The Effects of Probiotics On Inflammation

Heart, Lung and Circulation (2022) 31, e45–e71 REVIEW
1443-9506/21/$36.00
https://doi.org/10.1016/j.hlc.2021.09.006
The Effects of Probiotics on Inflammation,

Endothelial Dysfunction, and
Atherosclerosis Progression:
A Mechanistic Overview
Marjan Mahdavi-Roshan, PhD a,b, Arsalan Salari, MD a,
Jalal Kheirkhah, MD a, Zeinab Ghorbani, PhD a,b,*
a
Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical
Sciences, Rasht, Iran
b
Department of Clinical Nutrition, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
Received 8 January 2021; received in revised form 7 June 2021; accepted 8 September 2021; online published-ahead-of-print 10 February 2022
Introduction The relationship between the intestinal microbiota dysbiosis, inflammation, and cardiovascular disorders
(CVDs) has become evident, based on a growing body of literature from animal models and human studies.
On the other hand, probiotics are believed to have promising effects on modifying dysbiosis and protecting
against CVDs.
Objective This narrative review provides an overview of the link between gut microbiota, inflammation, endothelial
dysfunction, and atherosclerosis. The influences of probiotic supplementation on biomarkers contributing
to these conditions as the primary underlying risk factors for developing CVDs are also discussed.
Methods An up-to-date review was performed of the available evidence from experimental studies, clinical trials,
and meta-analyses, considering their challenges and limitations. It also aimed to provide mechanistic
insight into the likely mechanisms of probiotics that could prevent atherosclerosis initiation and
progression.
Results Probiotic supplementation seems to be associated with reduced levels of inflammation and oxidative stress
biomarkers (C-reactive protein, tumour necrosis factor-a, interleukin (IL)-6, IL-12, and malondialdehyde).
Further, these agents might enhance antioxidant factors (IL-10, total antioxidant status, total antioxidant
capacity, glutathione, and nitric oxide). Probiotics also appear to improve intestinal barrier integrity, reduce
leakage of harmful metabolites (e.g., lipopolysaccharides), inhibit pro-inflammatory signalling pathways,
and possibly suppress the formation of trimethylamine/trimethylamine oxide. Probiotics have also been
found to enhance endothelial function and halter thrombosis.
Conclusion The current clinical evidence underlines belief that probiotics might be associated with reduced levels of
inflammation biomarkers. Experimental evidence reports that the beneficial effects of probiotics seem to be
mainly imposed by triggering the secretion of short-chain fatty acids and bile acids, in addition to sup-
pressing the NF-kB signalling pathway. However, the current studies are still in their infancy and it is of
high priority to design further research on the topic.
Keywords Atherosclerosis Cytokines Endothelial function Oxidants Probiotics Pro-inflammatory factors
*Corresponding author at: Assistant Professor of Nutrition, Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of
Medicine, Guilan University of Medical Sciences, 15 Khordad Street, District 2, Rasht, Guilan Province, Iran; Email: z.ghorbani.h@gmail.com
Ó 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Published by Elsevier B.V. All rights reserved.
e46 M. Mahdavi-Roshan et al.
Dispersal of various agents, including hormones or neu-

Introduction rotransmitters, between epithelial cells and neurons of the
The Intestinal Microbiota and its Effects enteric nervous system could be attributed to bidirectional
on Body Functions communications between these cells. Epithelial neuropod
cells and neurons also have direct synaptic contacts through
A community of live microorganisms (i.e., bacteria, parasites,
synaptic protein expression [23]. On the other hand, the
viruses, yeast, and fungi) in the human intestine is known as
metabolites released by the intestinal microbiota and medi-
the intestinal microbiota [1]. More than 500 bacterial species
ated by the epithelium and systemic circulatory system are
live in the human gastrointestinal (GI) tract as the prevailing
able to affect regulation of the other organs’ functions and
large intestine microorganism. Predominantly, Firmicutes
constitute the bidirectional relationships between this tissue
and Bacteroidetes phyla are responsible for about 90% of the
and other body organs [21]. In this regard, the bacterial
microbial population in the healthy GI tract; other phyla such
as Actinobacteria, Cyanobacteria, Proteobacteria, and Ver- strains of the human gut are able to closely interact with
rucomicrobia, Fusobacteria, are also found in smaller quan- epithelial cells in association with the enteric nervous system
tities. These phyla include various bacterial genera that affect and could therefore influence the mucosal innate immune
physiological processes through multiple mechanisms [1–7], function, epithelial layer maturation, integrity, and its
for example: the Firmicutes phylum consists of approxi- structural development, intestinal vascular system, regu-
mately .200 genera, including Lactobacillus, Clostridium, Ba- lating energy and metabolism, and the host immune function
cillus, Ruminicoccus, and Enterococcus, of which Clostridium [6,12,13,21,24]. As such, approximately 10% of the host’s
genera account for about 95% of this phylum. Besides, Bac- transcriptome, the genes responsible for metabolism or pro-
teroides and Prevotella are known as the main genera liferation cells, especially immune system-related genes, are
belonging to the Bacteroidetes phyla [1–7]. Bifidobacterium is believed to be modulated by the human microbiota [1].
known as the main genus belonging to Actinobacteria, which Although the exact mechanisms have not yet been fully
is present in the GI with less overall distribution [8–10]. The defined, the gut microbiota is also thought to modulate im-
relative populations of these bacterial genera and the mune cell structure and activities (i.e., lymphoid tissues, T
composition and characteristics of the human gut microbiota cells, and B cells) predominantly through the mucosal layer.
profile vary between human subjects and depend on genetic It has also been suggested that intestinal microbiota might
and environmental factors, including: age, host immune protect against immune dysfunction and infections, and
function, disease conditions, geographical region of resi- suppress pathogen overgrowth, which is known as the
dency, way of delivery (caesarean vs natural birth), dietary ‘barrier effect’ [1,12,13,25]. Furthermore, the gut microbiota
intake, physical activity, smoking status, and psychological may modulate reactive oxygen species (ROS) secretion from
factors such as stress level and depression. Additionally, mitochondria, inflammatory factor production from the im-
extrinsic substances to the organism (xenobiotics) that are mune cells, and inflammatory state through affecting the
metabolised by the intestinal microbiome, including specific nuclear factor-kB (NF-kB) signalling pathway [6,12,13,21].
medication (e.g., antibiotics, clindamycin, clarithromycin, Collectively, based on these relationships between the in-
metronidazole, ciprofloxacin, and metformin) could also testinal microbiota and other organs, this is called the ‘sec-
affect gut microbiota (Figure 1) [7,11–18]. ond brain’ in the body [26]. A growing body of research has
The epithelial and mucosal layers and intestinal tight shown that gut microbiota could be an essential influencing
junctions between enterocytes, which could act as physical factor in mood, pain, cognitive status, immune system
barriers, as well as several enzymes and antimicrobial dysfunction, and body weight. Gut microbiota with an
agents in addition to immune cells construct the intestinal exclusive, individualised profile could also affect develop-
barrier, which is recognised as having different functional ment, progression pattern, and response to treatment of
and immunological features [12,13,19–21]. Several cyto- many disorders, including obesity, metabolic syndrome, type
kines, chemokines, and humoral factors generated by I and type 2 diabetes mellitus (T1DM, T2DM), cardiovascular
epithelial cells in response to intestinal microbiota or its disorders (CVDs) such as hypertension (HTN), and liver and
metabolites could prompt immune responses, including GI disorders, including inflammatory bowel disease (IBD)
activating T cells (particularly pro-inflammatory T cells) [1,4,20,26–36]. It is also noteworthy that gut microbiota has
and antigen-specific IgA [22]. These activated T cells are been proposed as a probable diagnostic factor for coronary
able to generate various inflammatory mediators (e.g., artery disease (CAD) morbidity and prognosis [37]. Inter-
interleukin (IL)-17 and IL-22), which would consequently estingly, the gut microbiota is also thought to affect the
result in enhancement of the antimicrobial agents’ release bioavailability, metabolism, and function of several drugs
by the intestinal epithelial cells to modulate overgrowth of such as cardiac glycoside digoxin, metformin (among anti-
opportunistic pathogens [22]. To regulate augmented im- diabetic agents), and simvastatin (among hypolipidaemic
mune responses, the epithelial cells could also restrain the agents) [1]. The exact mechanisms by which the gut micro-
stimulators secreted by gut bacteria affecting host immune biota and its alterations modulate the physiological possesses
cells [22]. are yet to be explored, although there have been many efforts
Probiotics, Inflammation, and Atherosclerosis e47
Figure 1 Factors influencing intestinal microbiota composition and/or characteristics.
in this area [5,38]. The most frequently used approaches plasminogen activator inhibitor type 1 (PAI-1). These
when aiming to explore the gut microbiota and its roles in mechanisms also contribute to endothelial dysfunction
various conditions are using germ-free animals or animals [41,42,52].
infected by pathogenic bacteria, in addition to ingestion of Generation of arterial wall lesions, fatty streaks, excessive
antibiotics/prebiotics/probiotics [16,17]. intima fibrosis, atheroma, and atherosclerotic plaques are the
main stages of atherosclerosis development. Atherosclerotic
Cardiovascular Disorders and plaques comprise vascular endothelium epithelium, smooth
muscle, and lymphocytes. Foam cells, cell lesions, various
Atherosclerosis fatty compounds, cholesterol esters, and calcium form the
Several known CVDs risk factors–including ageing, cigarette core of the plaque [41,42,52]. From a more detailed
smoking, T2DM, and hypercholesterolaemia–could affect perspective, when lipids are present, oxidised LDL (Ox-LDL)
atherosclerosis initiation [28,39–45]. In particular, HTN and and a matrix of proteoglycans are trapped in the intima, and
insulin resistance appear to play major roles in causing pa- the endothelial cells and leukocytes are activated. These
tients to be more prone to atherosclerosis, CVDs develop- events could severely destroy vascular tissue and cause
ment, and premature death [46–49]. Diet-related factors, endothelial cells to produce various deleterious factors,
including overweight and obesity, and high intake of satu- including pro-inflammatory cytokines (e.g., IL-1 and tumour
rated and trans-fatty acids, also play a crucial role in necrosis factor-alpha), which in turn induce foam cells and
atherosclerosis pathophysiology [28,39–45]. Among the build-up of fatty streaks [41,42,52]. Fibrous plaques are
abovementioned risk factors, elevated blood pressure (BP), mainly recognised via deposition of extracellular lipids,
blood sugar, and low-density lipoprotein cholesterol (LDL) cholesterol levels, and smooth muscle cells, and their attrib-
levels closely interact with the diet and intensify its effects on uted matrix accumulation. Smooth muscle cells are thought
atherosclerosis and CVDs-related death [19,39,41,50,51]. As a to play an essential role in the formation of the collagen-
chronic inflammatory vascular disorder, atherosclerosis is enriched fibrous plaques in the sub-endothelium region.
believed to be a leading cause of morbidity and death in This process is also shown to be modulated by angiotensin II,
CVDs. It is of note that the progression of untreated insulin-like growth factor, and platelet-derived growth fac-
atherosclerosis leads to an increased incidence of peripheral tor. In addition, the stimulating effects of lymphocytes on
artery disease, cerebrovascular disease, transient ischaemic atherosclerotic plaque generation seem to primarily be
attack, CAD, heart failure, or sudden death [19,28,39–42,50]. mediating through type-1 and type-2 T-helper cells re-
Therefore, it is of great importance to seek optimal ap- sponses together with other pro-inflammatory factors,
proaches that help blunt progression of atherosclerosis including P-selectin, vascular cell adhesion molecule 1
[41,42]. (VCAM-1), and IL-1. The maturation of monocytes into
Atherosclerosis pathophysiology macrophages, which occurs in the presence of monocyte
The development of atherosclerosis mainly occurs following chemoattractant protein-1 (MCP-1) in the intima, saturates
repeated evolution of arterial wall lesions in response to modified lipids and triggers foam cell generation as the
prolonged preservation of lipids being trapped in the intima primary indicator of an early fatty streak lesion [41,42,52].
by a matrix of proteoglycans, leading to chronic inflamma- It is noteworthy that acute coronary events due to
tion at vulnerable sites in the arteries, which is primarily thrombosis have primarily been attributed to plaque
involved in all stages of atherosclerosis progression composition and vulnerability instead of stenosis severity.
