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1 Department for research 
and scientific work, 
University Medical Centre 
Maribor, Maribor, Slovenia
2 Faculty of Medicine, 
University of Maribor, 
Maribor, Slovenia
3 Institute of Biomedical 
Sciences, University 
of Maribor, Faculty of 
Medicine, Maribor, Slovenia
Correspondence/
Korespondenca:
Pavel Skok, e: pavel.skok@
guest.arnes.si
Key words:
gut microbiota; dysbiosis; 
diagnostic methods; 
pathophysiological 
mechanisms; 
cardiovascular diseases
Ključne besede:
črevesna mikrobiota; 
disbioza; diagnostične 
metode; patofiziološki 
mehanizmi; srčno-žilne 
bolezni
Received: 27. 9. 2019
Accepted: 6. 4. 2020
eng slo element
en article-lang
10.6016/ZdravVestn.2989 doi
27.9.2019 date-received
6.4.2020 date-accepted
Cardiovascular system Srce in ožilje discipline
Professional article Strokovni članek article-type
The gastrointestinal tract and cardiovascular 
diseases - do they have anything in common?
Prebavna cev in srčno-žilne bolezni – ali imajo kaj 
skupnega?
article-title
The gastrointestinal tract and cardiovascular 
diseases - do they have anything in common?
Prebavna cev in srčno-žilne bolezni – ali imajo kaj 
skupnega?
alt-title
gut microbiota, dysbiosis, diagnostic methods, 
pathophysiological mechanisms, cardiovascu-
lar diseases
črevesna mikrobiota, disbioza, diagnostične 
metode, patofiziološki mehanizmi, srčno-žilne 
bolezni
kwd-group
The authors declare that there are no conflicts 
of interest present.
Avtorji so izjavili, da ne obstajajo nobeni 
konkurenčni interesi.
conflict
year volume first month last month first page last page
2020 89 9 10 528 538
name surname aff email
Pavel Skok 1,2 pavel.skok@guest.arnes.si
name surname aff
Kristijan Skok 3
eng slo aff-id
Department for research and 
scientific work, University 
Medical Centre Maribor, 
Maribor, Slovenia
Oddelek za znanstveno-
raziskovalno delo, Univerzitetni 
klinični center Maribor, Maribor, 
Slovenija
1
Faculty of Medicine, University 
of Maribor, Maribor, Slovenia
Medicinska fakulteta, Univerza v  
Mariboru, Maribor, Slovenija
2
Institute of Biomedical Sciences, 
University of Maribor, Faculty of 
Medicine, Maribor, Slovenia
Inštitut za biomedicinske vede, 
Medicinska fakulteta, Univerza v 
Mariboru, Maribor, Slovenija
3
The gastrointestinal tract and cardiovascular 
diseases - do they have anything in 
common?
Prebavna cev in srčno-žilne bolezni – ali imajo kaj skupnega?
Pavel Skok,1,2 Kristijan Skok3
Abstract
Human gut microbiota is a collection of bacteria, archaea, fungi, viruses and parasites that in-
habit the gastrointestinal tract and produce a diverse ecosystem of about 1014 microorganisms. 
Microbiota diversity is caused by differences in the host genome and by environmental factors 
such as hygiene, lifestyle, nutrition and various drugs. The results of research over the last de-
cade have confirmed that altered gut microbiota, dysbiosis, contributes to the development of 
various diseases, including cardiovascular diseases, type 2 diabetes mellitus, chronic kidney dis-
ease, non-alcoholic fatty liver disease (NAFLD), chronic inflammatory bowel disease and even 
some cancers. In the article, the authors present some recent findings on the diversity of gut 
microbiota, diagnostic methods and some of the pathophysiological mechanisms that influence 
the development of cardiovascular diseases.
Izvleček
Človeška črevesna mikrobiota je združba bakterij, arhej, gliv, virusov in parazitov, ki v prebavni 
cevi tvorijo ekosistem, sestavljen iz približno 1014 mikroorganizmov. Raznolikost te združbe je 
posledica razlik v genomu gostitelja in vplivu okoljskih dejavnikov, med katere sodijo higiena, 
prehrana, življenjski slog in uporaba različnih zdravil. Rezultati raziskovalnega dela v zadnjem 
desetletju so potrdili, da spremenjena sestava mikrobiote (disbioza) prispeva k razvoju različnih 
bolezni, vključno s srčno-žilnimi, sladkorno boleznijo tipa 2, kronično boleznijo ledvic, nealko-
holno zamaščenostjo jeter (NASH), kronično vnetno črevesno boleznijo in celo nekaterimi vrst-
ami raka. V prispevku avtorja predstavita nekaj sodobnih spoznanj o raznoliki sestavi človeške 
črevesne mikrobiote, diagnostičnih postopkih in nekaterih patofizioloških mehanizmih, ki vpli-
vajo na razvoj srčno-žilnih bolezni.
Cite as/Citirajte kot: Skok P, Skok K. The gastrointestinal tract and cardiovascular diseases - do they have 
anything in common? Zdrav Vestn. 2020;89(9–10):528–38.
DOI: https://doi.org/10.6016/ZdravVestn.2989
Copyright (c) 2020 Slovenian Medical Journal. This work is licensed under a
Creative Commons Attribution-NonCommercial 4.0 International License.
