amine- oxide (TMAO), a metabolite found in various tissues
and biological fluids [91].Derived from red meat, milk, fish and other
dietary sources of choline, phosphatidylcholine, lecithin and L-carnitine,
TMAO possesses a risk factor for the development of cardiac and renal
diseases [92]. Elevated TMAO concentration both in urine and plasma is
a marker of medullary damage and chronic kidney failure [93].
Increased plasma levels of TMAO effect renin- angiotensin system, and
reflecthypertension associated with coronary artery diseases [92–94].
High salt intake has shown increased plasma concentration of TMAO,
which caused gut dysbiosis in rats [95]. Elevated TMAO levels have also
been augmented to atherosclerosis, the increased risk of death and
non-fatal myocardial infection [36,87]. In a dose- response meta –
analysis, higher levels of circulating TMAO were associated with
significantly higher prevalence of hypertension [96], and also increased
the risk of first stroke in hypertensive patients [97] as compare to that of
lower TMAO concentration.
6. Salt, hypertension and gut
Sodium intake is an independent risk factor for the emergence of
hypertension and other cardiovascular diseases. High salt can also lead
to a decline in cognitive ability [98,99], and enhance cardiovascular
complications [100] via hypertension. Dietary sodium comprises almost
99 % of the total salt intake [101]. WHO recommends a consumption of
less than 5gm of salt per day to prevent hypertension and other cardiac
diseases [52]. If global salt intake is reduced to the recommended level,
then 2.5 million deaths are estimated to be prevented annually [52].
Sodium is highly absorbed in colon via sodium-proton exchanger-3
(NHE3). An alteration in gut microbial environment and a decrease in
blood pressure was observed on deletion of NHE-3 in mice [102]. It is
thus, most likely that gut microbiota is involved in uptake of salt in the
body and may respond to salt sensitivity in hypertension. High salt
consumption affects the digestion of proteins and alters gut bacterial
diversity [103]. This alteration may include an increase in Cor­
ynebacteriaceae and decrease in Lactobacillus species (Tables 3 and 4),
respectively responsible for chronic kidney diseases [38] intestinal
inflammation and colitis [104]. As investigated by Wilck et al., salt
administration decreased the prevalence of Lactobacillus murinus, and
increased the count of pro-inflammatory splenic Th17 cells in a rat
model (Table 3). However, daily administration of Lactobacillus murinus
as a probiotic therapy significantly reduced Th17 cells and ameliorated
the blood pressure in treated rats [105]. It can thus be postulated that
high salt intake and decreased abundance of Lactobacillus species com­
prises one of the several mechanisms causing gut homeostasis disruption
and hypertension.
In another study, Hu et al. analyzed the effects of high salt diet on gut
microbial composition. They elicited that 8-weeks administration of
high salt significantly transformed the gut microbial composition in
mice [106]. The results exhibited a considerable decrease in Bacter­
oidetes and Proteobacteria by 50.53 % and 2.96 % respectively, and
increase in Firmicutes by 42.77 % [106], (Table 3). At the same time,
SCFA levels in lower gut were found to be significantly reduced in high
salt diet - administered mice, which is attributed to inhibition of bac­
terial fermentation [106. Interestingly, a modest reduction in dietary
sodium can increase circulating SCFAs, and thereby increase the gut
microbiome. Increased levels of SCFAs in turn decrease blood pressure
and improve arterial compliance [107].
7. Molecular events in remodeling and salt compassion
There is an exhaustive literature available on the dietary salt intake
and its contribution to the inflammatory pathways. However, till date
there is no well-defined established molecular mechanism for its path­
ogenesis in cardiac remodeling. Researchers have proposed numerous
mechanisms that correlate the accumulation of salt with respect to
alteration in sympathetic activity associated with increase in blood
S. Naqvi et al. Biomedicine & Pharmacotherapy 134 (2021) 111156

Table 3
Bacterial taxa altered by dietary sodium with their full classification.
Phylum Class Order Family Genus Increase/ decrease References

Micrococcaceae Rothia Decrease [105]

Actinobacteria Actinobacteria Actinomycetales
Corynebacteriaceae Increase [46]
Rikenellaceae S24− 7 Alistipes Decrease 105
Bacteroidetes Bacteroidia Bacteroidales
Prevotellaceae Increase
[105]
Bacili Lactobacillales Lactobacillaceae Lactobacillus Decrease
Clostridiaceae Unclassified Decrease [104]
Anaerostipes Decrease 46
Clostridium XIVa Decrease
Lachnospiraceae [105]
Johnsonella Decrease
Firmicutes Roseburia Increase [103, 104]
Clostridia Clostridiales
Family unassigned Pseudoflavonifractor Decrease
[105]
Rikenellaceae Alistipes Increase
Christensenellaceae Increase [46]
Oscillospiraceae Oscillospira Increase [104]
Ruminococcaceae Ruminococcus Increase [103]
Proteobacteria Betaproteobacteria Burkholderiales Sutterellaceae Parasutterellaspp Increase [105]
Gammaproteobacteria Enterobacteriales Enterobacteriaceae Erwinia Increase [46]
Verrucomicrobia Verrucomicrobiae Verrucomicrobiales Verrucomicrobiaceae Akkermansia Increase [105]

Table 4
Human taxa reduced in abundance following a high sodium diet (5500 mg Na/d, 14 days).
Phylum Class Order Family Genus Increase/ decrease References

Firmicutes Bacili Lactobacillales Lactobacillaceae Lactobacillus Decrease [105]

pressure [108], including change in patho- physiological functions of
arteries [109], decrease in systemic resistance [110] and elevated
endothelial function [111] might contribute to remodeling. A report
published in lancet by Moriomoto et al. clearly states that
sodium-sensitive hypertensive patients are highly prone to cardiovas­
cular diseases [112]. The electrochemical charge developed on the
interstitial membrane due to stored inactive sodium plays an important
role in governing the blood pressure. The charge on RBC surface and
vascular endothelium regulates the pressure on the vessels [113]. Na +
content is generally high in extracellular fluid (blood) and is highly
sensitive to negatively charged surface of RBC and endothelium layer.
The elevated sodium level regularly causes significant alterations in the
blood pressure, which is a key factor for cardiac remodeling [114].
Decrease in sodium concentration compensatory stimulates the release
of sodium stored at the interstitial sites, which leads to sodium and water
retention [115]. Glycoaminoglycans control the storage of sodium ions
at endothelial surface layer (ESL) [116]. The nonosomic buildup of so­
dium in ESL is associated with decrease in the extracellular volume and
blood pressure, an adverse consequence of sodium upload in diabetic
and Chronic kidney disease (CKD) patients [117]. It is well, reported
that high sodium increases the expression level of vascular cell adhesion
molecule (VCAM-1), one of the mechanisms for microvascular inflam­
matory pathway. It triggers an immune response and the release of cy­
tokines lead to cardiac remodeling [118]. This phenomenon is followed
by alteration in TRPC3 expression and calcium influx in cells, a common
phenomenon observed in cardiac patients. Elevated level of calcium in
intracellular matrix induces oxidative stress and inflammation in cardiac
tissue [119]] Further, the cytokines released during inflammatory car­
diac hypertrophy stimulate lipoxygenase pathway [120] and produce
hydroperoxy eicosatetraenoic acids (HPETEs). HPETEs further disso­
ciate into more stable compounds like leukotrienes and hydro­
eicosatetraenoic acids (HETEs) [121]. 12- HPETEs also mediate the
release of hormones like insulin and renin [122,123]. This, in turn, ac­
tivates RAAS/ACE/Ang II system that further facilitates the release of
aldosterone, and hence, activates the sympathetic nervous system (SNS).
Noradrenaline released on SNS activation compensates to increase the
heart rate. In long run higher level of these hormones in blood pro­
gresses to the cardiac remodeling [124].
Renin-angiotensin system (RAS) plays a crucial role in hypertension
and electrolyte and fluid homeostasis through its local and systemic
actions on both circulatory and renal systems [167]. Angiotensinogen
produced in this system is cleaved to Angiotensin (AT)-I, which gets
converted to AT-II in presence of Angiotensin converting enzyme (ACE).
AT-II, the major component of RAS acts via AT-II receptor type 1
(AT1R), and stimulates various deleterious effects including vasocon­
striction, hypertension, inflammation and fibrosis. Angiotensin con­
verting enzyme-2 (ACE-2), a homologue of ACE, is located in the
epithelial cells of kidneys, heart and small intestine. It counterbalances
the action of ACE, and hydrolyses AT-II to vasodilators AT- (1–7),
thereby regulating electrolyte and fluid homeostasis and reducing the
blood pressure [168]. As gastrointestinal system is the main organ for
intake and excretion of fluid and salt, it is reported that
Renin-angiotensin system (including ACE2) is present throughout the
GIT, regulating its pathophysiological functions. Apart from its action on
RAS, ACE2 also regulates SLC6A19, a neutral amino acid transporter
[169] along with gut microbial ecology and homeostasis [170]. Gut
microbiome has a plausible role in regulation of genes associated with
immune response. The commensal gut microbiota can be a target of
invading viruses and stimulate a suppressive or stimulatory response.