[41,42,52]. Various biochemical mechanisms could affect Thin fibrous caps and accumulation of inflammatory cells
atherosclerosis development, which are likely to consist of certainly characterise the vulnerable plaques that are formed
accumulated LDL/very-LDL (VLDL) levels, oxidation of following matrix degradation under the control of various
lipids, hyperglycaemia, high homocysteine concentrations, proteinases secreted by macrophages and suppression of
hypercoagulation, decreased nitric oxide (NO) and prosta- matrix production by T cells and interferon (IFN)-g
cyclin levels or their dysfunction, inflammation, and/or an [41,42,52]. Plaque vulnerability and its rupture cause the
elevation in cell adhesion molecules (CAMs), and discharge of plaque contents into the intima, which could
induce thrombosis and its associated clinical manifestations also seems to contribute to alterations in immunological
[19]. Further, it has been shown that, as a critical protein of function and modulating metabolic pathways [55].
coagulation cascade onset, increased secretion of tissue factor Different subtypes of leukocytes are found in atheroscle-
by macrophages and endothelial cells–which is modulated rotic lesions, with activated macrophages being the most
by Ox-LDL, infection or the immune and inflammatory frequently found cells that can secret chemokines, cytokines,
cells–is considered to be one of the determining factors in and matrix metalloproteinases. Matrix metalloproteinases
thrombogenicity of the core lesion [41,42,52]. are able to affect plaque destabilisation through degrading
extracellular matrix ingredients. Finally, macrophage
The role of inflammation in atherosclerosis development destruction occurs as a result of lipid aggregation within the
and progression
cells and hence is conducive to the development of necrotic
Inflammation plays a crucial role in atherosclerosis devel-
core in advanced plaques [56]. Macrophages with pro-
opment and progression that is mainly reflected by the
inflammatory effects are known to play an important role
activation of NF-kB and increased expression of pro-
in inducing inflammatory state and causing unstable plaque
inflammatory compounds (TNF-a, IL-6, and IL-18), C-reac-
development. On the other hand, macrophages with anti-
tive protein (CRP), fibrinogen, and adhesion molecules
inflammatory properties could suppress the inflammatory
(VCAM-1 and intercellular adhesion molecule-1 ICAM-1).
state and promote tissue repair. Interestingly, since differ-
Aggravated proinflammatory responses coupled with
entiation of monocytes to macrophages is connected with
endothelial barrier disruption and subsequently elevated
alterations in metabolic pathways, such as metabolism of
permeability of endothelial junctions could result in trans-
cholesterol and glucose and oxidative stress, targeting these
location of atherogenic lipoproteins and immune cells into
pathways may be of value in introducing new therapeutic
the arterial intima through the endothelium. Further,
agents for atherosclerosis [55]. Also, atherosclerosis pro-
increased oxidative stress, as manifested by the accumulation
gression can be restricted through inhibiting macrophage
of malondialdehyde (MDA) and lipid oxidation product (Ox-
apoptosis and recruitment of leukocytes to the area of the
LDL), has also been recognised as a primary step in athero-
lesion [56]. As a component of the innate immune system,
sclerosis initiation. Ox-LDL has an immediate effect on
pattern recognition receptors include receptors with various
atheromatous plaque formation, including suppressing the
functions such as toll-like receptors (TLRs), nucleotide-
secretion of NO. Ox-LDL may also play a role in triggering
binding oligomerisation domain-like receptors, C-type lec-
endothelial cells to secret proteins, adhesion molecules,
tin receptors, and retinoic acid-inducible gene 1-like
chemotactic (e.g., MCP-1), and macrophage colony-
receptors. Surface-expressed pattern recognition receptors
stimulating factor, which could lead to the recruitment of
are found on the surface and cytoplasm of cells, where they
monocytes to the vessel wall [41,42,52]. Hence, vasodilator
recognise pathogen-associated molecular patterns such as
agent levels like NO are reduced, whereas the levels of
lipopolysaccharides (LPS) produced by viral RNA Gram-
vasoconstrictor substances like endothelin-1 are raised in this
negative bacteria [54].
context [6,11,19,40,53]. Moreover, the increased levels of pro-
Specifically, the implication of TLRs in the pathogenesis of
inflammatory agents, in addition to lipid accumulation
CVDs risk factors, including metabolic syndrome, has pre-
within the vessel wall, could suppress the expression of the
viously been explored, and it was demonstrated that
specific cholesterol transporters and might further trigger
disturbed TLRs (particularly TLR2) and innate immune
foam cell cholesterol efflux and thereby result in foam cell
function might contribute to insulin resistance and high-
generation and plaque destabilisation [6,19,39,53]. In addi-
density lipoprotein-associated endothelial dysfunction [54].
tion to Ox-LDL, homocysteine, infection, haemodynamic
Since TLRs play a crucial role in the early stages of innate
forces, hormones, and immune pathways are among the
immune functions through triggering pro-inflammatory
other factors that contribute to augmenting the pro-
mechanisms, they could affect atherosclerosis progression
inflammatory state in atheromatous plaque sites [41,42,52].
[54–56]. The initiation of these pro-inflammatory responses is
The role of immune mechanisms in atherosclerosis mainly recognised by activation of TLR2, TLR4, and TLR6
development and progression signalling pathways together with scavenger receptors,
As previously mentioned, a prolonged pro-inflammatory which are also involved in the detection of Ox-LDL [54,55].
state and acquired and innate immune mechanisms have In addition, cholesterol accumulation in myeloid cells, which
been identified as prevailing components of atherosclerosis is considered a critical pro-inflammatory condition, could
onset and progression [54,55]. In this regard, the alterations have an effect in association with TLRs signalling and trig-
in the recruitment of myeloid cells to atherosclerotic lesion gering inflammasome activation. The association between
regions have further stimulated chronic pro-inflammatory saturated fatty acids and TLR2 activation and inducing in-
responses [56]. Various distinct types of myeloid cells have sulin resistance additionally suggests a possible link between
also been found within the plaques [55]. It has conclusively obesity and TLR2 [56]. Further, significant upregulation of
been indicated that the imbalance of pro-inflammatory and TLR2 and TLR4 in T2DM patients has also been noted in the
anti-inflammatory myeloid cells is involved in atheroscle- literature [54,55]. These observations provide further evi-
rotic lesion onset in the arteries. In addition to cholesterol dence of the involvement of TLRs in pro-atherogenic trig-
metabolism, myeloid cell stimulation with modified LDL gering signalling pathways [54–56]. In this regard, the
Figure 2 Effects of dysbiosis on atherosclerosis initiation and chronic metabolic disorder development.
Abbreviations: SCFAs, short-chain fatty acids; BHS, bile salt hydrolase; GLP-2, glucagon-like peptide-2; LPS, lipopolysac-
charides; PCSK9, proprotein convertase subtilisin/kexin 9; TMAO, Trimethylamine N-oxide; NF-kB, Nuclear factor-kB;
CRP, C-reactive protein; IL, interleukin; TNF-a, tumour necrosis factor-alpha; MDA, malondialdehyde; MCP1, monocyte
chemoattractant protein 1; ROS, reactive oxygen species; RNS, reactive nitrogen species; ICAM-1, intercellular adhesion
molecule-1; VCAM-1, vascular cell adhesion molecule 1; NO, nitric oxide; eNOS, endothelial NO synthase; iNOS, inducible
NO synthase; TLR, toll-like receptor; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; Ox-LDL, oxidised
low-density lipoprotein; T2DM, type 2 diabetes mellitus; PAD, peripheral artery disease; CVA, cerebrovascular disease; TIA,
transient ischaemic attack; ACS, acute coronary syndromes; CVDs, cardiovascular disorders.
biological importance of TLRs as imperative signal trans- Aims of This Review

ducers that modulate immune responses in the atheroscle-
rosis process has already been intensively studied [54–56]. This narrative review first provides the key points from
Concerning these pieces of evidence, recent studies have experimental studies concerning the link between gut
begun to examine whether suppression of TLR2 and possibly microbiota, inflammation, endothelium dysfunction, and
TLR4 might attenuate the formation of atherosclerotic le- atherosclerosis as interesting topics of research. It then dis-
sions, stability of plaque, and release of proinflammatory cusses the influences of probiotic supplementation on bio-
mediators and chemokines through blocking the NF-kB sig- markers contributing to the risk of pro-inflammatory state,
nalling pathway; suppressing TLR2 has also been found to endothelial function, and gut microbiota metabolites based
lower infarct size. However, more extensive evidence is on the available evidence from clinical trials and meta-
needed to explore various aspects of targeting TLRs in CVDs analysis articles, considering their challenges and limita-
[54,55]. tions. It also aims to provide a mechanistic insight into how
probiotics could prevent atherosclerosis initiation and A variety of cardiovascular pathologic events–including
progression. acute coronary syndromes, myocardial infarction, and
stroke–have been identified as certain manifestations of un-
stable thrombus. The events leading to the generation of
atherothrombosis principally initiate from disruption of an
The Gut Microbiota as an atherosclerotic lesion [64,65]. Recently, in addition to the
Influencing Factor of well-known risk factors of CVDs, augmented TMAO levels
Atherosclerosis and Thrombosis in correlation with gut microbiota-liver metabolic activity
have been linked to the risk of thrombosis and its conse-
There are many experimental studies on germ-free mice in quences such as myocardial fibrosis, heart failure, and other
which the gut microbiota and dietary influences on athero- CVDs; however, its mechanistic background is not clearly
genesis are explored. In particular, it was previously sug- understood [58,62–65]. For instance, in a longitudinal cohort
gested that gut microbes could notably affect platelet of 4,007 individuals referred to a cardiology clinic for elective
function and thrombosis through various pathways such as coronary angiography, a correlation between plasma TMAO
the trimethylamine (TMA)/trimethylamine oxide (TMAO) concentration and incident risk of stroke, myocardial
synthesis pathway. The current evidence that has acknowl- infarction, death, or requiring revascularisation was noted
edged the effects of the intestinal microbiota on atheroscle- after three years of follow-up [62]. In a study by Tang et al.,
rosis seems to depend on dietary intake and special dietary increased TMAO plasma concentration was reported to be
compounds such as choline, which are necessary for the related to elevated risk of long-term mortality among 720
formation of TMAO, a gut microbiota-liver derived metab- patients suffering from heart failure, regardless of traditional
olite [57–63]. Concerning the effects of diet and gut micro- risk factors. These patients were also shown to have greater
biota on atherosclerotic susceptibility, Stepankova et al. TMAO levels than those without heart failure [63]. Addi-
reported that no atherosclerotic plaque was detected tionally, augmented TMAO levels were observed to be dose
following a low-cholesterol diet for conventionally raised dependently associated with the risk of thrombotic event
ApoE–/– mice. Nevertheless, the same diet was likely to incidence, regardless of having a history of CVDs, traditional
induce aortic atherosclerotic plaque development among CVD risk factors, kidney function, and drug consumption
germ-free ApoE–/– knockout mice, in which signs of mac- [58]. To further clarify the determinant role of TMAO in the
rophages, lipid deposition, and foam cells in their arterial thrombogenesis process, Roberts et al. investigated the con-
walls were detected. These results could also support the sequences of targeting TMA-producing enzyme pair in ani-
protective effects of intestinal commensal bacteria on mal models. They observed a significant reduction in TMAO
atherogenesis [60]. Further, Lindskog Jonsson et al. demon- plasma levels, reversal of platelet responsiveness to choline,
strated that the structure, composition, and relative fre- and reduced generation of thrombus following administra-
quency of different taxa of the gut microbial community tion of a TMAO pathway inhibitor as a novel therapeutic
varied between mice that were fed fibre-rich chow diet or a strategy against thrombosis. Additionally, no significant
high-sugar, high-fat, Western diet that had additional high toxicity or elevated bleeding risk were reported. Interest-
choline content. It was also found that a close interaction ingly, the authors suggested that providing drugs that
between gut microbiota, dietary macronutrient proportion, selectively suppress the enzymes and metabolites linked to
and cholesterol level could modify the gut microbiota’s the adverse effects of gut microbiota and involved in host
protective effects on atherosclerotic lesion development and disease development could be of high value. In particular,
progression in apolipoprotein E (ApoE)2/2 mice [59]. A the medication that inhibits TMA/TMAO synthesis pathway
broader perspective was adopted by Kiouptsi et al., who might be an effective approach for attenuating potential risk
studied the effects of feeding an atherogenic high-fat Western of thrombosis among patients prone to thrombotic events
diet for 16 weeks to germ-free or conventional LDL receptor- and CVDs [57].
deficient (LDLr2/2) mice. They reported that an athero- Human studies have also found several related results.
genic high-fat Western diet, which also contained high According to the findings of metagenome-wide association
choline levels, compared with a control diet with low research on stool samples collected from 218 atherosclerotic
cholesterol content lowered caecal gut microbiome diversity subjects diagnosed with cardiovascular disease, their gut
in germ-free and conventional LDLr2/2 mouse models. In microbiome exhibited a different profile when compared
this regard, a reduced Bacteroidetes phylum distribution and with 187 healthy control subjects [66]. It was observed that
an elevated abundance of Firmicutes phylum in mice fed the subjects suffering from cardiometabolic risk factors and
high-fat Western diet was documented compared with the liver cirrhosis had a higher abundance of Enterobacteriaceae
control diet. The authors described that although hyper- and Streptococcus species, with less fermentative bacteria in
cholesterolaemia is considered a key factor in developing the gut [66].