Slovenian
Medical
Journal
1 Introduction
In the last decade, understanding the human gut microbiota and its role in var-
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The gastrointestinal tract and cardiovascular diseases - do they have anything in common?
ious diseases has advanced significantly 
(1). The gut microbiota is a collection 
of bacteria, archaea, fungi, viruses, and 
parasites in the gastrointestinal tract that 
produce a diverse ecosystem of about 
1014 microorganisms. It is crucial for 
maintaining the homeostatic functions 
of the gastrointestinal tract, as it partici-
pates in the processes of the host’s diges-
tion, metabolism and regulation of the 
intestinal immune system (2). At birth, 
the gastrointestinal tract of the newborn 
is not populated with microorganisms, 
in the following hours it is colonized by 
the mother’s microorganisms, initially 
coliform bacteria and streptococci, later 
lactobacilli and enterococci. Of course, 
this colonization of microorganisms al-
so depends on the method of delivery 
(vaginal or by caesarean section). In 
adulthood, most of the gut microbiota 
is composed of five phyla, namely: Bac-
teroidetes, Firmicutes, Actinobacteria, 
Proteobacteria, and Cerrucomicrobia, in 
which the relative abundance of Bacte-
roidetes and Firmicutes phyla are >90% 
(3-5). The Firmicutes/Bacteroidetes ra-
tio is not the same in all individuals, the 
differences are due to differences in host 
genomes, environmental factors such as 
hygiene, diet, lifestyle and the use of an-
tibiotics (4). 
The gut microbiota is much more di-
verse than researchers have predicted in 
the past. Modern molecular diagnostic 
methods, compared to isolation and in 
vitro cultivation, have provided a more 
detailed insight into the diversity of the 
microbiota and the intensity of coloniza-
tion in the gastrointestinal tract. Due to 
the acidic environment and intense peri-
stalsis (rapid passage of intestinal con-
tents), fewer microorganisms (101-103/
ml) are present in the stomach and du-
odenum, most of which are Gram-pos-
itive bacteria. Lactobacilli and entero-
cocci are also present in the duodenum, 
and the number of bacteria in this area is 
usually 104/ml (5). The richest in num-
ber and diversity of types is the large in-
testine (1012/ml), which is mostly popu-
lated with Gram-negative and anaerobic 
bacteria.
Gut microbiota homeostasis is cru-
cial for maintaining human health, while 
dysbiosis contributes to the development 
of a variety of diseases, including cardio-
vascular diseases, chronic kidney dis-
ease, type 2 diabetes, non-alcoholic fat-
ty liver disease, and even some cancers 
Table 1: Summary of the effects of possible forms of cardiovascular disease treatment aiming 
at changing the composition of the gut microbiota (Adapted from 1).
Treatment / 
measure
Prebiotics Probiotics
Definition Nutritional ingredients that promote a 
“healthy” (appropriate) composition of 
the gut microbiota.
Beneficial living microorganisms that 
can colonize the human gut, establish 
and/or restore a healthy gut microbiota.
Examples and 
effects
• plant polyphenols,
• fruits and vegetables (e.g., apples): 
reduce inflammation and total 
cholesterol levels and promote the 
growth of bifidobacteria,
• dietary fructans,
• foods rich in inulin and/or 
oligofructose, stimulate the growth 
of bifidobacteria, the restoration of 
the population of bacteria that form 
butyrates.
Lactobaccillus strains,
L. reuteri (microencapsulated in 
yogurt): reduces LDL cholesterol, total 
cholesterol, and non-HDL cholesterol.
L. plantarum (capsules): reduce total 
cholesterol.
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(1,6,7). Some effects of possible forms 
of cardiovascular disease treatment that 
aim at changing the composition of the 
gut microbiota are shown in Table 1. 
Gut dysbiosis is a change in the com-
position of the gut microbiota that can 
result from exposure to various factors 
such as diet, increased stress levels, local 
and systemic inflammation, and the use 
of antibiotics. Gut dysbiosis may explain 
why some individuals are more prone to 
developing certain diseases. The change 
in the composition of the microbiota has 
recently been identified as an important 
factor contributing to the development 
of atherosclerosis and hypertension, 
which are the two main risk factors for 
the development of cardiovascular dis-
eases (1,7,8). In recent years, the influ-
ence of microbiota composition on var-
ious chronic and autoimmune diseases 
has been studied, especially in animal 
studies (3,8). They found statistically 
significant differences between the com-
position of the microbiota in lean and 
obese mice and animals with different 
chronic diseases. These results point to 
the importance of the microbiota in re-
lation to health and immunity and offer 
new, as yet undiscovered possibilities for 
applying this knowledge in the treatment 
of other diseases, such as metabolic syn-
drome, insulin resistance, some cancers, 
chronic inflammatory bowel disease and 
other (1,6,9). 
The paper presents some modern di-
agnostic methods that have provided a 
more accurate insight into the diversity 
of the gut microbiota, and certain patho-
physiological mechanisms that influence 
the development of certain cardiovascu-
lar diseases.
2 Diagnostic procedures for 
determining the composition 
of the gut microbiota
The composition of the microbiota, 
its diversity and potential role in main-
taining epithelial cell homeostasis, in 
inhibiting the growth of pathogenic mi-
croorganisms and the formation of var-
ious components, can be defined by a 
number of methods that differ in resolu-
tion (2,5,8). With different methods we 
can compare the composition of the mi-
crobiota between different samples, de-
termine the microbiota composition and 
what the interrelationships are, deter-
mine the metabolic potential of microbes 
with their sets of genes, their interde-
pendence and their metabolic role (10). 
Accurately determining the composition 
of the gut microbiota is a key goal of the 
“Human Microbiome” and “MetaHit” 
(Metagenomics of the Human Intesti-
nal tract) projects, which were launched 
in the recent past (11,12). Methods for 
determining the composition of the mi-
crobiota include traditional ones, such 
as cultivation, and molecular methods. 
Traditional methods include “counting 
colonies on selective medium” and “the 
method of the most probable number 
of cells” (10). Cultivation methods are 
associated with some important limita-
tions: testing being time-consuming and 
the difficulty of culturing most of the gut 
microbiota (10). It should be noted that 
only 0.01-10% of all cells present in the 
microbial sample can grow on the me-
dia. In most molecular methods, 16S- 
and 18S-ribosomal RNA (rRNA), which 
are preserved in all bacteria, archaea and 
eukaryotes, are used as a phylogenetic 
marker for the taxonomic classification 
of organisms. An overview of the differ-
ent techniques is shown in Table 2.