Respiratory viral infections can disrupt the dynamic of microbiota and
result in dysbiosis and make patients prone to secondarily bacterial in­
fections [171]. There exists an association between increase in inflam­
mation, poor outcome and gut dysbiosis. Recent studies have exhibited
that broncho-alveolar fluid of COVID-19 (SARS-CoV-2) infected patients
predominantly contains oral and upper respiratory commensal bacteria
[172]. Also there are several studies which report that comorbidities in
COVID patients like obesity, coronary artery disease, hypertension and
others are related to dysbiosis, primarily alteration in Bacteroidetes and
Firmicutes ratio [173,174]. Along with fever, cough and hypoxia,
nausea and diarrhoea are highly frequent symptoms in SARS-CoV-2
infection, which suggests its impact on GI- enteric system. Calpro­
tectin expression was found to be elevated in COVID-19 patients with
diarrhoea, which indicates intestinal inflammation in gut. It is estab­
lished that SARS-CoV-2 enters the host via ACE2 receptors, highly
expressed in respiratory and GI tract and disrupt RAS regulation. This
infection induces ACE2 shedding, which results in loss of protective
functions of ACE2. Reduced ACE2 expression disrupt AT-II/AT (1–7)
ratio, and promote the deleterious functions of AT-II. The resultant effect

5
S. Naqvi et al.
is vasoconstriction, hypertension and inflammation [175]. ACE2 shed­
ding favours the progression of gut dysbiosis.
8. Augmentation of pharmacology and microbiome
Where there are several evidences exhibiting that alteration in
microbiome may influence various pathological conditions, like hyper­
tension, obesity, diabetes, cardiac functions etc., at the same time, the
microbiota also influences the responses of drugs [125,126]. Various gut
bacterial metabolites may interfere with the pharmacokinetic and/ or
pharmacodynamic properties of a drug [127,128]. Although liver is the
major organ for metabolism of most of the drugs, recently it has been
explored that almost all the drugs administered orally affect gut
microbiome [129,130]. Therapeutic response and drug – related adverse
effects vary from individual to individual, depending upon various
factors like age, gender, BMI, nutritional status, disease condition,
environmental exposure and genetic variations [131].
Various studies have reported gut microbiome mediated interactions
between antibiotics and several antihypertensive drugs. Yoo et al.
demonstrated a significant increase in plasma concentration of amlo­
dipine, a calcium-channel blocker widely prescribed to hypertensive
patients, by 133 % in ampicillin treated rats [132]. This increase is
attributed to reduction in gut microbiota, which enhances the meta­
bolism of amlodipine.
Angiotensin converting enzyme (ACE) -inhibitors are highly effective
anti-hypertensive drugs. Sodium butyrate, a SCFA metabolite works in
accordance with ACE-inhibitors has shown improvement in Ag-II
induced hypertension [133].Enalapril, a commonly prescribed ACE
Fig. 1. Association of salt intake with change in Gut microbiota and CVD.
6
Biomedicine & Pharmacotherapy 134 (2021) 111156
inhibitor can stimulate gut perfusion [134,135], and hence can improve
intestinal barrier. It may result in a significant therapeutic outcome in
the treatment of a hypertensive patient. Similarly, propranolol, a
beta-blocker antihypertensive drug, has been shown to inhibit the bac­
terial translocation [136], thereby improving the intestinal functions
(Fig. 1).
9. Dietary interventions
9.1. Blood pressure and gut microbiota
Our life-style interventions and inadequate diet can assess the reg­
ulations and functions of our cardiovascular system. High cholesterol
and high- salt diet can complicate the cholesterol modulation, leading to
coronary artery disease (CAD) and hypertension respectively. Con­
sumption of such food interferes with the diversity of gut microbial
colony, modifies bile acid, SCFA and TMAO production, and in-turn,
affect the associated physiological functions like blood pressure [137].
At the same time, the diet enriched with fermentable fiber like Medi­
terranean diet and dietary approaches to stop hypertension (DASH) diet
can modulate gut microbiota and may tend to prevent hypertension,
enhance protective microbiome and increase formation of SCFAs [138].
Hypertension and other cardiac diseases can be prevented due to mod­
ifications in gut microbiota by administering high fiber rich diet and
acetate, a gut metabolite [139].
S. Naqvi et al.
9.2. Western diet and BP
Western diet is generally composed of artificial sweeteners [140] and
emulsifiers [141], high salt content [95], high fat content and low fibers
[142] along with direct or indirect administration of antibiotics [143],
high content of saturated fats, refined carbohydrates and sodium [144].
All these poor dietary choices are highly indicative of impaired immune
system, enhanced inflammation due to increase in plasma levels of
C-reactive proteins and increased blood pressure [137,145]. Inflam­
matory response is mediated by gut microbiome as it interacts with
immune system and assists in maturation of immune cells. Dietary so­
dium salt causes a shift in microbial composition and disrupts this
microbiota homeostasis of inflammation [146]. Dietary inflammatory
index is associated with the incidence of hypertension [147].
9.3. Diet for a healthy gut microbiome and reduced Hypertension
It’s a universal fact, and also evidenced by several epidemiological
studies, that diet rich in micronutrients and especially high fiber diet is
crucial for a healthy gut and BP homeostasis. Fruits, vegetables and le­
gumes, usually associated with increased SCFA levels, accomplish this
requirement [148].
A significant reduction in blood pressure in hypertensive patients,
along with reduction in inflammation has been reported with the use of
Mediterranean and DASH diet [149–152]. Apart from BP and inflam­
mation, improvement in obesity, coronary artery disease and other
metabolic alterations has also been reported [153,154].
Fruits like blueberries contain anthocyanin which can increase the
diversity of gut microbiome [155]. Other anti-oxidants like omega-3
fatty acids inhibit the activation of TLR-4 on the gut epithelium and
produce an anti-inflammatory response [156,157].
Pre- and pro-biotic diets have also been reported to strengthen the
intestinal barrier, regulate immune function and improve the gut envi­
ronment. They tend to decrease inflammation and increase levels of
SCFA, Bacteroidetes, bifidiobacterium and decrease Firmicutes [158,
159]. Prebiotics, mainly derived from the plants, are the food substances
which are not digested in upper GIT, but are broken down and fer­
mented by colonic bacteria. Their ability to reduce the cholesterol levels
has been attributed to lower the blood pressure in isolated systolic hy­
pertension [160].
Probiotics are the living organisms, few strains of which are known
to possess anti-hypertensive properties. Researchers have reported
reduction in blood pressure on consumption of probiotic milk for 8
weeks [161], fermented milk containing whey protein [162], lactoba­
cillus plantarum for 6 weeks in smokers [163] and probiotics fermented
potato yogurt [164].
Symbiotic, the nutritional supplements containing combination of
prebiotics and probiotics are able to modulate the metabolic activities of
the gut. The prebiotics majorly added to the symbiotic preparations
include dietary fibers, inulin and oligosaccharides, while probiotics
composition includes Lactobacilli, B. coagulans, S. boulardii and Bifido­
bacteria [45].
10. Conclusion
Accomplishing evidences show that high-salt intake elicits appre­
ciable effects on gut in both rodents and human cohort, beyond its
impact on hypertension. There exists a triangular relationship between
dietary salt, hypertension and gut microbiota. High salt may cause an
increase in TMAO, and decrease in SCFAs in gut. These transformations
in gut microbiota are cross related to hypertension. Any alteration in
bacterial composition may affect the gut integrity and interfere with the
pharmacological properties of antihypertensive drugs. However, Ena­
lapril, an ACE inhibitor, and Propranolol, a beta blocker, have shown to
inhibit the bacterial translocation. As these antihypertensive drugs
improve the intestinal integrity, they can be beneficial in therapeutic
7
Biomedicine & Pharmacotherapy 134 (2021) 111156
outcome of patients’ prognosis. It can be assumed that gut dysbiosis-
induced cardiac remodeling not only depends upon hypertension, but is
also associated with dietary salt intake. The salt alters the phylogenetic
communities of gut. It affects the microbial pathways involved in the
synthesis and degradation of SCFA, TMAO and other metabolites
responsible for regulation of normal heart function. However, a major
question which still remains unanswered is whether there exists a direct
link between gut microflora composition and cardiac remodeling.