atherosclerotic plaques, the effects of gut microbiota, as a Some evidence also indicates that bacterial DNA in
stimulant factor of the innate immune responses, on the atherosclerotic plaque of the arterial walls correlates with the
atherosclerosis advancement and atherothrombosis should bacterial strains found in the same individuals’ gut and
be additionally considered [61]. atherosclerotic plaque instability and ischaemic heart disease
occurrence. These reports are supported by the results ob- augmented inflammation within the gut, which in turn
tained from metagenomic sequencing representing the might affect the gut metagenome, particularly among pa-
divergent intestinal microbiome profile in patients who had tients with symptomatic atherosclerosis [66,67].
unstable atherosclerotic plaques from those with stable pla- These findings propose that the recovery of the bacterial
ques [6,19,27,53,67]. As such, the patients with unstable strains of the healthy gut microbiota, possibly through
plaques were more likely to have a lower faecal distribution applying an anti-inflammatory approach, could effectively
of the bacterial genus, which produces butyrate that reflects improve or at least decrease various cardiometabolic risks
activation of the pro-inflammatory state among these pa- and perhaps liver cirrhosis [66,67]. Furthermore, the gut
tients. These events link the gut microbiota to the progres- microbial composition is assumed to be involved in the
sion of inflammatory disorders, particularly atherosclerosis processes leading to the generation of cerebral cavernous
[6,19,27,53,67]. malformations, which are the principal causes of stroke and
Consistent with these observations, various compositional seizure [64].
and functional changes of the gut metagenome have been
detected, which might be connected with symptomatic Dysbiosis
atherosclerosis regardless of other CVDs risk factors, In general, dysbiosis refers to any alterations in the intestinal
including body mass index, T2DM, or smoking. However, it microbial population, functional structure, metabolic fea-
should be mentioned that the confounding effects of these tures, and the gut epithelial barrier and local deposition
risk factors, which on the one hand are associated with patterns compared with the homeostatic balance of a healthy
medication consumption, dietary habits, individual health individual’s microbiota. An increased number of pathogenic
conditions, and on the other hand correlated with the intes- (harmful) microorganisms along with the concurrent
tinal microbiota profile, require additional in-depth explo- decrease in a nonpathogenic or commensal (beneficial) bac-
ration [67]. With respect to this, the proposed link between terial species community mainly characterise a dysbiotic gut
periodontal disease and atherosclerosis may also highlight microbiome. Dysbiosis might be classified as three types: a) a
the roles played by oral cavity bacteria and possibly even the lack of beneficial bacteria, b) an abundance of pathogenic
gut microbiota in the formation of atherosclerotic lesions microorganisms, and c) a lack of diversity in microbial spe-
and, as a result, CVDs development. The presence of bacte- cies, which may all arise concomitantly. Consuming antibi-
rial DNA in the human atherosclerotic plaque, which is otics or dietary factors may disturb the bacterial homeostasis
consistent with the bacterial phylotypes of both oral cavity of the gut, which might eventually induce dysbiosis
and gut, has been suggested to be connected with leukocyte [4,10,11,13,20,21,24,25,39,53,70].
distribution in the plaque area. It has also been noted that Currently available evidence suggest that coexistence of
there might be a probable link between the oral cavity and dysbiosis and a pro-inflammatory state, oxidative stress,
the gut bacterial taxa and plasma cholesterol levels [68]. neuroendocrine system dysfunction, and insulin resistance of
When exploring the interaction between gut microbiota the host could link this condition with several chronic dis-
and immune pathways in atherosclerosis, it has been noted orders such as obesity, diabetes, and CVDs (notably, HTN,
that microbiota could modify TLRs signalling pathway. LPS atherosclerosis, and heart failure). Although no causal rela-
(also known as endotoxaemia) is likely to be a metabolite of tionship has yet been confirmed, recent reports have noted
gut microbiota metabolic function. Previous reports have that disturbed function of the intestinal barrier and
linked LPS leakage to the circulation, following an elevation elevated gut permeability may play a role in making the
of the abundance of Firmicutes and Actinobacteria phyla and subjects more prone to these pathological states
decreased gut Bacteroidetes phylum (i.e., dysbiosis) to acti- [4,7,11,13,20,21,24,25,39,53,70]. Of note, accelerated inflam-
vated TLR4 [54,64]. The TLRs intracellular domain (and matory factor levels in addition to the elevated production
particularly TLR-4) might trigger several pathways, partic- and increased intestinal permeability to gut microbiota-
ularly NF-kB and the activator protein signalling pathway, derived metabolites, such as endotoxaemia (or LPS),
resulting in intensifying pro-inflammatory factor production concurrent with dysbiosis could consequently result in dys-
in plaques. Of note, TLR2 has been introduced as a prevail- regulation of energy metabolism, immunological and
ing sensor for intestinal microbial ligands that can remotely epithelial barrier dysfunction, disturbed vascular tone,
trigger signalling in the hepatic endothelium. Hence, it might vascular fibrosis, and vasoconstriction. All of these events
contribute to adaptive alterations in clotting factor plasma contribute to the pathophysiology of chronic metabolic dis-
concentrations following host-microbial colonisation orders (Figure 2) [1–4,20,21,28,38,71]. However, it is still
[6,11,19,53,54,64,69]. These events could also induce insulin unclear whether dysbiosis might be induced following dis-
signalling to be disturbed [54,64]. Therefore, a close persis- ease development or whether it might lead to an increase in
tent interaction between the systemic chronic pro- the risk of disease. In general, previous investigations have
inflammatory state present in cardiometabolic disorders proven that this condition could highly intensify metabolic
and the gut microbiota has been proven. It seems that this disease progression and reduce the treatment responses
pro-inflammatory state could additionally contribute to [13,28].
Table 1 Summary of the selected meta-analyses exploring the effects of probiotics on inflammatory and oxidative stress
biomarkers in those with cardiometabolic risk factors.
Number of Pooled Results of Probiotic and/or Synbiotic Reference

Trials Included Intervention Compared with Placebo or other
Treatments
n=3 on TNBF-a YTNF-a: SMD, –70.80 pg/mL; 95% CI, –116.39, –25.22 pg/mL Liang,
(n=134 subjects) No significant effects on CRP levels et al. 2020 [80]
n=5 on CRP
(n=81 subjects)
n=13 [TAS: SMD, 0.33; 95% CI, 0.11–0.55 Ardeshirlarijani,
(n=840 subjects) [GSH: SMD, 0.41; 95% CI, 0.26–0.56 et al. 2019 [94]
YMDA: SMD, –0.54; 95% CI, 20.83, 20.26)
No significant effects on NO levels
n=13 on Y hs-CRP: SMD, –0.38; 95% CI, –0.51, –0.24 Zheng,
hs-CRP Y MDA: SMD, –0.61; 95% CI, –0.89, –0.32 et al. 2019 [92]
(n=915 subjects) More prominent results with intervention duration of 12 wk
n=11 on [ TAC: SMD, 0.31; 95% CI, 0.09–0.52
TAC More prominent results with intervention duration of 12 wk
(n=779 subjects) [ NO: SMD, 0.62; 95% CI, 0.25–0.99
n=10 on MDA [GSH: SMD, 0.41; 95% CI, 0.26–0.55
(n=616 subjects)
n=11 on GSH
(n=734 subjects)
n=8 on NO
(n=516 subjects)
n=85 on TNF-a YCRP: Kazemi,
(n=4,659 subjects) Most reduction in IBD: SMD, –1.37; 95% CI, –1.81, –0.47, with high heterogeneity et al. 2019 [89]
n=128 on CRP Arthritis: SMD, –0.58; 95% CI, –1.15, –0.01, with high heterogeneity
(n=9,947 subjects) Critically ill patients: SMD, –0.66; 95% CI, –1.03, –0.29, with moderate heterogeneity
n=34 on IL-10 Small reduction in healthy subjects: SMD, –0.20 mg/L; 95% CI, –0.33, –0.06, with moderate
(n=2,230 subjects) heterogeneity
n=24 on IFN-g Metabolic disorders: SMD, –0.32 mg/L; 95% CI, –0.57, –0.08, with high heterogeneity
(n=1,515 subjects) No significant changes in renal failure patients
n=11 on IL-4 IL-1B
(n=869 subjects) No significant changes in arthritis and healthy individuals
n=11 on IL-8 Y TNF-a
(n=1,055 subjects) Most reduction in IBD: SMD, –0.87; 95% CI, –1.23, –0.50; p with moderate heterogeneity
n=7 on IL-12 Cirrhosis: SMD, –0.42; 95% CI, –0.67, –0.16
(n=567 subjects) healthy individuals: SMD, –0.30 pg/mL; 95% CI, –0.49, –0.08, with high heterogeneity
n=6 on TGF-b Fatty liver: SMD, –0.75; 95% CI, –0.97, –0.54
(n=411 subjects) No significant change in diabetic, metabolic syndrome, PCOS and arthritis patients
n=77 on IL-6 [ IL-6
(n=2,081 subjects) Cirrhosis: SMD, 0.36; 95% CI, 0.05–0.68, with moderate heterogeneity
Y IL-6
Metabolic syndrome and PCOS: SMD, –0.31; 95% CI, 0.58–0.03, with moderate heterogeneity
No significant change in healthy, metabolic disorders and arthritis patients
[IL-10
Moderately in arthritis: SMD, 0.51; 95% CI, 0.17–0.86
No significant changes in healthy, IBD, and metabolic disorders subjects
IL-4, IL-8, IL-12, IFN-g, and TGF-b
No significant change in healthy subjects
Table 1. (continued).
Number of Pooled Results of Probiotic and/or Synbiotic Reference

Trials Included Intervention Compared with Placebo or other
Treatments
N=18 YTNF-a: SMD, 22.99; 95% CI, 24.77, 21.20, with high heterogeneity Tabrizi,
(n=1,337 subjects) YCRP: SMD, 20.87; 95% CI, 21.27, 20.48, with high heterogeneity et al. 2019 [86]
More prominent results with intervention duration of 8 and multi-strain probiotic
supplements
[NO: SMD, 1.49; 95% CI, 0.81, 2.16, with high heterogeneity
No significant effects on IL-6 levels
n=31 on hs-CRP Yhs-CRP: SMD, 20.33; 95% CI, 20.44, 20.23, with high heterogeneity Milajerdi,
(n=1,579 subjects) YTNF-a: SMD, 20.21; 95% CI, 20.34, 20.08, with high heterogeneity et al. 2019 [90]
n=18 on TNF-a YIL-6: SMD, 20.37; 95% CI, 20.51, 20.24, with moderate heterogeneity
(n=987 subjects) YIL-12: SMD, 20.47; 95% CI, 20.67, 20.27, with moderate heterogeneity
n=16 on IL-6 YIL-4: SMD, 20.48; 95% CI, 20.76, 20.20
(n=840 subjects) [IL-10: SMD, 0.21; 95% CI, 0.04, 0.38
n=8 on IL-12 No significant effects on IL-1b, IL-8, IFN-g, and IL-17 levels
(n=439 subjects)
n=11 on IL-10
(n=545 subjects)
n=9 on IL-1B
(n=442 subjects)
n=4 on IL-8 and IFN-g
n=3 on IL-17 and IL-4
n=9 on TAC [TAC: WMD, 77.30 mmol/L; 95% CI, 2.60, 152.01, with high heterogeneity Zamani,
n=9 on MDA YMDA: WMD, 20.31 mmol/L; 95% CI, 20.54, 20.08, with high heterogeneity et al. 2019 [95]
n-8 on GSH More prominent results with intervention duration of .8 wk and in those aged 50 yr
(n=577 subjects) No significant effects on GSH levels
n=8 on GSH [GSH: WMD, 132.36 mmol/L; 95% CI, 27.76–236.95, with high heterogeneity Roshan,
(n=512 subjects) More prominent results among non-diabetic patients et al. 2019 [93]
n=14 on TAC No significant effect on TAC levels and SOD activity
(n=832 subjects)
n=4 on SOD
(n=190 subjects)
n=11 on CRP YCRP: SMD, 20.40; 95% CI, 20.73, 20.06, with high heterogeneity McLoughlin,
(n=608 subjects) YTNF-a: SMD, 20.90; 95% CI, 21.50, 20.30, with high heterogeneity et al. 2017 [88]
n=5 on IL-6 No significant effects on IL-6 levels
(n=209 subjects)
n=6 on TNF-a
(n=258 subjects)
Abbreviations: SMD, Standardised mean difference; CI, confidence interval; WMD, weighted mean differences; TAS, total antioxidant status; GSH, glutathione;
MDA, malondialdehyde; IBD, inflammatory bowel disease; PCOS, polycystic ovary syndrome; CRP, C-reactive protein; TNF, tumour necrosis factor; TGF,
transforming growth factor; hsCRP, high sensitive C-reactive protein; IFN, interferon; IL, interleukin.