3 Mechanisms of 
microbiota activity in 
the etiopathogenesis of 
cardiovascular diseases
Atherosclerosis is a major risk factor 
for cardiovascular disease. This process 
is characterized by the accumulation of 
cholesterol and macrophages (inflam-
matory cells) in the vascular walls, which Legend: NGS - new generation sequencing, LG/GC - liquid/gas chromatography, MS - mass spectrometry.
Table 2: A brief summary of possible methods for the analysis of the gut microbiota (the first part summarized from 
Durack J and Lynch SV (53)).
Area Name Principle Method Positive Negative
Composition Profiling of biological markers DNA NGS Cost effective; semi-
quantitative.
No functional 
information.
Metagenomics DNA NGS Strain level resolution. Expensive. 
Compute-intensive.
Metabolic 
production
Metabolomics Metabolites LG/GC - MS Semi-quantitative. 
Targeted or non-
targeted.
The origin of the 
metabolite is 
unclear.
Function Metatranscriptomics RNA NGS Gene transcription 
of the host or of 
microorganisms.
Samples require 
RNA preservation; 
host genes may 
predominate.
Metaproteomics Proteins LG/GC - MS Semi-quantitative. The origin of the 
protein is unclear.
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PROFESSIONAL ARTICLE
The gastrointestinal tract and cardiovascular diseases - do they have anything in common?
number of methods that differ in resolu-
tion (2,5,8). With different methods we 
can compare the composition of the mi-
crobiota between different samples, de-
termine the microbiota composition and 
what the interrelationships are, deter-
mine the metabolic potential of microbes 
with their sets of genes, their interde-
pendence and their metabolic role (10). 
Accurately determining the composition 
of the gut microbiota is a key goal of the 
“Human Microbiome” and “MetaHit” 
(Metagenomics of the Human Intesti-
nal tract) projects, which were launched 
in the recent past (11,12). Methods for 
determining the composition of the mi-
crobiota include traditional ones, such 
as cultivation, and molecular methods. 
Traditional methods include “counting 
colonies on selective medium” and “the 
method of the most probable number 
of cells” (10). Cultivation methods are 
associated with some important limita-
tions: testing being time-consuming and 
the difficulty of culturing most of the gut 
microbiota (10). It should be noted that 
only 0.01-10% of all cells present in the 
microbial sample can grow on the me-
dia. In most molecular methods, 16S- 
and 18S-ribosomal RNA (rRNA), which 
are preserved in all bacteria, archaea and 
eukaryotes, are used as a phylogenetic 
marker for the taxonomic classification 
of organisms. An overview of the differ-
ent techniques is shown in Table 2.
3 Mechanisms of 
microbiota activity in 
the etiopathogenesis of 
cardiovascular diseases
Atherosclerosis is a major risk factor 
for cardiovascular disease. This process 
is characterized by the accumulation of 
cholesterol and macrophages (inflam-
matory cells) in the vascular walls, which Legend: NGS - new generation sequencing, LG/GC - liquid/gas chromatography, MS - mass spectrometry.
Table 2: A brief summary of possible methods for the analysis of the gut microbiota (the first part summarized from 
Durack J and Lynch SV (53)).
Area Name Principle Method Positive Negative
Composition Profiling of biological markers DNA NGS Cost effective; semi-
quantitative.
No functional 
information.
Metagenomics DNA NGS Strain level resolution. Expensive. 
Compute-intensive.
Metabolic 
production
Metabolomics Metabolites LG/GC - MS Semi-quantitative. 
Targeted or non-
targeted.
The origin of the 
metabolite is 
unclear.
Function Metatranscriptomics RNA NGS Gene transcription 
of the host or of 
microorganisms.
Samples require 
RNA preservation; 
host genes may 
predominate.
Metaproteomics Proteins LG/GC - MS Semi-quantitative. The origin of the 
protein is unclear.
contributes to the formation of athero-
sclerotic plaques (1,8,9). Recent studies 
have shown that intestinal dysbiosis can 
contribute to the development of athero-
sclerosis by modulating inflammatory 
processes and the formation of certain 
microbial metabolites (13-15).
3.1 Gut dysbiosis and 
atherosclerosis
The integrity of the gut mucosa is the 
first barrier that protects the host from 
the intrusion of pathogens, the passage 
of intestinal contents and bacterial com-
ponents into the blood vessels. Reduced 
concentration of proteins that ensure 
close contact between cells and their 
impermeability, including ZO-1 (TJP1), 
claudin-1 and occludin, allows increased 
permeability of the gastrointestinal wall 
with an imbalance between mucosal cell 
death and regeneration (1,13,14). If the 
mucous barrier is damaged, the intru-
sion of microbes with their products, i.e., 
with pathogens associated with molecu-
lar patterns (PAMPs) in the blood vessels 
triggers an immune response, tissue and 
systemic inflammation. Lipopolysaccha-
rides (LPS) and peptidoglycans (PG) are 
components of bacteria associated with 
the development of cardiovascular dis-
ease. LPS is a component of the cell wall 
of Gram-negative bacteria. The associa-
tion between plasma LPS levels and the 
risk of heart disease was first studied in 
1999 by Niebauer et al. (15). The results 
of the study confirmed that the level of 
endotoxemia was highest in patients 
with most severe cardiovascular diseas-
es. Cani and colleagues confirmed in 
their study that gut dysbiosis prevented 
the formation of “close-contact proteins,” 
resulting in increased permeability of 
the gut mucosa and thus the passage of 
LPS into the blood (16). LPS, which are 
produced in increased amounts in gut 
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dysbiosis, may play an important role 
in the modulation of “Toll-like recep-
tors” that recognize bacterial products 
and regulate the immune system of the 
host. Clinical studies have shown that 
the upregulation of “Toll-like receptors” 
is associated with anti-inflammatory ac-
tivity and promotes the development of 
atherosclerosis in humans. PG, a minor 
component of the cell wall of Gram-neg-
ative bacteria and an important compo-
nent of Gram-positive bacteria, has also 
been found to be associated with a risk of 
cardiovascular disease because it dam-
ages the epithelial barrier (8,9). It was 
also shown that patients with atheroscle-
rosis had an increased number of genes 
encoding the synthesis of pro-inflam-
matory bacterial peptidoglycans (8,17). 