Though it is well reported that commensal microbiota is involved in
vascular contractility through the action of polymerase, however, it is
yet to be explored whether the major player for mediation of this action
is salt intake or other factors that regulate vascular contraction in
presence of actin polymerase. Some researchers have reported that gut
microbiome composition fluctuates with factors like diurnal cycles and
consecutively impact the host’s circadian rhythm, although the study is
in juvenile phase. Further long term studies are still required to decipher
the changes in metabolic functional pathways, like taurine and aromatic
amino acid metabolism along with renal association of lipocalin2, the
factors associated with changes in heart pathology, creating its remod­
eled structure.
Declaration of Competing Interest
All the authors declare none.
References
[1] E.J. Benjamin, P. Muntner, A. Alonso, M.S. Bittencourt, C.W. Callaway, A.
P. Carson, et al., Heart disease and stroke statistics—2019 update: a report from
the American Heart Association, Circulation 139 (10) (2019) e56–528.
[2] Writing Group Members, et al., Heart disease and stroke Statistics-2020 update: a
report from the American Heart Association, Circulation 141 (January 9) (2020)
e139–596, https://doi.org/10.1161/CIR.0000000000000757.
[3] I. Kazmi, W.H. Al-Maliki, H. Ali, F.A. Al-Abbasi, Biochemical interaction of salt
sensitivity: a key player for the development of essential hypertension, Mol. Cell.
Biochem. (2020), https://doi.org/10.1007/s11010-020-03942-0 [published
online ahead of print, 2020 Oct 18]doi:10.1007/s11010-020-03942-0.
[4] S. Nagase, S. Karashima, H. Tsujiguchi, H. Tsuboi, S. Miyagi, M. Kometani,
D. Aono, T. Higashitani, M. Demura, H. Sakakibara, A. Yoshida, A. Hara,
H. Nakamura, Y. Takeda, H. Nambo, T. Yoneda, S. Okamoto, Impact of gut
microbiome on hypertensive patients with low-salt intake: Shika study results,
Front. Med. 7 (2020) 475, https://doi.org/10.3389/fmed.2020.00475.
[5] Intersalt Cooperative Research Group, Intersalt: an international study of
electrolyte excretion and blood pressure. Results for 24-hour urinary sodium and
potassium excretion, BMJ 297 (1988) 319–328, https://doi.org/10.1136/
bmj.297.6644.319.
[6] S.K. Ha, Dietary salt intake and hypertension, Electrolyte Blood Press. 12 (1)
(2014) 7–18, https://doi.org/10.5049/EBP.2014.12.1.7.
[7] S. Ahmadmehrabia, W.H. Wilson Tang, Gut microbiome and its role in
cardiovascular diseases, CurrOpinCardiol 32 (6) (2017) 761–766.
[8] W.H. Tang, T. Kitai, S.L. Hazen, Gut microbiota in cardiovascular health and
disease, Circ. Res. 120 (7) (2017) 1183–1196, https://doi.org/10.1161/
CIRCRESAHA.117.309715. March 31.
[9] D. Ríos-Covián, P. Ruas-Madiedo, A. Margolles, M. Gueimonde, C.G. de los Reyes-
Gavilán, N. Salazar, Intestinal short chain fatty acids and their link with diet and
human health, Front. Microbiol. 7 (2016).
[10] S. Tuteja, J.F. Ferguson, Gut microbiome and response to cardiovascular drugs,
CircGenom Precis Med. 12 (2019), e002314.
[11] W.R. Wikoff, et al., Metabolomics analysis reveals large effects of gut microflora
on mammalian blood metabolites, Proc. Natl. Acad. Sci. U.S.A. 106 (2009)
3698–3703, https://doi.org/10.1073/pnas.0812874106.
[12] E. Thursby, N. Juge, Introduction to the human gut microbiota, Biochem. J. 474
(11) (2017) 1823–1836, https://doi.org/10.1042/BCJ20160510. May 16.
[13] E. Rinninella, P. Raoul, M. Cintoni, F. Franceschi, G.A.D. Miggiano, A. Gasbarrini,
M.C. Mele, What is the healthy gut microbiota composition? A changing
ecosystem across age, environment, diet, and diseases, Microorganisms 7 (1)
(2019) 14, https://doi.org/10.3390/microorganisms7010014. Jan 10PMID:
30634578, PMCID: PMC6351938.
[14] A. Almeida, A.L. Mitchell, M. Boland, S.C. Forster, G.B. Gloor, A. Tarkowska, T.
D. Lawley, R.D. Finn, A new genomic blueprint of the human gut microbiota,
Nature 568 (7753) (2019) 499–504, https://doi.org/10.1038/s41586-019-0965-
1.
[15] G.P. Donaldson, S.M. Lee, S.K. Mazmanian, Gut biogeography of the bacterial
microbiota, Nat. Rev. Microbiol. 14 (2016) 20–32.
[16] M. Rajilic-Stojanovic, W.M. de Vos, The first 1000 cultured species of the human
gastrointestinal microbiota, FEMS Microbiol. Rev. 38 (2014) 996–1047.
[17] J. Qin, R. Li, J. Raes, et al., A human gut microbial gene catalogue established by
metagenomic sequencing, Nature 464 (2010) 59–65.
S. Naqvi et al.
[18] C.S. Cardinelli, P.C. Sala, C.C. Alves, R.S. Torrinhas, D.L. Waitzberg, Influence of
intestinal microbiota on body weight gain: a narrative review of the literature,
Obes. Surg. 25 (2015) 346–353.
[19] Human Microbiome Project Consortium, Structure, function and diversity of the
healthy human microbiome, Nature 486 (7402) (2012) 207–214, https://doi.org/
10.1038/nature11234, 13.
[20] D. Ríos-Covián, P. Ruas-Madiedo, A. Margolles, et al., Intestinal short chain fatty
acids and their link with diet and human health, Front. Microbiol. 7 (2016) 185.
[21] G. denBesten, K. Lange, R. Havinga, et al., Gut-derived short-chain fatty acids are
vividly assimilated into host carbohydrates and lipids, Am. J. Physiol.
Gastrointest. Liver Physiol. 305 (2013) G900–G910.
[22] H.L. Simpson, B.J. Campbell, Review article: dietary fibre-microbiota
interactions, Aliment. Pharmacol. Ther. 42 (2015) 158–179.
[23] R.K. Singh, H.W. Chang, D. Yan, K.M. Lee, D. Ucmak, K. Wong, M. Abrouk,
B. Farahnik, M. Nakamura, T.H. Zhu, T. Bhutani, W. Liao, Influence of diet on the
gut microbiome and implications for human health, J. Transl. Med. (2017) 15.
[24] M. Usami, K. Kishimoto, A. Ohata, et al., Butyrate and trichostatin A attenuate
nuclear factor kappaB activation and tumor necrosis factor alpha secretion and
increase prostaglandin E2 secretion in human peripheral blood mononuclear
cells, Nutr. Res. N Y N 28 (2008) 321–328.
[25] N. Cerf-Bensussan, V. Gaboriau-Routhiau, The immune system and the gut
microbiota: friends or foes? Nat. Rev. Immunol. 10 (2010) 735–744.
[26] N. Shulzhenko, A. Morgun, W. Hsiao, et al., Crosstalk between B lymphocytes,
microbiota and the intestinal epithelium governs immunity versus metabolism in
the gut, Nat. Med. 17 (2011) 1585–1593.
[27] J.Y.L. Chiang, Bile acid metabolism and signaling, ComprPhysiol 3 (2013)
1191–1212.
[28] E.M. Bik, J.A. Ugalde, J. Cousins, A.D. Goddard, J. Richman, Z.S. Apte, Microbial
biotransformations in the human distal gut, Br. J. Pharmacol. 175 (2018)
4404–4414.
[29] A. Sandek, M. Valentova, S. von Haehling, W. Doehner, S.D. Anker, The small
intestine: a critical linkage in pathophysiology of cardiac cachexia, Int. J. Cardiol.
146 (2) (2011) 277–278, https://doi.org/10.1016/j.ijcard.2010.10.083. Jan
21Epub 2010 Nov 27. PMID: 21112652.
[30] B.J. Bennett, et al., Trimethylamine-N-oxide, a metabolite associated with
atherosclerosis, exhibits complex genetic and dietary regulation, Cell Metab. 17
(January 1) (2013) 49–60.
[31] V. Magrini, et al., An obesity-associated gut microbiome with increased capacity
for energy harvest, Nature 444 (2006) 1027–1131.
[32] M.L. Matey-Hernandez, et al., Genetic and microbiome influence on lipid
metabolism and dyslipidemia, Physiol. Genomics 50 (2018) 117–126.
[33] K. Nakaya, K. Ikewaki, Microbiota and HDL metabolism, CurrOpinLipidol. 29
(2018) 18–23.