Dietary Manipulation of Gut Microbiota a healthy condition), dietary manipulations, including pre-
Using Probiotics biotic/probiotic foods or supplements that incorporate
several bacterial species, are gaining much attention [17,70].
Interestingly, in comparison with the human genome, the
It is likely that applying dietary modifications mainly
gut microbiome-associated genomics are more likely to be
following a healthy diet with high prebiotic content (such as
prone to be affected by modifications in CVDs risk factors
a fibre-enriched diet) and consuming probiotics that target
such as environmental factors, antibiotic use, dietary intake,
intestinal microbiota could be considered promising in alle-
and the metabolites produced by the living microorganisms
viating atherosclerosis and CVDs development [20,27,72].
in the gut [64]. Among various approaches proposed for
Prebiotic/probiotic supplementation is an appropriate and
rebiosis (i.e., restoring the intestinal microbial community to
safe way to restore dysbiosis, modify gut microbiota
Table 2 Summary of the last 5 years of clinical trials exploring the effects of probiotics on inflammatory and oxidative
stress biomarkers.
Study Type Study Population Dosage and Type of Supplement/ Results at the End of the Reference
Duration Study in Treatment Group
vs Control groupa
Double-blind, Elderly patients Intervention group (n=30): liquid vial Synbiotics compared with Cicero, et al.
randomised, with metabolic containing a synbiotic formula of 23109 placebo: 2020 [98]
placebo-controlled, syndrome CFU/dose Lactobacillus plantarum YVAI
parallel-group 65–80 yr PBS067-DSM 24,937, Lactobacillus YhsCRP and YTNF-a
clinical trial acidophilus PBS066—DSM 24,936, and Synbiotics within group
Lactobacillus reuteri PBS072-DSM 25,175 changes:
(total CFU/dose, 63109 CFU) plus YMAP
prebiotic fibre, inulin and FOS
Placebo group (n=30): vegetable
magnesium stearate plus maltose
8 wk
Randomised, T2DM overweight, Intervention group (n=30): synbiotic Yhs-CRP and MDA Farrokhian,
double-blind, diabetic, subjects supplements containing Lactobacillus [NO et al. 2019 [99]
placebo-controlled with BMI 25 kg/ acidophilus strain T16 (IBRC-M10785), No significant effect on
trial m2 and CHD Lactobacillus casei strain T2 (IBRC- TAC and GSH levels
40–85 yr M10783), and Bifidobacterium bifidum No significant effect on
strain T1(IBRC-M10771) (23109 CFU/g CIMT
each) plus 800 mg inulin/day
Placebo group (n=30): starch/day
12 wk
Randomised, T2DM patients Intervention group 1 (n=25): synbiotic Synbiotic plus lactic acid Ghafouri,
double-blinded, 20–60 yr plus lactic acid bread containing beta- bread or synbiotic bread et al. 2019 [100]
controlled clinical glucan (3 g), Bacillus coagulans (13108 compared with the control:
trial CFU), inulin (10 g), and lactic acid (4 g) [SOD
Intervention group 2 (n=25): synbiotic [GSH-Px
bread containing beta-glucan (3 g), Yhs-CRP no significant
Bacillus coagulans (13108 CFU), and effect on TAC levels
inulin (10 g)
Intervention group 3 (n=25): lactic acid
bread containing beta-glucan (3 g) and
lactic acid (4 g)
Placebo group (n=25): control bread
containing beta-glucan (3 g)
8 wk
Triple-blind, Metabolic syndrome Intervention group (n=23): 250 mg No significant effects on hs- Rabiei, et al.
randomised patients with BMI synbiotic capsule containing 23108 CFU CRP and IL-6 levels 2019 [110]
controlled trial .25 kg/m2, 25–70 Lactobacillus casei, Lactobacillus rhamnosus,
yr Streptococcus thermophilus, Bifidobacterium
breve, Lactobacillus acidophilus,
Bifidobacterium longum, Lactobacillus
bulgaricus 1125 mg FOS, plus
magnesium stearate and hydroxy propyl
methyl cellulose/twice a day, plus
weight-loss diet
Placebo group (n=23): 250 mg placebo
capsule containing maltodextrin twice/
day plus weight-loss diet
12 wk
vs Control groupa
Randomised, Metabolic syndrome Intervention group 1 (n=22): 300 Probiotic yoghurt within Rezazadeh, et al.
double-blind, patients g/d probiotic yogurt containing group changes: YVCAM-1 2019 [107]
placebo-controlled aged 20–65 yr Lactobacillus bulgaricus, Streptococcus and YPAI-1
clinical trial thermophiles 4.41*106 CFU/g Lactobacillus No significant effects on
acidophilus La5 and 3.55*106CFU/g ICAM-1
Bifidobacterium lactis Bb12
Placebo group (n=22): 300 g/d regular
yogurt containing Lactobacillus bulgaricus
and Streptococcus thermophilus
8 wk
Randomised Obese (BMI 30–45 Intervention group 1 (n=24): low-dose HD probiotic: Szulinska, et al.
placebo-controlled, kg/m2), (LD) probiotic (2.53109 CFU/d) twice a YLPS, 2018 [96,97]
double-blind postmenopausal day Yvascular endothelial
intervention women Intervention group 2 (n=23): high-dose growth factor, Ypulse
Aged 55–58 yr (on (HD) (131010 CFU/d) probiotic sachets wave analysis,
average) containing 2 g freeze-dried powder of the Y pulse wave analysis
probiotic mixture containing 9 bacterial pulse pressure, Ypulse
strains: Bifidobacterium bifidum W23, wave analysis
Bifidobacterium lactis W51, Bifidobacterium augmentation index,
lactis W52, Lactobacillus acidophilus W37, Ypulse wave velocity,
Lactobacillus brevis W63, Lactobacillus casei Yinterleukin-6, YTNF-a,
W56, Lactobacillus salivarius W24, Ythrombomodulin
Lactococcus lactis W19, and Lactococcus LD probiotic: no significant
lactis W58 twice a day effect on LPS
Placebo group (n=4): containing only the Yinterleukin-6
excipients (i.e., maize starch and
maltodextrins) twice a day
12 wk
Double-blind, T2DM patients with Intervention group (n=31): 1 sachet (10 g) Probiotic compared with Kobyliak, et al.
randomised, BMI 25 kg/m2 containing 14 live probiotic strains of placebo: 2018 [102]
placebo-controlled 18–75 yr Lactobacillus 1 Lactococcus (631010 CFU/ YTNF-a, YIL-1b
trial g), Bifidobacterium (131010/g),
Propionibacterium (331010/g), and
Acetobacter (13106/g) genera
Placebo group (n=22): a placebo sachet
(10 g)
8 wk
Non-randomised Men with stable Intervention (n=20): 27 oz/day of a drink YIL-8 and IL-12 levels no Malik, et al.
trial coronary artery containing Lactobacillus plantarum 299v significant effect on IL1b, 2018 [108]
disease as formulation 20 billion CFU TNF-a, IFN-g, TGF-b,
diagnosed 6 wk ICAM1, VCAM1, TMAO
40–75 yr levels
Yleptin levels no
significant effect on
adiponectin levels
Yacetic acid levels
[propionic acid levels no
significant effect on butyric
acid levels
[brachial FMD%
vs Control groupa
Randomised, T2DM patients with Intervention group (n=30): probiotic Yhs-CRP Raygan, et al.
double-blind, CHD supplements containing Bifidobacterium [TAC 2018 [101]
placebo-controlled 40–85 yr bifidum 23109, Lactobacillus casei 23109, [GSH
trial Lactobacillus acidophilus 23109 CFU/d
Placebo group (n=30)
12 wk
Randomised, Healthy or mildly Intervention (n=29): fermented milk Results among subjects Ito, et al.
double-blind, hyper-LDL- containing Streptococcus thermophilus YIT with baseline serum MDA- 2017 [146]
placebo-controlled cholesterolaemic 2001 (ST) LDL levels .median:
trial adults (serum LDL Control (n=30): non-fermented placebo YMDA-LDL, YMDA-LDL/
.100 mg/dL) milk LDL
20–64 yr 12 wk Results among subjects
with baseline serum MDA-
LDL levels ,median:
No significant effect on
MDA-LDL, MDA-LDL/
LDL
Randomised, T2DM patients Intervention group (n=23): 120 g/d of YTNF-a Tonucci, et al.
double-blind, 35–60 yr probiotic fermented goat milk containing Yresistin 2017 [103]
placebo-controlled 109 CFU of Lactobacillus acidophilus La-5 [faecal acetic acid
study and109 CFU of Bifidobacterium animalis No significant effect on IL-
subsp. lactis BB-12 10 and adiponectin serum
Placebo group (n=22): 120 g/day of levels
conventional fermented goat milk
contained Streptococcus thermophilus TA-
40
6 wk
Randomised, women Intervention group (n=21): probiotic [activity of glutathione Gomes, et al.
double-blind, with excess weight sachet containing Lactobacillus acidophilus peroxidase 2017 [112]
placebo-controlled, or obesity with a LA-14, Lactobacillus casei LC-11, [TNF-a
two arm, parallel- BMI 24.9–40 kg/m2 Lactococcus lactis LL-23, Bifidobacterium No significant effect on
group study 20–59 yr bifidum BB-06, and Bifidobacterium lactis cytokines, LPS, glutamyl
BL-4, 2*1010 CFU/d, 48.3% maltodextrin, transferase, activity of
24.21% modified starch, 24.21% xylitol, antioxidant enzyme SOD
and 0.97% silicium dioxide: 4 sachets/
day 1 a normocaloric diet
Placebo group (n=22): placebo sachet: 4
sachets/day a normocaloric diet
8 wk
Randomised, T2DM patients Intervention group 1 (n=25): synbiotic Synbiotic bread compared Bahmani, et al.
double-blind, 35–70 yr bread containing the probiotic to the probiotic and control 2016 [105]
placebo-controlled Lactobacillus sporogenes (1*108 CFU) and breads:
trial 0.07 g inulin per 1 g [NO, YMDA
Intervention group 2 (n=25): probiotic No significant effect on
bread containing Lactobacillus sporogenes plasma TAC, GSH,
(1*108 CFU) (3 times/day) catalase, liver enzymes,
Control group (n = 26): 120 g/d control calcium, iron, and
bread (3 times/day) magnesium levels and
8 wk blood pressure
vs Control groupa
Randomised trial Metabolic syndrome Intervention group (n=26): 80 mL of the YTNF-a Bernini, et al.
patients probiotic milk containing 3.4*108 CFU/ YIL-6 2016 [106]
18-60 yr mL of B. animalis ssp. lactis ssp. nov.
HN019.
Control group (n=25): untreated
45 d
Randomised, T2DM patients Intervention group (n=23): 300 mL/ No significant effect on Hove, et al.
double-blind, 40–70 yr d Cardi04 yogurt made from skimmed CRP, plasminogen 2015 [111]
placebo-controlled milk fermented by L. helveticus activator inhibitor-1, TNF-
trial Placebo group (n=18): 300 mL artificially a, tissue-type plasminogen
acidified milk containing glucono-d- activator: Ag, and von
lactone 1.75% Willebrand factor: Ag
12 wk
Abbreviations: CFU, colony forming units; TMAO, trimethylamine oxide; TNF-a, tumour necrosis factor-a; SOD, superoxide dismutase; GPx, glutathione
peroxidase; CIMT, carotid intima-media thickness; CHD, coronary heart disease; FOS, fructooligosaccharide; LPS, lipopolysaccharide; hsCRP, high-sensitivity
C-reactive protein; LAP, lipid accumulation product; VAI, visceral adiposity index; FMD, flow-mediated dilation; VCAM-1, vascular cell adhesion molecule 1;
ICAM-1, intercellular adhesion molecule 1; TGF, transforming growth factor; T2DM, type 2 diabetes mellitus; BMI, body mass index; LDL, low-density
lipoproteins.
a
Results showing between-group comparisons of intervention vs control groups otherwise indicated.
composition and/or characteristics, bacterial variance, and strains, which eventually leads to reduced pH and an altered
growth of beneficial bacteria [20,73]. Diet-related factors can gut microbiota community such as an elevated abundance of
influence the microbiota composition and also its meta- Lactobacillus and Bifidobacterium genera and diminished
bolism, particularly through serving as a source of fuel for pathogenic bacteria [24,73].