PAMPs that can promote inflammatory 
processes include CpG-oligodeoxinu-
cleotides and flagellin, lipopeptides, and 
others. The results of research in recent 
years confirm the role and importance of 
gut microbiota and dysbiosis in the risk 
of atherosclerosis (1,3,8).
3.2 Gut microbial metabolites 
in atherosclerosis
In the metabolism of gut bacteria, 
various metabolites are formed that 
participate in the development of ath-
erosclerosis. Among the most import-
ant are various amines, methylamines, 
polyamines, short-chain fatty acids, 
trimethylamine, and secondary bile ac-
ids. In particular, short-chain fatty acids 
are a group of gut microbial metabolites 
that are important in metabolic diseases. 
Studies have shown that the gut microbi-
ota is involved in the formation of trime-
thylamine N-oxide (TMAO) (8,14). 
Trimethylamine (TMA) is a by-product 
of bacterial metabolism that is absorbed 
into the bloodstream and converted to 
TMAO in the liver by specific liver en-
zymes, flavin-containing monooxygen-
ases. Different bacterial compositions 
naturally have different abilities to pro-
duce TMAO. Studies have confirmed 
that TMAO promotes the development 
of atherosclerosis by stimulating cho-
lesterol influx, inhibiting cholesterol ex-
cretion, inhibiting secondary bile acid 
metabolic pathways, and/or by increas-
ing platelet activation (1,8). According 
to the researchers, TMAO, in addition to 
the role of a biological marker for ath-
erosclerosis and cardiovascular diseases, 
could also represent a possible therapeu-
tic goal in the future (18).
3.3 Gut microbiota and 
hypertension
As early as 1982, Honor and colleagues 
demonstrated that antibiotic treatment 
could cause higher blood pressure (15). 
A 2015 Yang et al. study in rats with hy-
pertension confirmed that altering the 
gut microbiota by significantly reducing 
microbial diversity and increasing the 
ratio of bacteria from Firmicutes/Bacte-
roidetes phyla can affect blood pressure 
regulation (8). Although the relationship 
and mechanism of the gut microbiota 
and hypertension activity have not yet 
been fully elucidated, existing evidence 
highlights the important role of short-
chain fatty acids and oxidized low-den-
sity lipoproteins (LDL) in hypertension. 
The microbiota of an individual is very 
specific and relatively stable throughout 
the adult life, despite the fact that 90% 
of it is represented by only two phyla of 
the bacteria Firmicutes and Bacteriode-
tes. Bacteria of these phyla (e.g., Lacto-
bacillus sp., Bacteriodes sp., Prevotella 
sp., etc.) form structural polysaccharides 
and short-chain fatty acids (acetate, pro-
pionate and butyrate) that are crucial for 
intestinal microbiome homeostasis, im-
mune system and host response (1,5,8). 
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The gastrointestinal tract and cardiovascular diseases - do they have anything in common?
Interestingly, different bacteria form 
different types of short-chain fatty ac-
ids. Clinical studies have shown that an 
increased abundance of butyrate-form-
ing bacteria (families Lachnospiraceae, 
Ruminococcaceae and Acidaminococ-
caceae) is associated with lower blood 
pressure in overweight pregnant women 
(14). Short-chain fatty acids can stimu-
late the regulation of G-protein Coupled 
Receptors, which affect renin secretion 
and thus blood pressure (19). The reg-
ulation of blood pressure also depends 
on the control of vasoconstriction and 
vasodilation of blood vessels. Gut dys-
biosis contributes to hypertension with 
vasoconstriction that is regulated by 
LDL oxidation. Dysbiosis may promote 
the expression of inflammatory cyto-
kines. Inflammation can cause oxida-
tive stress, which can promote LDL ox-
idation (1,14). Higher levels of oxidized 
LDL can lead to insufficient production 
of vasodilator substances and excessive 
production of vasoconstrictor substanc-
es. A disturbed balance, however, leads 
to hypertension.
3.4 Gut microbiota and heart 
failure
There is growing evidence of an asso-
ciation between the gut and the patho-
genesis of heart failure. In the English 
literature, the term “gut hypothesis of 
heart failure” (20-23) is used to define 
this connection. This hypothesis ex-
plains that decreased cardiac output 
(DCO) and increased systemic conges-
tion can lead to intestinal ischemia and/
or edema of the intestinal wall, leading 
to increased bacterial passage into the 
blood vessels, thereby increasing the cir-
culating endotoxin level. This can trigger 
inflammation in patients with heart fail-
ure. Niebauer and colleagues found that 
patients with heart failure with peripher-
al edema had higher levels of endotoxin 
and inflammatory cytokines in plasma 
compared to patients without edema 
(15). Following short-term diuretic ther-
apy, serum concentrations of endotoxin, 
but not cytokines, decreased. In another 
study, the same researchers confirmed 
that patients with heart failure with re-
duced intestinal blood flow had higher 
serum concentrations of immunoglob-
ulin A - anti-lipopolysaccharide. Com-
pared with the control group, patients 
had a different microbiota composition 
(24). Studies have also confirmed that 
circulating TMAO levels are higher in 
patients with heart failure compared to 
the control group without heart failure 
(20-23). 