[34] F.H. Karlsson, et al., Symptomatic atherosclerosis is associated with an altered gut
metagenome, Nat. Commun. 3 (1245) (2012) 30.
[35] T. Yang, M.M. Santisteban, V. Rodriguez, E. Li, N. Ahmari, J.M. Carvajal,
M. Zadeh, M. Gong, Y. Qi, J. Zubcevic, B. Sahay, C.J. Pepine, M.K. Raizada,
M. Mohamadzadeh, Gut dysbiosis is linked to hypertension, Hypertension 65
(2015) 1331–1340 [PubMed: 25870193].
[36] Kazemian, et al., Gut microbiota and cardiovascular disease: opportunities and
challenges, Microbiome 8 (36) (2020).
[37] S. Kim, R. Goel, A. Kumar, Y. Qi, G. Lobaton, K. Hosaka, M. Mohammed, E.
M. Handberg, E.M. Richards, C.J. Pepine, M.K. Raizada, Imbalance of gut
microbiome and intestinal epithelial barrier dysfunction in patients with high
blood pressure, ClinSci. (Lond). 132 (2018) 701–718.
[38] S.H. Karbach, T. Schonfelder, I. Brandao, E. Wilms, N. Hormann, S. Jackel,
R. Schuler, S. Finger, M. Knorr, J. Lagrange, M. Brandt, A. Waisman, S. Kossmann,
K. Schafer, T. Munzel, C. Reinhardt, P. Wenzel, Gut microbiota promote
angiotensin II–Induced arterial hypertension and vascular dysfunction, J. Am.
Heart Assoc. 5 (2016), e003698.
[39] J. Oyama, K. Node, Gut microbiota and hypertension, Hypertens. Res. 42 (2019)
741–743, https://doi.org/10.1038/s41440-018-0203-5.
[40] T. Yang, E.M. Richards, C.J. Pepine, M.K. Raizada, The gut microbiota and the
brain-gut-kidney axis in hypertension and chronic kidney disease, Nat. Rev.
Nephrol. 14 (2018) 442–456.
[41] A. Chockalingam, Impact of world hypertension day, Can. J. Cardiol. 23 (7)
(2007) 517–519, https://doi.org/10.1016/s0828-282x(07)70795-x. May 15.
[42] A. Grillo, L. Salvi, P. Coruzzi, P. Salvi, G. Parati, Sodium intake and hypertension,
Nutrients 11 (9) (2019) 1970, https://doi.org/10.3390/nu11091970. Aug 21.
[43] F.Z. Marques, et al., Beyond gut feelings: how the gut microbiota regulates blood
pressure, Nat. Rev. Cardiol. 15 (2018) 20–32, https://doi.org/10.1038/
nrcardio.2017.120.
[44] M. Pevsner-Fischer, E. Blacher, E. Tatirovsky, I.Z. Ben-Dov, E. Elinav, The gut
microbiome and hypertension, CurrOpinNephrolHypertens 26 (2017) 1–8,
https://doi.org/10.1097/MNH.0000000000000293.
[45] S. Al Khodor, B. Reichert, I.F. Shatat, The microbiome and blood pressure: can
microbes regulate our blood pressure? Front. Pediatr. 19 (5) (2017) 138, https://
doi.org/10.3389/fped.2017.00138.
[46] A. Bier, T. Braun, R. Khasbab, et al., A high salt diet modulates the gut microbiota
and short chain fatty acids production in a salt-sensitive hypertension rat model,
Nutrients 10 (9) (2018) 1154, https://doi.org/10.3390/nu10091154. Published
2018 Aug 23.
[47] S. Adnan, J.W. Nelson, N.J. Ajami, V.R. Venna, J.F. Petrosino, R.M. Bryan Jr, D.
J. Durgan, Alterations in the gut microbiota can elicit hypertension in rats,
Physiol. Genomics 49 (2017) 96–104 [PubMed: 28011881].
8
Biomedicine & Pharmacotherapy 134 (2021) 111156
[48] D.J. Durgan, B.P. Ganesh, J.L. Cope, N.J. Ajami, S.C. Phillips, J.F. Petrosino, E.
B. Hollister, R.M. Bryan Jr., Role of the gut microbiome in obstructive sleep
apnea- induced hypertension, Hypertension 67 (2016) 469–474.
[49] M. Toral, I. Robles-Vera, N. de la Visitacion, M. Romero, M. Sanchez, M. Gomez-
Guzman, A. Rodriguez-Nogales, T. Yang, R. Jimenez, F. Algieri, J. Galvez, M.
K. Raizada, J. Duarte, Role of the immune system in vascular function and blood
pressure control induced by faecal microbiota transplantation in rats,
ActaPhysiol. (Oxf). 227 (2019), e13285.
[50] M. O’Donnell, A. Mente, S. Yusuf, Sodium intake and cardiovascular health, Circ.
Res. 116 (2015) 1046–1057.
[51] B. Mell, V.R. Jala, A.V. Mathew, J. Byun, H. Waghulde, Y. Zhang, B. Haribabu,
M. Vijay-Kumar, S. Pennathur, B. Joe, Evidence for a link between gut microbiota
and hypertension in the dahl rat, Physiol. Genomics 47 (2015) 187–197
[PubMed: 25829393].
[52] https://www.who.int/news-room/fact-sheets/detail/salt-reduction.
[53] J. Li, F. Zhao, Y. Wang, J. Chen, J. Tao, G. Tian, S. Wu, W. Liu, Q. Cui, B. Geng,
W. Zhang, R. Weldon, K. Auguste, L. Yang, X. Liu, L. Chen, X. Yang, B. Zhu, J. Cai,
Gut microbiota dysbiosis contributes to the development of hypertension,
Microbiome 5 (2017) 14.
[54] F. Shikata, K. Shimada, H. Sato, T. Ikedo, A. Kuwabara, H. Furukawa, et al.,
Potential influences of gut microbiota on the formation of intracranial aneurysm,
Hypertension 73 (2019) 491–496.
[55] A. Hakansson, G. Molin, Gut microbiota and inflammation, Nutrients 3 (June 6)
(2011) 637–682, https://doi.org/10.3390/nu3060637.
[56] Y. Zheng, B. Yu, D. Alexander, T.H. Mosley, G. Heiss, J.A. Nettleton,
E. Boerwinkle, Metabolomics and incident hypertension among blacks: the
atherosclerosis risk in communities study, Hypertension 62 (2013) 398–403,
https://doi.org/10.1161/HYPERTENSIONAHA.113.01166.
[57] E. Holmes, R.L. Loo, J. Stamler, et al., Human metabolic phenotype diversity and
its association with diet and blood pressure, Nature 453 (2008) 396–400, https://
doi.org/10.1038/nature06882.
[58] H. Xu, X. Wang, W. Feng, Q. Liu, S. Zhou, Q. Liu, L. Ca, The gut microbiota and its
interactions with cardiovascular disease, Microb. Biotechnol. 13 (3) (2020)
637–656, https://doi.org/10.1111/1751-7915.13524.
[59] X. Dan, Z. Mushi, W. Baili, L. Han, W. Enqi, Z. Huanhu, et al., Differential analysis
of hypertension-associated intestinal microbiota, Int. J. Med. Sci. 16 (2019)
872–881, https://doi.org/10.7150/ijms.29322.
[60] H. Li, B. Liu, J. Song, Z. An, X. Zeng, J. Li, et al., Characteristics of gut microbiota
in patients with hypertension and/or hyperlipidemia: a cross-sectional study on
rural residents in Xinxiang County, Henan Province, Microorganisms 7 (2019)
E399, https://doi.org/10.3390/microorganisms7100399.
[61] S. Sun, A. Lulla, M. Sioda, K. Winglee, M.C. Wu, D.R. Jacobs Jr., J.M. Shikany, D.
M. Lloyd-Jones, L.J. Launer, A.A. Fodor, K.A. Meyer, Gut microbiota composition
and blood pressure, Hypertension 73 (May 5) (2019) 998–1006, https://doi.org/
10.1161/HYPERTENSIONAHA.118.12109.
[62] G. Silveira-Nunes, D.F. Durso Jr., A.O. Luiz Roberto, E.H.M. Cunha, T.U. Maioli,
A.T. Vieira, E. Speziali, R. CorrÃaa-Oliveira, O.A. Martins-Filho, A. Teixeira-
Carvalho, C. Franceschi, S. Rampelli, S. Turroni, P. Brigidi, A.M.C. Faria,
Hypertension is associated with intestinal microbiota dysbiosis and inflammation
in a brazilian population, Front. Pharmacol. (2020), https://doi.org/10.3389/
fphar.2020.00258.
[63] G. Rook, F. Backhed, B.R. Levin, M.J. McFall-Ngai, A.R. McLean, Evolution,
human-microbe interactions, and life history plasticity, Lancet 390 (2017)
521–530.