the bacteria [29]. However, there is still a long way to fully Specifically, resistant starches are known as the total
characterise the most efficacious dietary sources for the amount of starch plus the degraded starch, which are stable
microbiota [17,70]. in terms of digestion in the healthy individual’s small in-
testine and act like fibre in the human large intestine. These
Prebiotics agents can be fermented by microbial strains in the large
To be considered a prebiotic, a food ingredient should pre- intestine and produce carbon dioxide, methane, hydrogen,
dominately fulfil three main criteria: a) be stable in the and SCFAs as the end products. Resistant starches have been
presence of gastric acid and digestive enzymes, and resistant categorised into four general groups known as RS1 (resistant
to absorption by the upper parts of the GI tract (i.e., stomach starch-1, physically inaccessible in term of digestion), RS2
and small intestine); b) be fermented and metabolised by gut (native starch granules, which are ungelatinised with low
microbial strains, particularly in the colon; and c) selectively hydrolysation by a-amylases), RS3 (starch-derived materials,
trigger the expansion of gut beneficial bacteria, and/or which are nongranular), and RS4 (reduced digestibility
improve their abundance and activities, which could confirm through etherising, esterifying, or cross-linking with chem-
the beneficial roles of prebiotics in the host’s health icals) [76–78]. Their resistance to digestion in the small in-
[9,10,24,73,74]. According to these criteria, a range of carbo- testine varies, as RS4 has been shown to be stable against
hydrates, including fibres (i.e., hemicellulose, cellulose, xy- hydrolysis due to chemical modifications. These agents
lans, gums, inulin, and pectin) and non-digestible substrates might be water-soluble (such as resistant maltodextrins and
(e.g., resistant starches, galactooligosaccharides, glucooligo- Fibersol 2) or insoluble [75,77]. Elevation of the solubility of
saccharide, isomaltose, fructooligosaccharide, and lactulose), resistance starches seems to increase their prebiotic effi-
are listed among the well-known prebiotics. These plant- ciency. Resistant starches can be found in whole or partly
based prebiotics could be obtained from sugar beet, fruits, milled grains such as bread, pasta, potatoes, corn flakes,
vegetables, asparagus, onion, garlic, chicory, wheat, barley, green bananas, and some commercial food products with
and tomato [24,73,75]. As a type of indigestible carbohydrate, modified starches. About 30–70% of resistant starches are
fermentation of prebiotics, including fibres, fructooligo- reported to be absorbed in the large intestine, which yields
saccharide, and inulin, into short-chain fatty acids (SCFAs) high prebiotic capability [76–78]. Like other prebiotics,
and gas is performed in the large intestine by bacterial resistant starches are shown to be fermented by the intestinal
probiotic microbiota, particularly Lactobacilli and Bifidobac- bacteria like Lactobacillus and Bifidobacterium genera could
teria genera, which contribute to enhancing their growth. modify the intestinal microbiota and, as a result, the amount
Also, in the case of incorporating resistant starches to other of the SCFAs produced in the large intestine [84].
types of prebiotics such as fructooligosaccharides, their On the grounds that much literature has confirmed in-
synergistic effects in promoting the gut bacterial variety to- teractions between diet, host, and the microbiota, which is
ward these beneficial genera would be observed [77]. believed to play a key role in metabolic dysfunction and
Overall, the prebiotic efficacy of these indigestible food various chronic disorders as mentioned earlier, targeting the
ingredients depends on the type of substrates, location of pathways involved in these interactions, whether through
degradation in the GI tract, dose, solubility, and length of pharmacological interventions or dietary compounds such as
carbohydrate chain, which consequently determine the rate probiotics or prebiotics, is speculated to be most helpful
of fermentability of prebiotics. With increasing solubility, the [1,4,6,12,13,20,21,26–35,85]. With respect to this, a recently
rate of prebiotic capacity seems to be elevated. Thus, fructans published review noted that according to the evidence from
with a short chain length (fructooligosaccharides) have been meta-analysis, as the most reliable estimates of treatment
shown to possess an excellent prebiotic effect and b-glucan to effects, consuming some types of probiotic bacterial species
deliver high prebiotic efficacy. On the other hand, resistant could be promising in ameliorating risk factors for several
starches and inulin as long-chain carbohydrates with lower well-known atherosclerotic and cardiometabolic disorders
degradation and fermentation rate have been demonstrated [72]. These risk factors included increased BP, hyper-
to have lower prebiotic capability [77,78]. glycaemia, insulin resistance, and elevated total and LDL
cholesterol and triglyceride concentrations. These findings
Probiotics were particularly pronounced when consuming specific
As nonpathogenic microorganisms, probiotics are thought to bacterial genera such as Lactobacillus, Bifidobacterium, and
modify the gut microbiota composition through establishing Streptococcus salivarius subs. among younger patients and
colonies or implantation in terms of administration in those who were more likely to have higher serum levels of
adequate amounts; as such, the healthy intestinal bacterial these risk biomarkers, (e.g., those who had T2DM, HTN,
composition would be developed or restored. Although hypertriglyceridaemia, or hypercholesterolaemia) [72].
probiotics were first isolated from dairy products, vegetable- However, more studies are required to prove the most
derived probiotic strains have also been utilised in recent beneficial probiotic bacterial strains, their optimal dosages,
decades [6,9,10,72,74,79]. In addition to a growing number of and supplementation duration in these conditions.
probiotics strains that are on their way to being recognised as
health-protective agents, the best known probiotics strains in
the world market include: the Lactobacillus genus (especially
Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus para-
Review of the Recently Available
casei, Lactobacillus fermentum, Lactobacillus reuteri, Lactobacillus Evidence
plantarum, Lactobacillus rhamnosus, Lactobacillus salivarius,
Lactobacillus sporogenes, and Lactobacillus latis), Bifidobacterium Meta-Analysis Findings
genus (especially Bifidobacterium bifidum, Bifidobacterium The effects of probiotics on inflammation and oxidative
breve, Bifidobacterium infantis, Bifidobacterium lactis, Bifido- stress biomarkers have been an exciting area of research. The
bacterium longum, Bifidobacterium thermophilum, and Bifido- findings of the major meta-analyses exploring the impact of
bacterium longum), and Streptococcus genus (Streptococcus probiotics on inflammatory and oxidative stress biomarkers
thermophillus, Streptococcus fecalis, and Streptococcus lactis). In are summarised in Table 1. As acute reactants, the levels of
general, the estimated dosage of probiotics that may CRP [86–89] and high-sensitivity(hs)-CRP [90–92] were re-
accompany health benefits is approximately 106–108 colony ported to decrease with the ingestion of probiotics or syn-
forming units (CFU)/g or mL or 108–1010 CFU/day biotics. TNF-a levels were also shown to be lower following
[6,9,10,72,74,79]. Probiotic yogurts are mainly produced us- probiotics and/or synbiotic administration [80,86,88–90].
ing one or two bacterial strains (i.e., Lactobacillus acidophilus, Moreover, a meta-analysis of 42 controlled trials conducted
Lactobacillus reuteri, and/or Bifidobacterium lactis) [10]. To be by Milajerdi et al. demonstrated that levels of several in-
considered a qualified product, probiotics should have some flammatory markers, including IL-6, IL-12, and IL-4, were
prerequisites, including: a) having human origin and being significantly lowered by probiotic supplementation [90].
obtained from nonpathogenic bacterial strains; b) being sta- Regarding anti-inflammatory biomarkers, it was found
ble during the technological procedure and in the GI tract probiotic and/or synbiotic supplementation resulted in
when exposed to gastric acid and bile acids (BAs); c) pro- increasing levels of IL-10 [90], glutathione (GSH) [92–94], NO
ducing agents with antimicrobial activities; d) positively [86,92,95], total antioxidant status (TAS) [94], and total anti-
affecting the metabolic and immune function of the host (e.g., oxidant capacity (TAC) [92,95]. On the other hand, MDA
serum lipid profile and immune cells balance); and e) levels as an oxidative stress biomarker were shown to be
contributing to the formation of active substances such as lower in the placebo-receiving group [92,94,95]. Interestingly,
lactase, SCFAs, or vitamins [5,6,10,80–84]. Specifically, the Zamani et al. reported that the reduction in the MDA levels
current evidence has highlighted that several probiotic was more pronounced with an intervention duration of .8
Figure 3 Hypothetical immune protective, hypocholesterolaemic, anti-inflammatory, and anti-atherogenic effects of pro-
biotic supplementation.
Abbreviations: SCFAs, short-chain fatty acids; GI, gastrointestinal system; BSH, bile salt hydrolase; GLP-2, Glucagon-like
peptide-2; LPS, lipopolysaccharides; Ox-LDL, oxidised low-density lipoprotein; PCSK9, proprotein convertase subtilisin/
kexin 9; TMAO, Trimethylamine N-oxide; NF-kB, nuclear factor-kB; CRP, C-reactive protein; IL, interleukin; TNF-a, tumour
necrosis factor-alpha; MDA, malondialdehyde; BP, blood pressure; NO, nitric oxide; TAC, total antioxidant capacity; TAS,
total antioxidant status; GSH, glutathione; NADPH, nicotinamide adenine dinucleotide phosphate; TLR, toll-like receptor.
weeks and among those aged 50 years [95]. Similarly, factors mentioned above following probiotic or synbiotic
Zheng et al. showed that the improving effects of probiotics ingestion.
on MDA and TAC levels were more prominent with an
intervention duration of 12 weeks [92]. In a large meta-
analysis on 168 controlled trials performed by Kazemi Clinical Trials Findings
et al., it was noted that probiotic/synbiotic supplementation Several clinical trials have compared the anti-inflammatory
lowered TNF-a levels, particularly in IBD, cirrhosis, fatty and anti-oxidative efficacy of probiotics and/or synbiotics
liver, and healthy individuals; meanwhile, no changes were versus placebo (Table 2). Most of them reported superior
found among those with T2DM, metabolic syndrome, poly- efficacy of these supplements compared with the placebo-
cystic ovary syndrome, and arthritis [89]. Additionally, the receiving groups in reducing levels of hs-CRP, TNF-a, IL-6,
supplements were shown to decrease IL-6 levels, particularly IL-1b, IL-8, IL-12, MDA, vascular endothelial growth factor,
among those with metabolic syndrome and polycystic ovary thrombomodulin, VCAM-1, and PAI-1, while elevating
syndrome; in contrast, no changes in IL-6 levels were noted plasma NO concentrations [96–108]. A variety of bacterial
for healthy individuals and those with metabolic disorders genera, including Lactobacillus (e.g., Lactobacillus acidophilus
and arthritis. The levels of the anti-inflammatory cytokine IL- and Lactobacillus casei) and Bifidobacterium (e.g., Bifidobacte-
10 were reported to be moderately higher among arthritis rium lactis and Bifidobacterium bifidum) were reported to be
patients who received probiotics and/or synbiotics. In particularly useful in improving inflammation and oxidative
contrast, no change in IL-10 levels of healthy individuals, stress [96–99,101–103,106]. Interestingly, the dose-dependent
patients with IBD, and metabolic disorders was detected. effects of probiotics on vascular function-related biomarkers
The authors concluded that probiotic and/or synbiotic sup- and LPS levels have been previously indicated [96,97]. Szu-
plementation might be more effective as anti-inflammatory linska et al. evaluated the outcomes of probiotic sachets of
agents when administered in an augmented inflammatory nine bacterial strains, including: Bifidobacterium bifidum W23,
state rather than a healthy condition [89]. Bifidobacterium lactis W51, Bifidobacterium lactis W52, Lactoba-
However, a number of previous meta-analyses have re- cillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus
ported that there is no difference in inflammatory or oxida- casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19,
tive markers between those receiving probiotics or synbiotics and Lactococcus lactis W58 probiotics in a low dose (2.53109
compared with placebo. These reports include a study on CFU, twice a day) (n=24) or a high dose (131010 CFU, twice a
CRP levels [81], a survey of TNF-a levels [91], two studies on day) (n=23) against placebo (n=24) among obese post-
IL-6 concentration [86,88], a study on IL-8, IFN-g, and IL-17 menopausal female subjects (Table 2). This 12-week clinical
levels [90], two studies on IL-1b concentrations [89,90], a trial showed that high-dose probiotic sachet consumption
survey of TAC level and activity of SOD [93], and a study on resulted in lowering LPS, IL-6, TNF-a, thrombomodulin, and
GSH [95], which all failed to find significant changes in the endothelial function biomarkers, including pulse wave
analysis, pulse pressure, pulse wave analysis augmentation combinations of different probiotic strains, the time duration
index, pulse wave velocity, and vascular endothelial growth that the beneficial effects of probiotics may remain, as well as
factor in a greater magnitude compared with low-dose sa- the supplements’ safety levels should also be well-described.
chets and a placebo group. In contrast, low-dose probiotics Given that the gut microbiota of each subject is thought to be
only reduced IL-6 levels and failed to affect LPS [96,97]. specific and exclusive, there is a need for considering vari-
However, it should be noted that the effects of probiotics ability between subjects when it comes to investigating
and/or synbiotics on some vascular function and inflam- individualised responses to the probiotic strains that are
matory markers are still controversial [99,108–112]. For used. This issue also needs to be elucidated in additional
example, in a non-randomised trial on 20 males who had metabolomics studies, in which the expression of micro-
stable CAD, it was reported that consuming 27 oz/day of a RNAs linked to genes associated with bacterial-derived
drink with Lactobacillus plantarum 299v for 6 weeks led to metabolites (i.e., SCFAs, LPS, TMA, and TMAO) in
reductions in plasma levels of acetic acid, IL-8, and IL-12, response to probiotic supplements and strain-specific effects
while no significant effects on plasma IL-1b, TNF-a, IFN-g, with regard to the gut microbial diversity are explored. Also,
transforming growth factor (TGF)-b, ICAM-1, VCAM1, and investigating the impact of supplementation with various
TMAO levels were noted [108]. Few trials have indicated no probiotic strains on the host metabolic, immune, and in-
significant differences in levels of hs-CRP [109,110], IL-6 flammatory pathways, in addition to gut microbiota function
levels [110] or IL-10 levels [103] following probiotic or syn- and its related mechanisms including SCFAs, and TMA/
biotic supplementation. In another trial, T2DM subjects were TMAO synthesis pathway, and LPS reciprocal relationship
randomised to an intervention group (n=23) (received 300 with LDL co-receptor, and proprotein convertase subtilisin/
mL Cardi04 skimmed yogurt fermented by Lactobacillus hel- kexin 9 (PCSK9) are required to extend the present knowl-
veticus) or placebo group (n=18) (received 300 mL artificial edge on the topic.
acidified milk containing glucono-d-lactone 1.75%) for 12
weeks. The researchers reported that Cardi04 did not
significantly change CRP, PAI-1, TNF-a, tissue-type plas- Potential Mechanisms Attributed
minogen activator: Ag, and von Willebrand factor: Ag [111].