3.5 Gut microbiota in 
myocardial infarction
Atherosclerotic plaques contain bac-
terial DNA. Bacterial species found in 
atherosclerotic plaques, however, are al-
so present in the intestines of the same 
individuals (18,20). From this, it can be 
concluded that intestinal microbial com-
munities may be a source of bacteria in 
plaque, which may affect plaque stability 
and the development of cardiovascular 
disease. A recent study in rats reported 
an association between the gut microbi-
ota and the extent of myocardial infarc-
tion (21,22). The study looked at Dahl S 
rats that drank drinking water to which 
the vancomycin antibiotic was added, 
which reduced circulating leptin levels 
by 38%, caused a smaller myocardial 
infarction (27% reduction of the area) 
and improved restoration of post-isch-
emic myocardial contractility (35%) 
compared to control specimens that did 
not receive it. Vancomycin altered the 
abundance of gut bacteria and fungi as 
measured by the amount of 16S and 18S 
rRNA. In rodent studies, administration 
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of Lactobacillus plantarum as a probiot-
ic (Goodbelly contains leptin-inhibiting 
bacteria, Lactobacillus plantarum 299v) 
resulted in a 41% reduction in circulat-
ing leptin, a 29% reduction in myocar-
dial infarction and a better recovery of 
shrinkage functions by 23% (21). How-
ever, if rodents received leptin at a dose 
of 0.12 µg/kg i.v. prior to the study, it nul-
lified the protective effect of the probiot-
ic on the heart. This study was the first 
to confirm a direct link between changes 
in the gut microbiota and myocardial in-
farction. It demonstrates that probiotic 
supplementation can reduce the extent 
of myocardial infarction (21). Another 
animal study using Lactobacillus rham-
nosus GR-1 similarly showed a beneficial 
effect on cardiac function after artificial-
ly induced myocardial infarction (23).
3.6 Gut microbiota and chronic 
kidney disease
Cardiovascular diseases and kidney 
diseases are closely related, the so-called 
“cardiorenal syndrome” is associated 
with poor clinical outcome. Patients 
with chronic kidney disease (CKD) are 
at greater risk of accelerated atheroscle-
rosis and increased mortality. Studies 
have confirmed that the composition of 
the gut microbiota in patients with CKD 
is markedly altered, which leads to an in-
crease in urea and other uremic toxins 
in the intestinal lumen (25–28). In the 
gastrointestinal tract, urease hydrolyzes 
urea to produce large amounts of ammo-
nia, which is then converted to ammoni-
um hydroxide. Ammonia and ammoni-
um hydroxide damage the close contacts 
of the mucosa in patients with CKD 
and cause mucosal barrier dysfunction. 
This allows bacterial components and 
uremic toxins to pass from the gut in-
to the systemic circulation and triggers 
systemic inflammation (8,29). Recently, 
intestinal DNA microbiota with 16S rR-
NA amplification and DNA sequencing 
were detected in the plasma of patients 
with CKD during chronic hemodialysis. 
Bacterial DNA levels matched elevated 
plasma levels of inflammatory mark-
ers (30). Uremic toxins associated with 
poorly dialyzable proteins (e.g., indoxyl 
sulfate and p-cresol sulfate) are associat-
ed with an adverse outcome in the pa-
tient. These two metabolites originate 
from the amino acid metabolism of the 
microbiota and are in renal dysfunction 
inefficiently cleared from the circulation 
(27). TMAO is known to accumulate in 
the plasma of patients with CKD. Higher 
TMAO levels, however, were associated 
with higher mortality and progressive 
renal impairment (28,31). Data from 
the Framingham Heart Study showed 
that TMAO was one of the rare metab-
olites in the plasma of healthy subjects, 
the level of which predicted the develop-
ment of CKD (32).
3.7 Gut microbiota and 
metabolic diseases
In recent years, researchers have al-
so studied the links between dysbiosis 
and obesity, type 2 diabetes, dyslipid-
emia, and non-alcoholic fatty liver dis-
ease (NAFLD) (33,34). Initial animal 
and human studies supported associa-
tions between obesity and abundance 
of the Firmicutes phylum compared to 
the Bacteroidetes phylum; type 2 diabe-
tes was associated with a reduced abun-
dance of butyrate-forming bacteria and 
an increased abundance of Lactobacil-
lus spp (1,3,8,9). In the development of 
dyslipidemias, the intestinal microbiota 
participates through secondary bile ac-
ids, which it produces and by modulat-
ing the metabolism of liver and/or sys-
temic lipids, as well as glucose (35,36). 
In the field of NAFLD research, it was 
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The gastrointestinal tract and cardiovascular diseases - do they have anything in common?
found that some bacteria (Clostridium 
coccoides, Lactobacillus reuteri, Parabac-
teroides) affect fat metabolism, gut wall 
integrity and the process of fibrosis, and 
therefore affect the progression of this 
disease (35).
Although we have presented on-
ly some of the mechanisms linking the 
gut microbiota and some cardiovascular 
diseases, we need to be aware of the po-
tential of this research area in the devel-
opment of potential drugs in the future. 
We must not forget that we already are 
using part of the acquired knowledge in 
this field. This includes treatment with 
“fecal microbiota transplantation” and 
influencing the course of chronic in-
flammatory bowel disease and ulcerative 
colitis, as well as the treatment of recur-
rent infections with Clostridium difficile 
(37). The newly elucidated links between 
dysbiosis and the pathogenesis of cardio-
vascular disease offer new opportunities 
for early and targeted action. However, a 
number of research questions and ther-
apeutic options also open up in other 
areas (38,39). The abundance of recent 
research contributions in this field con-
firms the importance of this field and the 
interest that has emerged in research en-
vironments.
4 Application in practice
Examples of clinical aplicability of 
microbiota changes that have been 
known for a long time are: fecal trans-
plantation, dietary measures, pre- and 
probiotic therapy, antibiotic therapy, in-
take of TMA lyase inhibitors, etc. (40).