[64] R.H. Straub, G. Pongratz, C. Weidler, H.J. Linde, C.J. Kirschning, T. Gluck,
J. Scholmerich, W. Falk, Ablation of the sympathetic nervous system decreases
gram-negative and increases gram-positive bacterial dissemination: key roles for
tumor necrosis factor/phagocytes and interleukin-4/lymphocytes, J. Infect. Dis.
192 (2005) 560–572 [PubMed: 16028124].
[65] R. Diaz Heijtz, S. Wang, F. Anuar, Y. Qian, B. Bjorkholm, A. Samuelsson, M.
L. Hibberd, H. Forssberg, S. Pettersson, Normal gut microbiota modulates brain
development and behavior, Proc. Natl. Acad. Sci. U.S.A. 108 (2011) 3047–3052
[PubMed: 21282636].
[66] W.H.W. Tang, D.Y. Li, S.L. Hazen, Dietary metabolism, the gut microbiome, and
heart failure, Nat. Rev. Cardiol. 16 (March 3) (2019) 137–154, https://doi.org/
10.1038/s41569-018-0108-7. PMID: 30410105, PMCID: PMC6377322.
[67] M.S. Donia, et al., HUMAN MICROBIOTA. Small molecules from the human
microbiota, Science 349 (2015), 1254766, https://doi.org/10.1126/
science.1254766.
[68] B.P. Ganesh, J.W. Nelson, J.R. Eskew, A. Ganesan, N.J. Ajami, J.F. Petrosino, R.
M. Bryan Jr., D.J. Durgan, Prebiotics, probiotics, and acetate supplementation
prevent hypertension in a model of obstructive sleep apnea, Hypertension 72
(2018) 1141–1150.
[69] H. Bartolomaeus, A. Balogh, M. Yakoub, S. Homann, L. Marko, S. Hoges,
D. Tsvetkov, A. Krannich, S. Wundersitz, E.G. Avery, N. Haase, K. Kraker,
L. Hering, M. Maase, K. Kusche-Vihrog, M. Grandoch, J. Fielitz, S. Kempa,
M. Gollasch, Z. Zhumadilov, S. Kozhakhmetov, A. Kushugulova, K.U. Eckardt,
R. Dechend, L.C. Rump, S.K. Forslund, D.N. Muller, J. Stegbauer, N. Wilck, Short-
chain fatty acid propionate protects from hypertensive cardiovascular damage,
Circulation 139 (2019) 1407–1421.
[70] R. Correa-Oliveira, J.L. Fachi, A. Vieira, F.T. Sato, M. Vinolo, A. Regulation of
immune cell function by short-chain fatty acids, Clin. TranslImmunol. 5 (2016)
e73.
[71] C.S. Byrne, E.S. Chambers, D.J. Morrison, G. Frost, The role of short chain fatty
acids in appetite regulation and energy homeostasis, Int. J. Obes. (Lond). 39
(September 9) (2015) 1331–1338, https://doi.org/10.1038/ijo.2015.84.
S. Naqvi et al.
[72] Yanling Chang, Yunyan Chen, Qiong Zhou, Chuan Wang, Lei Chen, Wen Di,
Yu Zhang, Short-chain fatty acids accompany ng changes in the gut microbiome
contribute to the development of hypertension in patients with preeclampsia,
ClinSci. (Lond.) 31 (January 2) (2020) 289–302, https://doi.org/10.1042/
CS20191253, 134.
[73] N. Natarajan, D. Hori, S. Flavahan, J. Steppan, N.A. Flavahan, D.E. Berkowitz, J.
L. Pluznick, Microbial short chain fatty acid metabolites lower blood pressure via
endothelial G protein-coupled receptor 41, Physiol. Genomics 48 (2016)
826–834.
[74] J.L. Pluznick, Microbial short-chain fatty acids and blood pressure regulation,
CurrHypertens Rep. 19 (4) (2017) 25, https://doi.org/10.1007/s11906-017-
0722-5.
[75] I. Kimura, D. Inoue, T. Maeda, T. Hara, A. Ichimura, S. Miyauchi, M. Kobayashi,
A. Hirasawa, G. Tsujimoto, Short-chain fatty acids and ketones directly regulate
sympathetic nervous system via G protein-coupled receptor 41 (GPR41), Proc.
Natl. Acad. Sci. U.S.A. 108 (2011) 8030–8035.
[76] Y. Lu, C. Fan, P. Li, Y. Lu, X. Chang, K. Qi, Short chain fatty acids prevent high-fat-
diet-induced obesity in mice by regulating g protein-coupled receptors and gut
microbiota, Sci. Rep. 6 (2016) 37589, https://doi.org/10.1038/srep37589.
[77] A.J. Bilotta, Y. Cong, Gut microbiota metabolite regulation of host defenses at
mucosal surfaces: implication in precision medicine, Precis. Clin. Med. 2 (2)
(2019) 110–119, https://doi.org/10.1093/pcmedi/pbz008.
[78] P.R. Murdock, N.B. Pike, M.M. Eilert, et al., The orphan G protein-coupled
receptors GPR41 and GPR43 are activated by propionate and other short chain
carboxylic acids, J. Biol. Chem. 278 (2003) 11312–11319, https://doi.org/
10.1074/jbc.m211609200.
[79] X. Xu, H. Fukui, Y. Ran, T. Tomita, et al., Alteration of GLP-1/GPR43 expression
and gastrointestinal motility in dysbiotic mice treated with vancomycin, Sci. Rep.
9 (2019) 4381, https://doi.org/10.1038/s41598-019-40978-9.
[80] B.O. Park, S.H. Kim, G.Y. Kong, D.H. Kim, M.S. Kwon, S.U. Lee, M.O. Kim, S. Cho,
S. Lee, H.J. Lee, S.B. Han, Y.S. Kwak, S.B. Lee, S. Kim, Selective novel inverse
agonists for human GPR43 augment GLP-1 secretion, Eur. J. Pharmacol. 771
(January 15) (2016) 1–9, https://doi.org/10.1016/j.ejphar.2015.12.010.
[81] Z. Ang, J.L. Ding, GPR41 and GPR43 in obesity and inflammation – protective or
causative? Front. Immunol. (2016) https://doi.org/10.3389/fimmu.2016.00028.
[82] S. Sivaprakasam, P.D. Prasad, N. Singh, Benefits of short-chain fatty acids and
their receptors in inflammation and carcinogenesis, PharmacolTher. 164 (2016)
144–151, https://doi.org/10.1016/j.pharmthera.2016.04.007.
[83] N. Singh, A. Gurav, S. Sivaprakasam, et al., Activation of Gpr109a, receptor for
niacin and the commensal metabolite butyrate, suppresses colonic inflammation
and carcinogenesis, Immunity 40 (2014) 128–139, https://doi.org/10.1016/j.
immuni.2013.12.007.
[84] K. Lednovich, M. Priyadarshini, K. Kotlo, K. Xu, S. Priyamvada, P. Dudeja,
B. Layden, OR31-3 role of a novel short chain fatty acid receptor OLFR78 in
mediating gluco-metabolic hormone secretion, J. Endo. Soc. 3 (2019) 1, https://
doi.org/10.1210/js.2019-OR31-3. OR31–3.
[85] B. Poll, J. Pluznick, Establishing an in vitro model of olfactory receptor78-
mediated rennin release, FASEB J. 32 (2018) lb352, https://doi.org/10.1096/
fasebj.2018.32.1_supplement.lb352.
[86] J.L. Pluznick, R.J. Protzko, H. Gevorgyan, Z. Peterlin, A. Sipos, J. Han, I. Brunet,
L.X. Wan, F. Rey, T. Wang, S.J. Firestein, M. Yanagisawa, J.I. Gordon,
A. Eichmann, J. Peti-Peterdi, M.J. Caplan, 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 (2013) 4410–4415.
[87] L. Calderón-Pérez, M.J. Gosalbes, S. Yuste, et al., Gut metagenomic and short
chain fatty acids signature in hypertension: a cross-sectional study, Sci. Rep. 10
(2020) 6436, https://doi.org/10.1038/s41598-020-63475-w.
[88] J. de la Cuesta-Zuluaga, N.T. Mueller, R. Álvarez-Quintero, E.P. Velásquez-Mejía,
J.A. Sierra, V. Corrales-Agudelo, J.A. Carmona, J.M. Abad, J.S. Escobar, Higher
fecal short-chain fatty acid levels are associated with gut microbiome dysbiosis,
obesity, hypertension and cardiometabolic disease risk factors, Nutrients 11 (1)
(2019) 51, https://doi.org/10.3390/nu11010051.
[89] K.A. Sharkey, SavidgeTC, Role of enteric neurotransmission in host defense and
protection of the gastrointestinal tract, AutonNeurosci. 181 (2014) 94–106
[PubMed: 24412639].