Although the majority of clinical studies found statistically
to the Protective Effects of
significant effects of probiotics and/or synbiotics on chang- Probiotics Against Inflammation,
ing inflammatory and oxidative markers, few studies failed
to show positive results of these agents on increasing the
Endothelial Dysfunction, and
activity or concentrations of antioxidant factors such as TAC Atherosclerosis
[99,100,105], GSH [99,105], catalase [105], or glutamyl
transferase and SOD [112]. An Overview on the Metabolic Activity of
Gut Microbiota
Intestinal bacteria have been demonstrated to produce a
Limitations and Challenges of the
variety of vitamins, including vitamin B groups (thiamine,
Available Evidence riboflavin, nicotinic acid, biotin, pantothenic acid, pyri-
Collectively, the currently available clinical evidence has a doxine, folate, and cobalamin) and vitamin K, as well as
number of limitations, making it difficult to draw a correct antimicrobial agents in the host, including C-type lectins
and comprehensive conclusion. Despite the beneficial impact and cathelicidins [13]. An emerging body of evidence has
of various probiotic supplements, no consistent data are highlighted the influence of intestinal microbiota on meta-
available for identifying the most effective probiotic bacterial bolic alterations, which is mainly imposed through the
strains, their exact dosage, and the rate of effectiveness. changes in the metabolic function of the host and inflam-
There is also a lack of analysis of gut microbiota character- matory status [67]. It has also been confirmed that the
istics, and most studies have used various combinations of occurrence of intestinal dysbiosis under any condition will
bacterial strains. There is a lack of comparing the effects of eventually result in disturbances in metabolic profile [64]. A
some strains alone or in combination with other strains large-scale metagenomics-based study investigated the
within the same population to detect strain-specific effects. probable link between 231 metabolites and microbial spe-
Moreover, the currently performed clinical trials–particularly cies in the plasma and pathways in individuals from
on endothelial dysfunction, microbiota function, and specific population-based and clinical obesity cohort studies. It was
biomarkers of atherosclerotic lesions–seem inadequate to found that the gut microbiome may be responsible for
give a holistic insight into the effects of probiotics on the approximately 11–16% variation in metabolites that are
pathways that lead to atherosclerosis. Finally, lack of con- present in the plasma, regardless of the effects of con-
sistency across studies is one of the other limitations. founding factors such as age, gender, and body mass index
Therefore, the studies performed so far to elucidate the [85]. It has also been suggested that metabolic pathways
mechanistic roles of probiotics in altering various metabolites related to intestinal bacteria may contribute to an elevated
and biomarkers involved in endothelial dysfunction and risk of developing cardiovascular events later in life, mainly
atherosclerosis are still in their infancy. Using diverse via the metabolites produced by bacterial fermentation of
carbohydrate, oligo, and polysaccharide fibre and resistant of cholesterol 7a-hydroxylase (CYP7A1) [19,53]. This event is
starches, as well as metabolism and catabolism of other accompanied by increasing plasma cholesterol uptake by the
nutrients including amino acids [85]. In addition, the rela- liver due to using higher amounts of cholesterol in the pro-
tionship between gut microorganisms and plasma clinical cess of denovo BAs synthesis [19]. On the other hand, as a
and plasmatic measurement biomarkers of metabolic func- pro-atherosclerotic condition, dysbiosis could result in the
tion such as lipid markers lipoprotein particle constitutional diminished activity of BSH; therefore, it may directly disturb
structure (i.e., VLDL and LDL), glycoprotein N-acetyls, and the cholesterol elimination procedure and intensify athero-
saturation of fatty acid, liver fat content, and atheroscle- sclerotic plaque generation [6,10,24,53,117].
rosis, particularly among obese individuals, was shown in Various probiotic genera, including Lactobacilli and Bifido-
the above-mentioned metagenomic study. Specifically, the bacteria, have been demonstrated to potentially trigger/have
relationship between these metabolites (e.g., biosynthesis of BSH activity and deconjugate BAs. Interestingly, the decon-
bacterial L-methionine) and CVDs is confounded by diet jugated BAs in the presence of probiotics have been shown to
and inflammatory status. This issue paves the way for be less soluble and absorbable by the intestinal cells, which
future interventional trials and prospective experiments results in increasing their faecal excretion [10,53,72,117–120].
concerning compounds with the capability of modifying These events would cause more amounts of cholesterol to be
microbiome-related pathways [85]. consumed during denovo BAs production; hence, serum
Briefly, recognising the link between some metabolites cholesterol levels decrease. Curiously, having potential BSH
produced following the metabolic activity of the gut micro- activity has recently been considered a factor for selecting
biota such as LPS, TMA, and TMAO and atherosclerosis appropriate probiotics with hypocholesterolaemic features. In
development in recent years could at least partially highlight this regard, lactic acid bacteria with BSH activity have been
the potential causative influences of changes in gut micro- suggested as being the most appropriate probiotics used in the
biota features on CVDs [27,67]. case of hypercholesterolaemia. These issues correlate well
with previous findings on cholesterol-lowering impacts
Metabolic Activity of Probiotics following probiotic administration [10,53,72,117–120]. There
might also be some other explanations for hypocholester-
The current evidence has found that probiotics might be able
olaemic and anti-atherogenesis effects of probiotics, including
to modulate metabolites produced by microbiota and
enhancement of the production of SCFAs in the intestine and
thereby could experimentally affect the risk of atheroscle-
promoting reverse cholesterol transport and cholesterol efflux
rosis, thrombosis, and thrombogenesis. The suggested
in the macrophages via triggering liver X receptor pathway
mechanisms by which probiotics might influence endothelial
activation. These effects were mainly observed following
function, arterial injury, and platelet function include
Lactobacillus acidophilus administration, which subsequently
affecting factors involved in pro-inflammatory and innate
causes activation of the anti-inflammatory and anti-foam cell
immune signalling pathways such as hepatic TLR2 signal-
processes, thereby lowering cholesterol concentrations. Pro-
ling, modulating platelet deposition mediated by the inter-
biotics might additionally shorten the absorption of choles-
action between prothrombotic factors such as von
terol in the intestine or increase its faecal excretion through
Willebrand factor binding to platelet integrins, and reducing
direct binding to intestinal cholesterol, consuming it via
cholesterol concentrations [69,72,113–116]. Figure 3 demon-
cholesterol internalisation into bacterial cells, or promoting its
strates the hypothetical immune-protective, hypocholester-
metabolisation to coprostanol [10,19,26,80,84,117]. However,
olaemic, anti-inflammatory, and anti-atherogenic effects of
more investigations are still needed in order to clarify the
probiotic supplementation.
exact anti-atherogenic and hypocholesterolaemic mechanisms
Bile acids of probiotic ingestion.
Cholesterol is metabolised into BAs in the liver; therefore,
BAs are products with a crucial role in cholesterol catabolism Short-chain fatty acids
Short-chain fatty acids (SCFAs), the end-products of large
and excretion in the small intestine. Notably, the intestinal
intestine bacterial fermentation of plant polysaccharides and
microbiota profile positively influences the metabolism of
complex carbohydrates (e.g., fibre), could certainly be
BAs, particularly via regulating the actions of bacterial
involved in regulating the host homeostasis, energy, and
bile-salt hydrolase (BSH). Bile-salt hydrolase deconjugates
nutrient metabolism, inhibiting hepatic cholesterol produc-
BAs into secondary BAs, which are recognised as having
athero-protective impacts through increasing faecal choles- tion, as well as modulating cholesterol and BAs metabolism
terol excretion and decreasing its concentrations [6,24,53]. and transportation [1,13,20,26,28,71,84]. SCFAs concentra-
Given that augmented levels of BAs could be toxic, the tion in the large intestine is affected by genetic and envi-
Farnesoid X receptor of the liver plays a particular role in ronmental factors, including the microbial profile and
modulating the recycling procedure of conjugated BAs in the bacterial variety, in addition to dietary substrates. An
proximal and distal ileum, and their reabsorption into the imbalance in the gut beneficial and opportunistic bacteria
liver portal circulation, which is known as enterohepatic and the resultant reduction in the abundance of SCFAs-
circulation. BAs might trigger the activation of the liver producing bacteria were among the reported changes
Farnesoid X receptor, leading to suppressing the expression observed in inflammatory-related chronic disorders such as
IBD, irritable bowel syndrom (IBS), obesity, and type 2 dia- cell differentiation enhancement, as well as regulating the
betes mellitus (T2DM) [84]. secretion of cytokines from these cells [121]. It has been
In addition to being a source of energy for enterocytes and demonstrated that butyrate and propionate could suppress
colonocytes, SCFAs are thought to strengthen the large in- the NF-kB pro-inflammatory signalling pathway and
testine mucosal defence, attenuate mucosal inflammation, downregulate TNF-a and nitric oxide synthase (NOS)
and abolish pathogenic bacterial growth by decreasing the expression in neutrophils and monocytes following cells
intestinal pH. Interestingly, these metabolites appear to in- being exposed to LPS [121]. Stimulating specific cell signals
fluence appetite and metabolism control [1,13,20,26,28,71,84]; through suppressing deacetylation of histone and improving
for example, propionate has been reported to enhance b-cell the secretion of IL-10 as an anti-inflammatory mediator are
function and reduce reward-related eating. Additionally, among the other suggested mechanisms of SCFAs anti-
SCFAs might affect the immune system development and inflammatory effects. SCFAs have been shown to be pleio-
function (e.g., regulatory T cell differentiation) throughout tropic, having both pro-inflammatory and anti-inflammatory
the GI tract. These compounds might also play a role in effects [121]. The dominance of either effect may possibly
alleviating inflammation and atherosclerotic lesion develop- depend on the cell on which SCFAs receptors are expressed:
ment, modulating BP and large intestine arterial resistance for example, target receptors including G protein-coupled
enhancement via vasodilator effects, leading to enhanced receptor GPR109A (which seems to contribute to anti-
microcirculation. Moreover, enhanced acetate secretion in the inflammatory and immune modulatory effects), free fatty
gut microbiota might contribute to parasympathetic nervous acid receptor 2/3, and the amount of SCFAs around the
system stimulation, which may modify insulin release location are among the possibly determining factors. How-
induced by glucose, obesity, and excessive eating ever, more intense in vivo studies are required to clearly
[1,13,20,26,28,71,84]. It has been demonstrated that the explore these effects [32,84,121].
butyrate might diminish the translocation of gut bacteria,
which can influence the production of mucin and tight SCFAs and endothelial function. Beside affecting the func-
junction construction and, therefore, improve the epithelial tion of immune cells, SCFAs and particularly butyrate are
cell barrier. Also, acetate and butyrate are thought to induce additionally proposed to modify endothelial cell function,
lipogenesis, whereas gluconeogenesis might be stimulated promote the anti-inflammatory signalling pathways of the
by propionate. Elevated liver lipogenesis is accompanied by endothelium, and lower the release of mediators involved in
an augmentation in the blood levels of VLDL. In addition, it oxidative stress or pro-inflammatory state that eventually
is of note that SCFAs might also be used as a precursor for lead to attenuating inflammation in the vasculature, mainly
cholesterol and fatty acid synthesis in the GI system via suppressing histone deacetylase and the NF-kB signalling
[4,13,24,84]. pathway [80,107,121–123]. These processes are described in
Several probiotic bacterial strains have been identified as detail in the following sections.