Research has shown that even a five-
day change in diet leads to a short-term 
rearrangement of the number and types 
of gut microbiota (4). An example of this 
is the DASH diet (Dietary Approaches 
to Stop Hypertension), which consists 
of meals with fruits, vegetables, whole 
grains, etc. (41). Patients in the study 
had better results in the six-minute walk 
test, better quality of life and reduced 
arterial elasticity after three months of 
implementing the diet (42). In addition, 
the individuals who do not follow a pre-
scribed diet are found to have elevated 
levels of TMAO in the urine compared 
to patients who followed the prescribed 
regimen (43,44). A high-fibre diet can 
also improve the growth of acetate-pro-
ducing bacteria, lower high blood pres-
sure, and prevent cardiac fibrosis and 
hypertrophy (45). The addition of pro-
biotics (bifidobacteria, yeast, lactic ac-
id bacteria, etc.) has, according to pre-
viously described studies on animals, 
contributed to better heart function and 
maintaining it (23,46). 
The use of antibiotics affects the com-
position, diversity and function of the 
normal flora. Non-steroidal anti-inflam-
matory drugs also lead to changes in the 
flora in elderly patients, which can cause 
side effects (47). However, antibiotics 
can also be helpful. We have already ex-
plained that antibiotics have been suc-
cessfully used in animal models to re-
duce translocation as well as to reduce 
the extent of cardiac cell damage after 
infarction (48,49). Polymyxin B and to-
bramycin have, for example, reduced 
levels of LPS in the gastrointestinal tract 
as well as the IL-1β, IL-6 and TNF-α lev-
els in patients with heart failure (50). 
Worthy of note are the results of a 
study in which mice were given choline 
analogues that inhibit the functioning 
of the enzyme CutC/D in the metab-
olism of TMA and thereby reduce the 
plasma concentration of TMAO, which 
is associated with increased thrombo-
genicity. The use of choline analogues 
could therefore allow for a possible new 
approach to reducing the chances of 
developing thrombosis (51). Another 
interesting active ingredient recently de-
536
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References
1. Lau K, Srivatsav V, Rizwan A, Nashed A, Liu R, Shen R, et al. Bridging the Gap between Gut Microbial 
Dysbiosis and Cardiovascular Diseases. Nutrients. 2017;9(8):859. DOI: 10.3390/nu9080859 PMID: 28796176
2. Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev. 
2010;90(3):859-904. DOI: 10.1152/physrev.00045.2009 PMID: 20664075
3. Brown JM, Hazen SL. The gut microbial endocrine organ: bacterially derived signals driving 
cardiometabolic diseases. Annu Rev Med. 2015;66(1):343-59. DOI: 10.1146/annurev-med-060513-093205 
PMID: 25587655
4. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and 
reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-63. DOI: 10.1146/annurev-
med-060513-093205 PMID: 25587655
5. Tamburini S, Shen N, Wu HC, Clemente JC. The microbiome in early life: implications for health outcomes. 
Nat Med. 2016;22(7):713-22. DOI: 10.1038/nm.4142 PMID: 27387886
6. Nallu A, Sharma S, Ramezani A, Muralidharan J, Raj D. Gut microbiome in chronic kidney disease: 
challenges and opportunities. Transl Res. 2017;179:24-37. DOI: 10.1016/j.trsl.2016.04.007 PMID: 27187743
7. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of 
phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368(17):1575-84. DOI: 10.1056/
NEJMoa1109400 PMID: 23614584
8. Tang WH, Kitai T, Hazen SL. Gut Microbiota in Cardiovascular Health and Disease. Circ Res. 
2017;120(7):1183-96. DOI: 10.1161/CIRCRESAHA.117.309715 PMID: 28360349
9. Yamashiro K, Tanaka R, Urabe T, Ueno Y, Yamashiro Y, Nomoto K, et al. Gut dysbiosis is associated with 
metabolism and systemic inflammation in patients with ischemic stroke. PLoS One. 2017;12(2):e0171521. 
DOI: 10.1371/journal.pone.0171521 PMID: 28166278
10. Šket R, Prevoršek Z, Košeto D, Sebastijanović A, Konda S, Bajuk J, et al. Analitski in konceptualni izzvi 
pri raziskovanju človeške mikrobiote za potrebe personalizirane večnivojske medicine. Med Razgl. 
2019;58(2):211-34.
11. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. 
Nature. 2007;449(7164):804-10. DOI: 10.1038/nature06244 PMID: 17943116
12. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al.; MetaHIT Consortium. A human gut 
microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59-65. DOI: 
10.1038/nature08821 PMID: 20203603
scribed in the Nature journal that acts as 
a protective factor for the intestinal mu-
cosa is Urolithin A (UroA) and its syn-
thetic analogue UAS03. The active sub-
stance triggers the signaling pathways 
of aryl hydrocarbon receptor (AhR) and 
nuclear factor erythroid 2-related factor 
2 (Nrf2), which enhances close contact 
and gastrointestinal barrier function 
(52). 
5 Conclusion
New technologies are radically 
changing medicine and enabling a new, 
different view of the body, organs and 
health, as well as causal factors of dis-
ease. Recent research work and some 
surprising findings have confirmed that 
the gut microbiota can affect the health 
of the host and trigger disease by a va-
riety of pathophysiological mechanisms. 
Intestinal microbiota and dysbiosis are 
areas of research that are likely to change 
some of today’s established methods of 
disease prevention and treatment in 
the future. Although we can change the 
composition of the microbiota with pre-
biotics, probiotics, antibiotics, diet and 
“targeted enzyme inhibitors”, we unfor-
tunately cannot yet predict these effects 
and evaluate them in the prevention of 
various diseases. With all the data ob-
tained in biomedicine in recent decades, 
it seems unusual that it took so long be-
fore researchers began to systematically 
deal with the impact of as much as 2 kg 
of microorganisms that colonize us and 
live with us “for better or for worse”.
537
PROFESSIONAL ARTICLE
The gastrointestinal tract and cardiovascular diseases - do they have anything in common?