[90] Qi Y. SantistebanMM, J. Zubcevic, S. Kim, T. Yang, V. Shenoy, C.T. Cole-Jeffrey,
G.O. Lobaton, D.C. Stewart, A. Rubiano, C.S. Simmons, F. Garcia-Pereira, R.
D. Johnson, C.J. Pepine, M.K. Raizada, Hypertension-linked pathophysiological
alterations in the gut, Circ. Res. 120 (2017) 312–323 [PubMed: 27799253].
[91] E.G. Stanley, N.J. Bailey, M.E. Bollard, J.N. Haselden, C.J. Waterfield, E. Holmes,
et al., Sexual dimorphism in urinary metabolite profiles of Han Wistar rats
revealed by nuclear-magnetic-resonance-based metabonomics, Anal. Biochem.
343 (2005) 195–202.
[92] N. Bergeron, P.T. Williams, R. Lamendella, N. Faghihnia, A. Grube, X. Li, et al.,
Diets high in resistant starch increase plasma levels of trimethylamine-N-oxide, a
gut microbiome metabolite associated with CVD risk, Br. J. Nutr. 116 (2016)
2020–2029, 10.1017/.
[93] T. Hauet, H. Baumert, H. Gibelin, F. Hameury, J.M. Goujon, M. Carretier, et al.,
Noninvasive monitoring of citrate, acetate, lactate, and renal medullary osmolyte
excretion in urine as biomarkers of exposure to ischemic reperfusion injury,
Cryobiology 41 (2000) 280–291.
[94] J.L. Griffin, X. Wang, E. Stanley, Does our gut microbiome predict cardiovascular
risk? A review of the evidence from metabolomics, Circ. Cardiovasc. Genet. 8 (1)
(2015) 187–191, https://doi.org/10.1161/CIRCGENETICS.114.000219.
[95] K. Bielinska, M. Radkowski, M. Grochowska, K. Perlejewski, T. Huc, K. Jaworska,
D. Motooka, S. Nakamura, M. Ufnal, High salt intake increases plasma
9
Biomedicine & Pharmacotherapy 134 (2021) 111156
trimethylamine N- oxide (TMAO) concentration and produces gut dysbiosis in
rats, Nutrition 54 (2018) 33–39.
[96] X. Ge, L. Zheng, R. Zhuang, P. Yu, Z. Xu, G. Liu, X. Xi, X. Zhou, H. Fan, The gut
microbial metabolite trimethylamine N-Oxide and hypertension risk: a systematic
review and dose-response meta-analysis, AdvNutr. 11 (1) (2020) 66–76, https://
doi.org/10.1093/advances/nmz064.
[97] J. Nie, L. Xie, B. Zhao, Y. Li, B. Qiu, F. Zhu, G. Li, M. He, Y. Wang, B. Wang, S. Liu,
H. Zhang, H. Guo, Y. Cai, Y. Huo, F.F. Hou, X. Xu, X. Qin, Serum Trimethylamine
N-Oxide concentration is positively associated with first stroke in hypertensive
patients, Stroke 50 (6) (2018) e175, https://doi.org/10.1161/
STR.0000000000000189.
[98] F.J. He, J. Li, G.A. Macgregor, Effect of longer term modest salt reduction on
blood pressure: cochrane systematic review and meta-analysis of randomised
trials, BMJ 346 (2013) f1325.
[99] G. Faraco, K. Hochrainer, S.G. Segarra, S. Schaeffer, M.M. Santisteban, A. Menon,
et al., Dietary salt promotes cognitive impairment through tau phosphorylation,
Nature 574 (7780) (2019) 686–690, https://doi.org/10.1038/s41586-019-1688-
z.
[100] D. Mozaffarian, S. Fahimi, G.M. Singh, R. Micha, S. Khatibzadeh, R.E. Engell, et
al., Global sodium consumption and death from cardiovascular causes, N. Engl. J.
Med. 371 (7) (2014) 624–634, https://doi.org/10.1056/NEJMoa1304127.
[101] X. Huang, K. Yang, Y. Zhang, Q. Wang, Y. Li, Quinolinic acid induces cell
apoptosis in PC12 cells through HIF-1-dependent RTP801 activation, Metab.
Brain Dis. 31 (435-) (2016) 444.
[102] M.A. Engevik, E. Aihara, M.H. Montrose, G.E. Shull, D.J. Hassett, R.T. Worrell,
Loss of NHE3 alters gut microbiota composition and influences
Bacteroidesthetaiotaomicron growth, Am. J. Physiol. Gastrointest. Liver Physiol.
305 (2013) G697–711.
[103] C. Wang, Z. Huang, K. Yu, R. Ding, K. Ye, C. Dai, X. Xu, G. Zhou, C. Li, High-salt
diet has a certain impact on protein digestion and gut microbiota: a sequencing
and proteome combined study, Front. Microbiol. 8 (2017) 1838.
[104] P.M. Miranda, G. De Palma, V. Serkis, J. Lu, M.P. Louis-Auguste, J.L. McCarville,
E.F. Verdu, S.M. Collins, P. Bercik, High salt diet exacerbates colitis in mice by
decreasing Lactobacillus levels and butyrate production, Microbiome 6 (2018) 57.
[105] N. Wilck, M.G. Matus, S.M. Kearney, S.W. Olesen, K. Forslund, H. Bartolomaeus,
S. Haase, A. Mähler, A. Balogh, L. Markó, O. Vvedenskaya, F.H. Kleiner,
D. Tsvetkov, L. Klug, P.I. Costea, S. Sunagawa, L. Maier, N. Rakova, V. Schatz,
P. Neubert, C. Frätzer, A. Krannich, M. Gollasch, D.A. Grohme, B.F. Côrte-Real, R.
G. Gerlach, M. Basic, A. Typas, C. Wu, J.M. Titze, J. Jantsch, M. Boschmann,
R. Dechend, M. Kleinewietfeld, S. Kempa, P. Bork, R.A. Linker, E.J. Alm, D.
N. Müller, Salt-responsive gut commensal modulates TH17 axis and disease,
Nature 551 (2017) 585–589.
[106] L. Hu, S. Zhu, X. Peng, K. Li, W. Peng, Y. Zhong, C. Kang, X. Cao, Z. Liu, B. Zhao,
High salt elicits brain inflammation and cognitive dysfunction, accompanied by
alternations in the gut microbiota and decreased SCFA production, J. Alzheimers
Dis. (Jully 25) (2020), https://doi.org/10.3233/JAD-200035.
[107] L. Chen, F.J. He, Y. Dong, Y. Huang, C. Wang, G.A. Harshfield, H. Zhu, Modest
sodium reduction increases circulating short-chain fatty acids in untreated
hypertensives, Hypertension 76 (1) (2020) 73–79, https://doi.org/10.1161/
HYPERTENSIONAHA.120.14800.
[108] Alissa A. Frame, et al., Sympathetic regulation of NCC in norepinephrine-evoked
salt-sensitive hypertension in Sprague-Dawley rats, Am. J. Physiol. Renal Physiol.
317.6 (2019) F1623–F1636.
[109] Ziau Hoe, et al., Effect of high-salt diet on mean arterial pressure, renal epithelial
sodium channels and aquaporins subunits expression levels in Spontaneously
Hypertensive Rats, BioRxiv (2019).
[110] Leon J. DeLalio, et al., Excessive dietary salt promotes aortic stiffness in murine
renovascular hypertension, Am. J. Phys. Heart Circul. Physiol. 318.5 (2020)
H1346–H1355.
[111] Lidija Barić, et al., Enhanced antioxidative defense by vitamins C and e
consumption prevents 7-Day high-salt diet-induced microvascular endothelial
function impairment in young healthy individuals, J. Clin. Med. 9.3 (2020) 843.
[112] Atsushi Morimoto, et al., Sodium sensitivity and cardiovascular events in patients
with essential hypertension, Lancet 350.9093 (1997) 1734–1737.
[113] Pretini, Virginia, et al., Red blood cells: chasing interactions, Front. Physiol. 10
(2019) 945.
[114] Dragana Komnenov, Peter E. Levanovich, Noreen F. Rossi, Hypertension
associated with fructose and high salt: renal and sympathetic mechanisms,
Nutrients 11.3 (2019) 569.
[115] Hans Oberleithner, et al., Salt overload damages the glycocalyx sodium barrier of
vascular endothelium, Pflügers Archiv. Eur. J. Physiol. 462.4 (2011) 519.
[116] Wladimir Peters, et al., Nanomechanics and sodium permeability of endothelial
surface layer modulated by hawthorn extract WS 1442, PLoS One 7.1 (2012),
e29972.
[117] Xiaoqiang Ding, Zhen Cheng, Qi Qian, Intravenous fluids and acute kidney injury,
Blood Purif. 43.1-3 (2017) 163–172.