being involved in generating SCFAs and lactic acid, which
exhibit immunomodulatory properties. According to a Anti-Inflammatory and Antioxidant
recently published review article, Bifidobacterium spp. was Activity of Probiotics
shown to provoke acetic and lactic acid production; Lacto- Augmented inflammatory responses and impaired immune
bacillus rhamnosus GG and Lactobacillus gasseri PA 16/8 could function, at least partly as consequences of gut microbiota
stimulate acetic, propionic, and lactic acid generation; Bifi- dysbiosis, are among the main mechanisms involved in
dobacterium longum SP 07/3 and Bifidobacterium bifidum MF 20/ atherosclerosis initiation and progression. Oxidative stress
5 could provoke acetic, propionic, and lactic acid production; and impaired mitochondrial function, in which high levels of
Lactobacillus salivarius spp. salcinius JCM 1230, and Lactoba- ROS and reactive nitrogen species are produced, may also
cillus agilis JCM 1048 were reported to increase the generation have an impact on atherosclerosis processes [39]. Raised ROS
of propionic, butyric, and lactic acid; Lactobacillus acidophilus and reactive nitrogen species secretion through oxidative
CRL 1014 appeared to induce the production of acetic, pro- stress could provoke inflammation, endothelial disturbances,
pionic, butyric, and lactic acid; and Lactobacillus casei Shirota Ox-LDL concentration, DNA damage, cell proliferation,
was observed to elevate the total SCFAs and propionic acid migration, autophagy, and necrosis, induce stress in endo-
levels and the faecal abundance of Bifidobacterium spp. and plasmic reticulum endothelium, as well as stimulate plaque
acetic acid. However, the exact mechanisms by which pro- development and advancement. In addition, pro-
biotics increase the production of SCFAs have not yet been inflammatory and pro-oxidant substances such as TNF-a,
well-defined [84]. CRP, ILs-1, ILs-6, ILs-8, ILs-1b and ILs-18, MCP-1, ICAM-1,
inducible NO synthase (iNOS), and VCAM-1 are secreted
SCFAs and inflammation. Specifically, the modification of within this process subsequent to activating some tran-
immune and inflammatory status by SCFAs is thought to be scription factors, including NF-kb [39]. According to the
explained through the effects of these metabolites on mentioned details, long-term increased inflammatory re-
lowering immune cell recruitment and migration, including sponses, as indicated by elevated secretion of these pro-
dendritic cells, macrophages, neutrophils, and T cell and B inflammatory agents, have been linked to various events
contributing to coronary artery disease (CAD) pathophysio- Probiotics, Endothelial Dysfunction and
logical processes such as atheromatous plaque and rupture Elevated Blood Pressure
development and advancement [37,39,122,123]. The intesti-
The endothelium is a membrane with selective translocation
nal bacterial composition may significantly impact the sig-
ability of fluid and solutes, in addition to other substances
nalling pathways that contribute to inflammatory and
such as inflammation-related products. It also can secret
immune responses. These responses primarily include pro-
various factors such as NO and prostacyclin (as vasodilators)
inflammatory NF-kB transcriptional factor, pro-atherogenic
and ROS, endothelin, angiotensin II, and endothelium-
natural killer T lymphocytes, and immune cell formation
derived hyperpolarising factor (as vasoconstrictors), which
(e.g., lymphocytes and macrophages) that ultimately lead to
in turn affect vascular tone, thrombosis, platelet aggregation,
atherosclerotic development [27]. Also, increased tissue
inflammation, and immune function [21,39,126–130]. When
activities, as well as high serum levels of metabolic endo-
the normal function of the endothelium is disrupted, a pro-
toxaemia (or LPS) induced by dysbiosis are among the well-
inflammatory state, oxidative stress, disturbances in endo-
known contributors to raised inflammatory factor secretion,
thelial and inducible NO synthase (eNOS and iNOS) enzyme
which in turn are associated with atherosclerosis progression
activity, and subsequent attenuated NO formation occurs. It
[41,42,52,80,124]. On the other hand, the levels of the above-
should be noted that reduced NO formation by eNOS seems
mentioned pro-inflammatory factors were found to be low-
to be additionally related to endothelial dysfunction
ered following probiotic consumption, particularly in the
[21,39,126–130]. On the other hand, augmented iNOS activity
context of a higher inflammatory state [80,86,88–90,96–108].
and the resultant accumulated NO release might cause pro-
Interestingly, the anti-inflammatory effects of probiotics
inflammatory and pro-atherogenic responses to be initiated.
might be dose-dependent [96,97].
Elevated production of ROS in hypertensive, hyper-
These protective effects of probiotics might be mediated
cholesterolaemic, diabetic patients, or those with other car-
through increasing bacterial variety of the intestine and pro-
diometabolic risk factors induces endothelial NO activity
voking the secretion of immunomodulatory metabolites such
reduction. These events could ultimately lead to disturbed
as SCFAs (particularly butyrate), histamine, and S-layer pro-
heart rate variability, HTN, and atherosclerosis development
tein A [80,84,107,122,123]. Increased bacterial variety and these
[21,39,126–130]. With respect to this, a large body of evi-
metabolites particularly seem to lower monocytes and the
dence, particularly from animal studies, has proposed that
activated endothelium, sticking to each other. Decreased
intestinal microbiota alterations play a role in HTN patho-
expression of pro-inflammatory agents and molecules
genesis [31–35].
involved in cell adhesion (e.g., Ox-LDL,TNF-a, IL-6, ICAM-1,
Curiously, shotgun metagenomics analysis of faecal sam-
VCAM-1,E-selectin, E-cadherin, and E-catenin) by suppressing
ples of subjects with elevated BP demonstrated alterations in
the NF-kB signalling pathway, pro-inflammatory T cells, in-
the taxonomic and functional properties of their gut micro-
testinal barrier cells apoptosis, and LPS formation are among
biota, such as some changes in butyrate formation, compared
the other mechanisms by which increased bacterial variety and
to reference individuals [31]. Roseburia, Eubacterium, Eubac-
the metabolites produced by probiotics could abolish inflam-
terium rectale, Butyricicoccus, Butyricimonas, Anaerostipes,
mation [80,107,122,123]. Probiotics have also been shown to
Coprococcus, Faecalibacterium, Subdoligranulum, and Fuso-
potentially impact strengthening of the gut barrier integrity,
bacterium were among the identified butyrate-generating
thereby lowering the increased intestinal permeability to me-
bacterial strains, with Eubacterium rectale as the major
tabolites, with potentially pro-inflammatory effects via adhe-
butyrate-generating bacterium of the gut. Higher capacity of
sion to intestinal mucosa as a requirement for colonisation
generating bacterial butyrate has been found to contributed
modulating the immune system [26].
to lower SBP [31]. Increased concentrations of various gut
Moreover, probiotics have also been shown to enhance
microbiota metabolites such as LPS, Zonulin as well as T
the expression of anti-inflammatory factors such as IL-10
helper 17 proinflammatory cells in these patients have
through affecting on and binding to the receptors
further indicated the presence of an augmented pro-
on the intestinal dendritic cells as well as regulatory
inflammatory state in the intestine and intestinal epithelial
T cells and acting on the TLR9 signalling pathway
barrier dysfunction [31]. In another report, it was also noted
[80,89,90,103,122,123]. Further, elevated secretion, activity,
that the distribution of SCFA propionate-producing bacterial
and serum levels of antioxidant factors, including GSH,
species might be lower in the intestine of hypertensive sub-
TAS, and TAC, as consequences of supplementation with
jects [34]. Propionate has been noted to have antihyperten-
probiotics [86,92–108] are mediated by increased large in-
sive and anti-inflammatory, and immune protective features
testine SCFAs production, especially butyrate. Other anti-
in addition to ameliorating atherosclerotic lesion burden
oxidant effects of probiotics include lowering pathogenic
through improving T helper cell homeostasis toward regu-
bacterial composition, enhancing intestinal polyphenol ab-
latory T cells that eventually lead to enhancement in cardiac
sorption and activation, and forming various vitamin B
function and protecting against CVDs progression in hy-
groups with potentially antioxidant features [93,95,125].
pertensive mice [34]. Regarding dietary interventions,
Increased oxidation of lipids, as indicated by augmented
deprivation of prebiotic fibre compared with a high prebiotic
MDA levels, has also been reported to be attenuated by
fibre diet in mice with or without the addition of SCFA
probiotic ingestion [84,92,94,95].
increased the probability of HTN development when the thrombosis, and protect against platelet aggregation medi-
mice were exposed to a mild hypertensive stimulus and ated by the effects of NO on NF-kb expression inhibition
consequently developed cardiac remodelling [32]. These [39]. Probiotics may also affect the regulation of the renin-
adverse effects of fibre-deprived diets on gut microbial angiotensin system; its association with gut microbiota
characteristics, cardiovascular health, and hypertension dysbiosis and probiotic supplementation is described in the
(HTN) seem to depend on reducing gut microbiota metab- following sections.
olite production, SCFAs, and subsequent disruption in the
mucus barrier of the large intestine and promoting growth of Probiotics and Renin-Angiotensin System
pathogenic microorganisms in addition to immune function
Regarding the roles played by gut microbiota in immune and
signalling pathways [32,33].
inflammation status, there are extensive shreds of evidence
Probiotics have also been linked to improving endothelial
obtained on the basis of the results in the studies on depleted
structure and function. With respect to this, in vitro experi-
gut microbiota in germ-free mice. In this respect, it has been
ments have shown long-term probiotic administration, with
mentioned that commensal microbiota depletion may be
Lactobacillus fermentum or Lactobacillus coryniformis and
involved in attenuation of HTN and vascular dysfunction
Lactobacillus gasseri, VSL#3, probiotic kefir, and Lactobacillus
due to the angiotensin II pathway, perhaps through sup-
fermentum possibly enhancing endothelial dysfunction
pression of immune cells, oxidative stress, and inflammatory
through the recovery of intestinal symbiosis and attenuating
factor accumulation in the vasculature [137]. These results
vascular inflammation and oxidative stress caused by LPS
have additionally emphasised the commensal role of micro-
release into the circulation [21]. Human trials have addi-
biota in the changes of systemic inflammation caused by
tionally indicated the positive effects of probiotics on various
angiotensin II, which may indicate its effects on BP elevation
factors that have contributed to endothelial dysfunction,
in vivo [137]. On the flip side, based on an experimental
including: elevated BP, vascular endothelial growth factor,
model of HTN due to mineralocorticoid excess, a fibre-rich
pulse wave velocity, and inflammatory cytokines
diet has been demonstrated to be effective in modifying the
[21,89,92,96,97,126,131,132]. There is also some clinical evi-
gut microbial composition and ameliorating inflammation
dence that has shown promising reports on the effects of
and gut dysbiosis, as marked by a reduced ratio of Firmi-
probiotic administration on BP [96,97,104,133]. In an 8-week
cutes phylum to Bacteroidetes phylum. In addition, attenu-
RCT on pre-HTN patients, Beltrán-Barrientos et al. showed
ated renin-angiotensin system activation and lowering SBP
that the intervention group who received fermented skim
and DBP levels, and cardiac function improvements have
milk containing Lactococcus lactis NRRL B-50571 (n=18) or
been reported following consumption of a fibre-rich diet [35].
acidified milk had lower levels of systolic and diastolic blood
These cardioprotective effects of fibre as a prebiotic com-
pressure (SBP and DBP) at the end of the fifth week of the
pound have been shown to be mainly imposed through
study compared with the control group [133]. Further, in a
promoting the abundance of bacterial species producing
12-week randomised controlled trial (RCT) on obese post-
SCFA acetate as a key metabolite of gut microbiota, which
menopausal females, the intervention groups received either
influences several molecular pathways involved in cardio-
high doses or low doses of probiotic sachets with nine bac-
vascular function and especially BP [35].
terial strains, including Bifidobacterium bifidum W23, Bifido-
In addition, probiotics are likely to influence the renin-
bacterium lactis W51, Bifidobacterium lactis W52, Lactobacillus
angiotensin system, with angiotensin-converting enzyme
acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei
having an essential effect on BP regulation and water (fluid)
W56, Lactobacillus salivarius W24, Lactococcus lactis W19, and
balance [1,10,53,71]. Vasoconstriction caused by angiotensin
Lactococcus lactis W58. High-dose probiotic sachet consump-
II can lead to BP elevation through inducing aldosterone
tion resulted in improved SBP and vascular function bio-
markers in greater magnitude compared with the low-dose release, augmentation of sodium concentration, and inacti-
sachets and placebo group. However, neither a low dose nor vation of bradykinin, a potent vasodilator. Therefore, sup-
high dose of the probiotic supplements imposed any signif- pression of angiotensin II synthesising enzyme is considered
icant changes on diastolic blood pressure (DBP) [96,97]. a critical target for lowering BP. In contrast, fermentation
Similar to probiotic supplements, consuming probiotic could secret bioactive peptides with angiotensin-converting
yogurt containing C. ficifolia by T2DM patients also lead to enzyme-suppression features. For instance, fermented milk,
reducing both systolic blood pressure (SBP) and DBP soy milk, cheese, yogurt, and recombinant Lactobacillus
compared to the control group [104]. There are, however, plantarum, and Lactobacillus helveticus CP790 are products
controversial reports on the effects of probiotic strains on BP fermented by specific microbial strains and known as
[108,109,111,134–136]. angiotensin-converting enzyme suppressors peptides.