13. Qi Y, Aranda JM, Rodriguez V, Raizada MK, Pepine CJ. Impact of antibiotics on arterial blood pressure 
in a patient with resistant hypertension - A case report. Int J Cardiol. 2015;201:157-8. DOI: 10.1016/j.
ijcard.2015.07.078 PMID: 26301638
14. Gomez-Arango LF, Barrett HL, McIntyre HD, Callaway LK, Morrison M, Dekker Nitert M; SPRING Trial 
Group. Increased Systolic and Diastolic Blood Pressure Is Associated With Altered Gut Microbiota 
Composition and Butyrate Production in Early Pregnancy. Hypertension. 2016;68(4):974-81. DOI: 10.1161/
HYPERTENSIONAHA.116.07910 PMID: 27528065
15. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, et al. Endotoxin and immune 
activation in chronic heart failure: a prospective cohort study. Lancet. 1999;353(9167):1838-42. DOI: 
10.1016/S0140-6736(98)09286-1 PMID: 10359409
16. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic Endotoxemia Initiates Obesity 
and Insulin Resistance. Diabetes. 2007;56(7):1761-72. DOI: 10.2337/db06-1491 PMID: 17456850
17. Karlsson FH, Fåk F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis 
is associated with an altered gut metagenome. Nat Commun. 2012;3(1):1245. DOI: 10.1038/ncomms2266 
PMID: 23212374
18. Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in 
patients with atherosclerosis. Proc Natl Acad Sci U S A. 2010/10/11. 2011 Mar 15;108 Suppl(Suppl 1):4592–
8. DOI: 10.1073/pnas.1011383107 PMID: 20937873
19. Ma J, Li H. The Role of Gut Microbiota in Atherosclerosis and Hypertension. Front Pharmacol. 2018;9:1082. 
DOI: 10.3389/fphar.2018.01082 PMID: 30319417
20. Ott SJ, El Mokhtari NE, Musfeldt M, Hellmig S, Freitag S, Rehman A, et al. Detection of diverse bacterial 
signatures in atherosclerotic lesions of patients with coronary heart disease. Circulation. 2006;113(7):929-
37. DOI: 10.1161/CIRCULATIONAHA.105.579979 PMID: 16490835
21. Lam V, Su J, Koprowski S, Hsu A, Tweddell JS, Rafiee P, et al. Intestinal microbiota determine severity of 
myocardial infarction in rats. FASEB J. 2012;26(4):1727-35. DOI: 10.1096/fj.11-197921 PMID: 22247331
22. Lam V, Su J, Hsu A, Gross GJ, Salzman NH, Baker JE. Intestinal Microbial Metabolites Are Linked to Severity 
of Myocardial Infarction in Rats. PLoS One. 2016;11(8):e0160840. DOI: 10.1371/journal.pone.0160840 PMID: 
27505423
23. Gan XT, Ettinger G, Huang CX, Burton JP, Haist JV, Rajapurohitam V, et al. Probiotic administration 
attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat. Circ Heart Fail. 
2014;7(3):491-9. DOI: 10.1161/CIRCHEARTFAILURE.113.000978 PMID: 24625365
24. Kitai T, Kirsop J, Tang WH. Exploring the Microbiome in Heart Failure. Curr Heart Fail Rep. 2016;13(2):103-9. 
DOI: 10.1007/s11897-016-0285-9 PMID: 26886380
25. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJ, Mann JF, et al. Chronic kidney 
disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339-
52. DOI: 10.1016/S0140-6736(13)60595-4 PMID: 23727170
26. Shi K, Wang F, Jiang H, Liu H, Wei M, Wang Z, et al. Gut bacterial translocation may aggravate 
microinflammation in hemodialysis patients. Dig Dis Sci. 2014;59(9):2109-17. DOI: 10.1007/s10620-014-
3202-7 PMID: 24828917
27. Lin CJ, Chen HH, Pan CF, Chuang CK, Wang TJ, Sun FJ, et al. p-Cresylsulfate and indoxyl sulfate level at 
different stages of chronic kidney disease. J Clin Lab Anal. 2011;25(3):191-7. DOI: 10.1002/jcla.20456 PMID: 
21567467
28. Tang WHW, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, et al. Gut Microbiota-Dependent 
Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency 
and Mortality Risk in Chronic Kidney Disease. Circ REs. 2015;116(3):448-55. DOI: 10.1161/
CIRCRESAHA.116.305360 PMID: 25599331
29. Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, et al. Chronic kidney disease alters intestinal 
microbial flora. Kidney Int. 2013;83(2):308-15. DOI: 10.1038/ki.2012.345 PMID: 22992469
30. Wang F, Jiang H, Shi K, Ren Y, Zhang P, Cheng S. Gut bacterial translocation is associated with 
microinflammation in end-stage renal disease patients. Nephrology (Carlton). 2012;17(8):733-8. DOI: 
10.1111/j.1440-1797.2012.01647.x PMID: 22817644
31. Tang WHW, Wang Z, Fan Y, Levison B, Hazen JE, Donahue LM, et al. 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. 2014;64(18):1908-14. DOI: 10.1016/j.jacc.2014.02.617 PMID: 
25444145
32. Ahmadmehrabi S, Tang WH. Gut microbiome and its role in cardiovascular diseases. Curr Opin Cardiol. 
2017;32(6):761-6. DOI: 10.1097/HCO.0000000000000445 PMID: 29023288
33. Tang WHW, Wang Z, Shrestha K, Borowski AG, Wu Y, Troughton RW, et al. Intestinal Microbiota-Dependent 
Phosphatidylcholine Metabolites, Diastolic Dysfunction, and Adverse Clinical Outcomes in Chronic Systolic 
Heart Failure. J Card Fail. 2015;21(2):91-6. DOI: 10.1016/j.cardfail.2014.11.006 PMID: 25459686
538
CARDIOVASCULAR SYSTEM
Zdrav Vestn | September – October 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2989
34. Rhee EP, Clish CB, Ghorbani A, Larson MG, Elmariah S, McCabe E, et al. J Am Soc Nephrol. 2013;24(8):1330-
8. DOI: 10.1681/ASN.2012101006 PMID: 23687356
35. Wree A, Geisler LJ, Tacke F. Mikrobiom & NASH – enge Komplizen in der Progression von 
Fettlebererkrankungen TT - Microbiome & NASH – partners in crime driving progression of fatty liver 
disease. Z Gastroenterol. 2019;57(07):871-82. DOI: 10.1055/a-0755-2595 PMID: 31288283