[118] Hae Jin Kee, et al., Selective inhibition of histone deacetylase 8 improves vascular
hypertrophy, relaxation, and inflammation in angiotensin II hypertensive mice,
Clin. Hypertens. 25.1 (2019) 13.
[119] Ken Donaldson, et al., Oxidative stress and calcium signaling in the adverse
effects of environmental particles (PM10), Free Radic. Biol. Med. 34.11 (2003)
1369–1382.
[120] Ganesh V. Halade, et al., Interaction of 12/15-lipoxygenase with fatty acids alters
the leukocyte kinetics leading to improved postmyocardial infarction healing,
Am. J. Physiol. Heart Circul. Physiol. 313.1 (2017) H89–H102.
S. Naqvi et al.
[121] Zaid H. Maayah, Ayman O.S. El-Kadi, The role of mid-chain
hydroxyeicosatetraenoic acids in the pathogenesis of hypertension and cardiac
hypertrophy, Arch. Toxicol. 90.1 (2016) 119–136.
[122] Indra Antonipillai, et al., Renin response to 12-hydroxyeicosatetraenoic acid is
increased in diabetic rats, Diabetes 44.3 (1995) 321–325.
[123] K. Ma, et al., 12-Lipoxygenase products reduce insulin secretion and β-cell
viability in human islets, J. Clin. Endocrinol. Metab. 95.2 (2010) 887–893.
[124] Qian Liu, et al., Renal denervation findings on cardiac and renal fibrosis in rats
with isoproterenol induced cardiomyopathy, Sci. Rep. 5 (2015) 18582.
[125] T.A. Clayton, et al., Pharmacometabonomic identification of a significant host-
microbiome metabolic interaction affecting human drug metabolism, Proc. Natl.
Acad. Sci. U.S.A. 106 (2009) 14728–14733, https://doi.org/10.1073/
pnas.090448910.
[126] P. Spanogiannopoulos, et al., The microbial pharmacists within us: a
metagenomic view of xenobiotic metabolism, Nat. Rev. Microbiol. 14 (2016)
273–287, https://doi.org/10.1038/nrmicro.2016.17.
[127] M. ElRakaiby, et al., Pharmacomicrobiomics: the impact of human microbiome
variations on systems pharmacology and personalized therapeutics, OMICS 18
(2014) 402–414, https://doi.org/10.1089/omi.2014.0018.
[128] A. Sharma, et al., Pharmacomicrobiomics: the holy grail to variability in drug
response? ClinPharmacolTher. 106 (2019) 317–328, https://doi.org/10.1002/
cpt.1437.
[129] L. Maier, M. Pruteanu, M. Kuhn, G. Zeller, A. Telzerow, E.E. Anderson, A.
R. Brochado, K.C. Fernandez, H. Dose, H. Mori, K.R. Patil, P. Bork, A. Typas,
Extensive impact of non-antibiotic drugs on human gut bacteria, Nature 555
(2018) 623–628, https://doi.org/10.1038/nature25979.
[130] V.A. Vila, V. Collij, S. Sanna, et al., Impact of commonly used drugs on the
composition and metabolic function of the gut microbiota, Nat. Commun. 11
(2020) 362, https://doi.org/10.1038/s41467-019-14177-z.
[131] L.A. Lammers, R. Achterbergh, R.A.A. Mathôt, J.A. Romijn, The effects of fasting
on drug metabolism, Expert Opin. Drug Metab. Toxicol. 16 (1) (2020) 79–85,
https://doi.org/10.1080/17425255.2020.1706728.
[132] H.H. Yoo, I.S. Kim, D.H. Yoo, D.H. Kim, Effects of orally administered antibiotics
on the bioavailability of amlodipine: gut microbiota-mediated drug interaction,
J. Hypertens. 34 (1) (2016) 156–162.
[133] L. Wang, Q. Zhu, A. Lu, X. Liu, L. Zhang, C. Xu, X. Liu, H. Li, T. Yang, Sodium
butyrate suppresses angiotensin II-induced hypertension by inhibition of renal
(pro)renin receptor and intrarenal renin-angiotensin system, J. Hypertens. 35
(2017) 1899–1908, https://doi.org/10.1097/HJH.0000000000001378.
[134] E.H. Kincaid, P.R. Miller, J.W. Meredith, M.C. Chang, Enalaprilat improves gut
perfusion in critically injured patients, Shock 9 (February 2) (1998) 79–83,
https://doi.org/10.1097/00024382-199802000-00001. PMID: 9488250.
[135] V.K. Holenarsipur, N. Gaud, J. Sinha, S. Sivaprasad, P. Bhutani, M. Subramanian,
S.P. Singh, R. Arla, S. Paruchury, T. Sharma, P. Marathe, S. Mandlekar,
Absorption and cleavage of enalapril, a carboxyl ester prodrug, in the rat
intestine: in vitro, in situ intestinal perfusion and portal vein cannulation models,
Biopharm. Drug Dispos. 36 (September 6) (2015) 385–397, https://doi.org/
10.1002/bdd.1950. Epub 2015 May 4. PMID: 25832562.
[136] M. Perez-Paramo, J. Munoz, A. Albillos, et al., Effect of propranolol on the factors
promoting bacterial translocation in cirrhotic rats with ascites, Hepatology 31
(2000) 43–48.
[137] Hamdi A. Jama, Anna Beale, Waled A. Shihata, Francine Z. Marques, The effect of
diet on hypertensive pathology: is there a link via gut microbiota-driven
immunometabolism? Cardiovasc. Res. 115 (July 9) (2019) 1435–1447, https://
doi.org/10.1093/cvr/cvz091, 15.
[138] F. De Filippis, N. Pellegrini, L. Vannini, I.B. Jeffery, A. La Storia, L. Laghi, D.
I. Serrazanetti, R. Di Cagno, I. Ferrocino, C. Lazzi, S. Turroni, L. Cocolin,
P. Brigidi, E. Neviani, M. Gobbetti, P.W. O’Toole, D. Ercolini, High-level
adherence to a Mediterranean diet beneficially impacts the gut microbiota and
associated metabolome, Gut 65 (2016) 1812–1821.
[139] F.Z. Marques, E. Nelson, P.Y. Chu, D. Horlock, A. Fiedler, M. Ziemann, J.K. Tan,
S. Kuruppu, N.W. Rajapakse, A. El-Osta, C.R. Mackay, D.M. Kaye, High-fiber diet
and acetate supplementation change the gut microbiota and prevent the
development of hypertension and heart failure in hypertensive mice, Circulation
135 (2017) 964–977, https://doi.org/10.1161/CIRCULATIONAHA.116.024545.
[140] J. Suez, T. Korem, D. Zeevi, G. Zilberman-Schapira, C.A. Thaiss, O. Maza,
D. Israeli, N. Zmora, S. Gilad, A. Weinberger, Y. Kuperman, A. Harmelin,
I. Kolodkin-Gal, H. Shapiro, Z. Halpern, E. Segal, E. Elinav, Artificial sweeteners
induce glucose intolerance by altering the gut microbiota, Nature 514 (2014)
181–186.
[141] B. Chassaing, O. Koren, J.K. Goodrich, A.C. Poole, S. Srinivasan, R.E. Ley, A.
T. Gewirtz, Dietary emulsifiers impact the mouse gut microbiota promoting colitis
and metabolic syndrome, Nature 519 (2015) 92–96.
[142] Z. Xu, R. Knight, Dietary effects on human gut microbiome diversity, Br. J. Nutr.
113 (Suppl) (2015) S1–S5.
[143] D.L. Smith, A.D. Harris, J.A. Johnson, E.K. Silbergeld, Morris JGJr, Animal
antibiotic use has an early but important impact on the emergence of antibiotic
resistance in human commensal bacteria, Proc. Natl. Acad. Sci. U.S.A. 99 (2002)
6434–6439.
[144] L. Cordain, S.B. Eaton, A. Sebastian, N. Mann, S. Lindeberg, B.A. Watkins, J.
H. O’Keefe, J. Brand-Miller, Origins and evolution of the Western diet: health
implications for the 21st century, Am. J. Clin. Nutr. 81 (2005) 341–354.
[145] I.A. Myles, Fast food fever: reviewing the impacts of the western diet on
immunity, Nutr. J. 13 (61) (2014).
10
Biomedicine & Pharmacotherapy 134 (2021) 111156
[146] K. Smiljanec, S.L. Lennon, Sodium, hypertension, and the gut: does the gut
microbiota go salty? Am. J. Physiol. Heart Circ. Physiol. 317 (6) (2019)
H1173–H1182, https://doi.org/10.1152/ajpheart.00312.2019.