36. Zeissig S. Microbial regulation of tumor development and responses to tumor therapy. Z Gastroenterol. 
2019;57(7):883-8. PMID: 31288284
37. Stallmach A, Grunert P, Pieper D, Steube A.. Ulcerative Colitis: Does the Modulation of Gut Microbiota 
Induce Long-Lasting Remission? Z Gastroenterol. 2019;57(07):834-42. DOI: 10.1055/a-0874-6603 PMID: 
30986885
38. Enck P, Mazurak N. Microbiota and irritable bowel syndrome: A critical inventory. Z Gastroenterol. 
2019;57(7):859-70. PMID: 31288282
39. Skok P. Gastrointestinal tract and associated heart and kidney diseases. In: Radenković S, Šmelcerović A, 
eds. Kardionefrologija = Cardionephrology. International Cardionephrology and Hypertension Congress. 
2019; Ribarska Banja. Niš: Punta; 2019.
40. Jia Q, Li H, Zhou H, Zhang X, Zhang A, Xie Y, et al. Microbiota and irritable bowel syndrome: A critical 
inventory. Cardiovasc Ther. 2019;2019:5164298. DOI: 10.1155/2019/5164298 PMID: 31819762
41. Salehi-Abargouei A, Maghsoudi Z, Shirani F, Azadbakht L. Effects of Dietary Approaches to Stop 
Hypertension (DASH)-style diet on fatal or nonfatal cardiovascular diseases—incidence: a systematic 
review and meta-analysis on observational prospective studies. Nutrition. 2013;29(4):611-8. DOI: 10.1016/j.
nut.2012.12.018 PMID: 23466047
42. Rifai L, Pisano C, Hayden J, Sulo S, Silver MA. Impact of the DASH diet on endothelial function, exercise 
capacity, and quality of life in patients with heart failure. Proc Bayl Univ Med Cent. 2015;28(2):151-6. DOI: 
10.1080/08998280.2015.11929216 PMID: 25829641
43. Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, Fung TT, Li S, Willett WC, et al. The Mediterranean-style dietary 
pattern and mortality among men and women with cardiovascular disease. Am J Clin Nutr. 2014;99(1):172-
80. DOI: 10.3945/ajcn.113.068106 PMID: 24172306
44. De Filippis F, Pellegrini N, Vannini L, Jeffery IB, La Storia A, Laghi L, et al. High-level adherence to 
a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome. Gut. 
2016;65(11):1812-21. DOI: 10.1136/gutjnl-2015-309957 PMID: 26416813
45. Marques FZ, Nelson E, Chu PY, Horlock D, Fiedler A, Ziemann M, et al. High-fiber diet and acetate 
supplementation change the gut microbiota and prevent the development of hypertension and heart 
failure in hypertensive mice. Circulation. 2017;135(10):964-77. DOI: 10.1161/CIRCULATIONAHA.116.024545 
PMID: 27927713
46. Lin PP, Hsieh YM, Kuo WW, Lin YM, Yeh YL, Lin CC, et al. Probiotic-fermented purple sweet potato yogurt 
activates compensatory IGFIR/PI3K/Akt survival pathways and attenuates cardiac apoptosis in the hearts 
of spontaneously hypertensive rats. Int J Mol Med. 2013;32(6):1319-28. DOI: 10.3892/ijmm.2013.1524 PMID: 
24127171
47. Tiihonen K, Tynkkynen S, Ouwehand A, Ahlroos T, Rautonen N. The effect of ageing with and without 
non-steroidal anti-inflammatory drugs on gastrointestinal microbiology and immunology. Br J Nutr. 
2008;100(1):130-7. DOI: 10.1017/S000711450888871X PMID: 18279548
48. Zhou X, Li J, Guo J, Geng B, Ji W, Zhao Q, et al. Gut-dependent microbial translocation induces 
inflammation and cardiovascular events after ST-elevation myocardial infarction. Microbiome. 
2018;6(1):66. DOI: 10.1186/s40168-018-0441-4 PMID: 29615110
49. Ponziani FR, Zocco MA, D’Aversa F, Pompili M, Gasbarrini A. Eubiotic properties of rifaximin: disruption of 
the traditional concepts in gut microbiota modulation. World J Gastroenterol. 2017;23(25):4491-9. DOI: 
10.3748/wjg.v23.i25.4491 PMID: 28740337
50. Conraads VM, Jorens PG, De Clerck LS, Van Saene HK, Ieven MM, Bosmans JM, et al. Selective intestinal 
decontamination in advanced chronic heart failure: a pilot trial. Eur J Heart Fail. 2004;6(4):483-91. DOI: 
10.1016/j.ejheart.2003.12.004 PMID: 15182775
51. Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, et al. Development of a gut microbe-targeted 
nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018;24(9):1407-17. DOI: 10.1038/s41591-
018-0128-1 PMID: 30082863
52. Singh R, Chandrashekharappa S, Bodduluri SR, Baby BV, Hegde B, Kotla NG, et al. Enhancement of the gut 
barrier integrity by a microbial metabolite through the Nrf2 pathway. Nat Commun. 2019;10(1):89. DOI: 
10.1038/s41467-018-07859-7 PMID: 30626868
53. Durack J, Lynch S V. The Gut Microbiome: Relationships With Disease and Opportunities for Therapy. J Exp 
Med. 2019;216(1):20-40. DOI: 10.1084/jem.20180448 PMID: 30322864