[147] N. Shivappa, M. Bonaccio, J.R. Hebert, A. Di Castelnuovo, S. Costanzo,
E. Ruggiero, G. Pounis, M.B. Donati, G. de Gaetano, L. Iacoviello, Moli-sani study
investigators. association of proinflammatory diet with low-grade inflammation:
results from the Moli-sani study, Nutrition 54 (2018) 182–188.
[148] K. Miura, P. Greenland, J. Stamler, K. Liu, M.L. Daviglus, H. Nakagawa, Relation
of vegetable, fruit, and meat intake to 7-year blood pressure change in middle-
aged men: the Chicago Western Electric Study, Am. J. Epidemiol. 159 (2004)
572–580.
[149] A. Alonso, C. de la Fuente, A.M. Martín-Arnau, J. de Irala, J. Alfredo Martínez,
M.Á. Martínez-González, Fruit and vegetable consumption is inversely associated
with blood pressure in a Mediterranean population with a high vegetable-fat
intake: the Seguimiento Universidad de Navarra (SUN) Study, BJN 92 (2004)
311–319.
[150] A. Sureda, M.D.M. Bibiloni, A. Julibert, C. Bouzas, E. Argelich, I. Llompart,
A. Pons, J.A. Tur, Adherence to the Mediterranean diet and inflammatory
markers, Nutrients 10 (2018) 62.
[151] P. Saneei, M. Hashemipour, R. Kelishadi, A. Esmaillzadeh, The Dietary
Approaches to Stop Hypertension (DASH) diet affects inflammation in childhood
metabolic syndrome: a randomized cross-over clinical trial, Ann. Nutr. Metab. 64
(2014) 20–27.
[152] C.M. Phillips, J.M. Harrington, I.J. Perry, Relationship between dietary quality,
determined by DASH score, and cardiometabolic health biomarkers: a cross-
sectional analysis in adults, ClinNutr (2018), https://doi.org/10.1016/j.
clnu.2018.08.028.
[153] Ž Krznarić, D. Vranešić Bender, T. Meštrović, The mediterranean diet and its
association with selected gut bacteria, Curr. Opin. Clin. Nutr. Metab. Care 22
(2019) 401–406.
[154] R.J. Widmer, A.J. Flammer, L.O. Lerman, A. Lerman, The mediterranean diet, its
components, and cardiovascular disease, Am. J. Med. 128 (2015) 229–238.
[155] K. Shondelmyer, R. Knight, A. Sanivarapu, S. Ogino, K.P.V. Vanamala, Ancient
Thali diet: gut microbiota, immunity, and health, Yale J. Biol. Med. 91 (2018)
177–184.
[156] P.C. Calder, Fatty acids and immune function: relevance to inflammatory bowel
diseases, Int. Rev. Immunol. 28 (2009) 506–534.
[157] P.C. Calder, Marine omega-3 fatty acids and inflammatory processes: effects,
mechanisms and clinical relevance, BBA Mol. Cell Biol. Lipids 1851 (2015)
469–484.
[158] M.G. Gareau, P.M. Sherman, W.A. Walker, Probiotics and the gut microbiota in
intestinal health and disease, Nat. Rev. Gastroenterol. Hepatol. 7 (2010) 503–514.
[159] H. Yadav, J.H. Lee, J. Lloyd, P. Walter, S.G. Rane, Beneficial metabolic effects of a
probiotic via butyrate-induced GLP-1 hormone secretion, J. Biol. Chem. 288
(2013) 25088–25097.
[160] K.E. Ferrier, M.H. Muhlmann, J.P. Baguet, J.D. Cameron, G.L. Jennings, A.
M. Dart, B.A. Kingwell, Intensive cholesterol reduction lowers blood pressure and
large artery stiffness in isolated systolic hypertension, J. Am. CollCardiol. 39 (6)
(2002) 1020–1025. Mar 20.
[161] L. Agerholm-Larsen, A. Raben, N. Haulrik, A.S. Hansen, M. Manders, A. Astrup,
Effect of 8 week intake of probiotic milk products on risk factors for
cardiovascular diseases, Eur. J. Clin. Nutr. 54 (April 4) (2000) 288–297.
[162] M. Kawase, H. Hashimoto, M. Hosoda, H. Morita, A. Hosono, Effect of
administration of fermented milk containing whey protein concentrate to rats and
healthy men on serum lipids and blood pressure, J. Dairy Sci. 83 (February 2)
(2000) 255–263.
[163] M. Naruszewicz, M.L. Johansson, D. Zapolska-Downar, H. Bukowska, Effect of
Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers,
Am. J. ClinNutr. 76 (December 6) (2002) 1249–1255.
[164] P.P. Lin, Y.M. Hsieh, W.W. Kuo, Y.M. Lin, Y.L. Yeh, C.C. Lin, F.J. Tsai, C.H. Tsai,
C.Y. Huang, C.H. Tsai, Probiotic-fermented purple sweet potato yogurt activates
compensatory IGF‑IR/PI3K/Akt survival pathways and attenuates cardiac
apoptosis in the hearts of spontaneously hypertensive rats, Int. J. Mol. Med. 32
(December 6) (2013) 1319–1328.
[165] M.J. Tetel, G.J. de Vries, R.C. Melcangi, G. Panzica, S.M. O’Mahony, Steroids,
stress and the gut microbiome-brain axis, J. Neuroendocrinol. 30 (2) (2018),
https://doi.org/10.1111/jne.12548.
[166] G.S. Hughes, R.S. Mathur, H.S. Margolius, Sex steroid hormones are altered in
essential hypertension, J. Hypertens. 7 (3) (1989) 181–187. PMID: 2523421.
[167] R.A. Gomez, M.L. Sequeira-Lopez, Novel functions of renin precursors in
homeostasis and disease, Physiology (Bethesda) 31 (1) (2016) 25–33, https://doi.
org/10.1152/physiol.00039.2015.
[168] M. Donoghue, F. Hsieh, E. Baronas, K. Godbout, M. Gosselin, N. Stagliano,
M. Donovan, B. Woolf, K. Robison, R. Jeyaseelan, R.E. Breitbart, S. Acton, A novel
angiotensin-converting enzyme–related carboxypeptidase (ACE2) converts
angiotensin I to angiotensin 1-9, Circ. Res. 87 (5) (2000) e1–e9, https://doi.org/
10.1161/01.RES.87.5.e1 (1 Sep).
[169] K. Kuba, Y. Imai, J.M. Penninger, Multiple functions of angiotensin-converting
enzyme 2 and its relevance in cardiovascular diseases, Circ. J. 77 (2) (2013)
301–308, https://doi.org/10.1253/circj.cj-12-1544.
[170] T. Zuo, F. Zhang, G.C.Y. Lui, Y.K. Yeoh, A.Y.L. Li, H. Zhan, Y. Wan, A.C.K. Chung,
C.P. Cheung, N. Chen, C.K.C. Lai, Z. Chen, E.Y.K. Tso, K.S.C. Fung, V. Chan,
L. Ling, G. Joynt, D.S.C. Hui, F.K.L. Chan, P.K.S. Chan, C. Siew, S.C. Ng,
Alterations in gut microbiota of patients with COVID-19 during time of
hospitalization, Gastroenterology 159 (3) (2020) 944–955, https://doi.org/
10.1053/j.gastro.2020.05.048.
S. Naqvi et al.
[171] S. Yildiz, B. Mazel-Sanchez, M. Kandasamy, et al., Influenza A virus infection
impacts systemic microbiota dynamics and causes quantitative enteric dysbiosis,
Microbiome 6 (2018) 9.
[172] Z. Shen, Y. Xiao, L. Kang, et al., Genomic diversity of SARS-CoV-2 in coronavirus
disease 2019 patients, Clin. Infect. Dis. 71 (2020) 713–720.
[173] R.E. Ley, P.J. Turnbaugh, S. Klein, et al., Human Gut Microbes Associated with
Obesity Nature, 444, 2006, pp. 1022–1023.
11
Biomedicine & Pharmacotherapy 134 (2021) 111156
[174] S. Gu, Y. Chen, Z. Wu, Y. Chen, H. Gao, L. Lv, F. Guo, X. Zhang, R. Luo, C. Huang,
H. Lu, B. Zheng, J. Zhang, R. Yan, H. Zhang, H. Jiang, Q. Xu, J. Guo, Y. Gong,
L. Tang, L. Li, Alterations of the gut microbiota in patients with COVID-19 or
H1N1 influenza, Clin. Infect. Dis. (2020) ciaa709.
[175] S.D. Viana, S. Nunes, F. Reis, ACE2 imbalance as a key player for the poor
outcomes in COVID-19 patients with age-related comorbidities - Role of gut
microbiota dysbiosis, Ageing Res. Rev. 62 (2020) 101123, https://doi.org/
10.1016/j.arr.2020.101123.