Probiotics have also been found to enhance endothelial Hence, dairy products, including bacteria-fermented milk
function by elevating NO levels and its bioavailability proteins accompanied by the particular probiotics, appear
[21,86,92,95–108,126]. As a specific anti-inflammatory to be appropriate agents with BP-lowering potential
vasodilator, NO is also thought to reduce BP, halt [1,10,53,126].
The Effects of Probiotics on Dysbiosis to thrombosis, atherosclerosis, and consequently CVDs pro-
Injurious Metabolites That May Be gression, the effects of gut microbes on augmented thrombo-
genesis and heightened activation of platelets, as mainly
Involved in Inflammation and indicated by increased TMAO production, become much more
Atherosclerosis important and worthwhile intensive considerations
Trimethylamine oxide [4,11,19,20,24,27,28,37,58,64,69,71,113,138–140].
The presence of choline, betaine, crotonobetaine, glycer-
Probiotics and TMAO
ophosphine, phosphatidylcholine, and L-carnitine, derived Modifying the gut microbiome through applying supple-
from red meat, enable some bacterial strains in the gut to ments or food items containing single or multi-strain
generate trimethylamine or TMA, which oxidise to trime- probiotics might enhance the beneficial or harmful bacte-
thylamine oxide or TMAO by flavin-containing mono- rial balance in the gut and, consequently, lead to sup-
oxygenase 3 (FMO3) in hepatocytes and are secreted into the pression of the TMA/TMAO synthesis pathway or
circulatory system. Several factors, such as the gut integrity reduction in the abundance of TMA-producing microor-
and microbiota composition, diet, activity of hepatic en- ganisms [20,57,58,64,69,142]. Interestingly, targeting
zymes, and the rate of methylamine excretion, might deter- microRNAs or inhibiting the activity of precursors and
mine TMAO levels in the blood. Mostly, Clostridiaceae and specific enzymes in this pathway, including TMA lyases,
Peptostreptococcaceae bacterial strains have been reported to and lowering TMA-generating species using anti-
play a significant role in metabolising the mentioned pre- inflammatory agents, particularly probiotics, have been
cursors to TMA and elevating TMAO levels in the plasma introduced as novel approaches in atherosclerosis pre-
[4,11,19,20,24,27,28,37,57–63,71,113,138–140]. vention; however, the studies in this regard are at their
A growing body of evidence has strongly linked accelerated infancy and the consequences of probiotic administration
levels of TMAO to insulin resistance, HTN, atherosclerosis, on serum TMAO levels are not yet clearly understood
myocardial injury, heart failure progression, acute coronary [20,57,58,64,69,142]. According to the available experi-
syndromes, and other CVDs, leading to high morbidity and mental data, probiotics are thought to remodel the human
death rates due to these conditions. Moreover, TMAO might intestinal microbiota and lower TMAO-associated athero-
play a role in physiological or functional cardiac remodelling, sclerosis. However, this effect might be supposed to be
leading to weakening ejection fraction. It has also been noted strain-specific. As such, among different bacterial strains,
that augmented plasma TMAO levels might help anticipate the cumulative evidence has indicated that Lactobacillus plan-
incidence of thrombotic events (e.g., stroke, heart attack) risk tarum ZDY04 and Enterobacter aerogenes ZDY01 could
during 3 years [4,11,19,20,24,27,28,37,58,64,69,71,113,138–140]. improve dysbiosis and lower TMAO levels in plasma
Mechanistically, TMAO has been linked to atherosclerotic [19,142]. In contrast, some other bacterial strains, including
plaque generation, vascular endothelium activation, inflam- Lactobacillus casei Shirota, Bifidobacteria longum (KB31),
mation, and ROS secretion. In particular, TMAO accumulation Streptococcus thermophilus (KB19), and Lactobacillus aci-
is shown to trigger nucleotide-binding oligomerisation dophilus (KB27) have failed to significantly affect TMAO
domain-like receptors, TLRs, and NF-lB signalling pathways, concentrations. However, the results of human studies
raise the expression of macrophage LDL receptors, modulate have not been conclusive to date [24,108].
macrophage activity in the intestine, and disturb gut integrity.
Additionally, it may suppress reverse cholesterol transport in Lipopolysaccharide
macrophages and disrupt lipid homeostasis. It has also been In the presence of dysbiosis, the intestinal barrier integrity is
proposed that TMAO could reduce plasma phospholipids and disturbed and the expression of proteins involved in the in-
high-density lipoprotein levels, and disrupt fatty acid beta- testinal tight junctions are altered. As depicted in Figure 2,
oxidation, metabolism of cholesterol and sterol in the liver, the outflow of numerous injurious substances–including
glucose metabolism, and hepatic enzyme functions bacteria and their metabolites such as peptidoglycans, LPS,
[4,11,19,20,24,27,28,37,58,64,69,71,113,138–140]. TMA has been and choline–from the gut into the circulatory system and
shown to enhance platelet deposition due to integrin pathway accelerated activity of the TMA/TMAO synthesis pathway
activation stimulated by adenosine diphosphate. TMAO is also might intensify the pro-inflammatory state, reverse choles-
thought to affect prothrombotic pathways and arterial terol transport and foam cell generation as consequences of
thrombus growth, most likely by accelerating von Willebrand dysbiosis, and disturb immunomodulatory actions of the
factor production via stimulating TLR2 signalling in the liver intestinal microbiota [4,6,11,28,46,47,71].
endothelial cells in addition to triggering intracellular signal- Among various gut microbiota-derived metabolites, LPS or
ling pathways and increasing Ca21 secretion. These events endotoxin, a constituent of the cell wall of Gram-negative
could ultimately lead to activation of platelets [58,64,69,141]. It bacteria, is believed to trigger innate immune responses and
is noteworthy that the accelerated platelet activity and expression of pro-inflammatory mediators such as NF-kB,
thrombosis-inducing effects of TMAO, which have been shown TLRs, and B cell-related pathways, which could ultimately
to be expeditious, were curiously reported to be reversible [58]. stimulate atherosclerosis development. In the normal state,
Considering the contribution of augmented platelet reactivity LPS cannot penetrate the circulatory system in large amounts
due to the ‘healthy intestinal barrier’, while in the dysbiotic evidence concerning the pro-atherogenic roles of these sub-
condition, in which this barrier’s function is disturbed and the stances in CVDs onset and progression [40,143].
permeability of the intestine consequently increased, high
Probiotics and metabolic endotoxaemia
levels of bacterial-generated LPS have been observed
In particular, the administration of Bifidobacteria and
[1–4,7,20,21,28,38,54,64,71]. In addition to activation of TLRs,
Lactobacillus spp. has been reported to promote growth of
the other particular mechanism by which LPS exerts these
beneficial bacterial strains, the function of the intestinal
effects may involve the CD14-dependent pathway, a specific
barrier, and diminish endotoxin levels, which might be
receptor of LPS that regulates sensitivity to insulin. Therefore, finally related to suppressing CVDs progression [28,144].
LPS-augmented concentrations would be able to affect the Although the mechanisms by which probiotics impose
development or progression of chronic metabolic disorders these favourable effects are not recognised, some direct and
such as obesity, T2DM, and CVDs complications indirect mechanisms have been proposed [19,28]. It seems
[4,6,11,28,46,47,71]. In recent decades, the contribution of that reinforcement of epithelial cell tight junctions by pro-
metabolic endotoxaemia to endothelial disturbances and the biotics, mainly through triggering secretion of GLP-2, could
occurrence of inflammatory diseases like atherosclerosis and ultimately lead to inhibition of production of injurious or
other types of CVDs have gained attention [4,6,11,28,40,71]. In pro-atherogenic agents (e.g., TMA/TMAO synthesis
addition to the reports indicating LPS presence in atheroscle- pathway) and outflow of some of these metabolites into
rotic plaques, it has also been observed that this agent may the systemic circulation (e.g., LPS) [19,28,80]. Interestingly,
play a major role in thrombosis of vessels by triggering the available evidence has linked elevated endogenous
platelet activation [40]. LPS might modulate macrophage GLP-2 secretion to higher concentrations of tight-junction
reverse cholesterol transport either in a direct manner through proteins and lower intestinal barrier permeability, which
decreasing liver X receptor, a cholesterol uptake inhibitor, could also support the favourable effects of probiotics on
expression or in a pathway that depends on other deleterious gut integrity [19,28]. Moreover, generating bacteriocins as
metabolites secretion (e.g., TMAO, pro-inflammatory cyto- potent antimicrobials by probiotics might suppress harmful
kines, chemokines, and cell adhesion molecules) [6,19,53]. bacterial growth and modulate the apoptosis and prolifer-
Evidence has shown that LPS could augment proatherogenic ation of intestinal epithelial cells. Further, lactic acid-
LDL and VLDL receptor expression in macrophages, which producing bacterial metabolites have been shown to
leads to lipid uptake increment by macrophages and trig- restrict LPS linkage to CD14 receptors found in mono-
gering of foam cell formation [6,19,53,139]. Besides, LPS might cytes/macrophages, which subsequently result in
suppress epithelial integrity in the large intestine through decreasing the inflammatory state via reducing NF-kB
lowering glucagon-like peptide-2 (GLP-2) and subsequently signalling in immune cells [11,28,125].
exacerbate intestinal permeability to some injurious metabo-
Other likely mechanisms
lites from the large intestine to the intestine, and worsen the Although the exact role of microRNAs in the gut microbiota
inflammatory state [139]. environment is not well-defined, they seem to be involved in
identifying the relevant receptors (e.g., TLRs) by microbial
Proprotein convertase subtilisin/kexin 9 metabolites in addition to producing SCFAs and other
The current experimental studies have proposed that LPS has microbiota-related metabolites [64]. It has been pointed out
a reciprocal relationship with the LDL co-receptor, known as that the expression of microRNAs can be affected by intes-
PCSK9. PCSK9 is believed to modulate lipid metabolism and tinal microbiota dysbiosis, which might consequently lead to
LDL uptake in the liver, in addition to elevating Ox-LDL disturbed vascular endothelial function and eventual
uptake by macrophages. Increased LPS levels seem to atherosclerosis progression [64]. Based on the reports of
cause PCSK9 expression and release to be elevated through in vitro experiments, various probiotic bacteria, including
triggering oxidative stress induced by the NADPH oxidase 2 Lactobacillus acidophilus, have been found to elevate the
(Nox2) complex [40,143]. Experimental evidence has shown expression of types of microRNAs with anti-apoptotic fea-
that the expression of PCSK9 is influenced by various factors tures and reduce the types with pro-inflammatory properties
such as LPS levels, the levels of pro-inflammatory factors involved in atherosclerotic development in a model of hu-
(e.g., TNF-a, IL-1, IL-6), and oxidative stress (ROS produc- man endothelial cell impaired function due to Escherichia coli
tion). Moreover, increased expression of this factor in LPS [64,145]. These promising findings shed light on new
vascular smooth muscle cells and atherosclerotic plaques has areas of probiotic clinical trials that are worth being
been previously detected [40,143]. Hence, it should be designed.
pointed out that the development and intensifying athero-
sclerosis procedure might be influenced by this pro-
atherogenic, pro-inflammatory factor, PCSK9. Notably,
augmented concentrations of PCSK9 in a direct relationship
Conclusion and Future Directions
with LPS levels were detected in patients suffering from non- The current evidence from meta-analysis and clinical trials
valvular atrial fibrillation, which supports the previous indicates that probiotic supplementation might be associated
with reduced levels of inflammation biomarkers (CRP, TNF- relationship with LDL co-receptor, PCSK9, are required to
a, IL-6, IL-12, and MDA). However, despite the beneficial extend the current knowledge on the topic.
impact of various probiotic supplements, no consistent data
are available for identifying the most effective probiotic
bacterial strains, their exact dosage, and the rate of effec- Declaration of Interest Statement
tiveness. There is also a lack of analysis on gut microbiota
The authors confirm that there are no known conflicts of
characteristics. Experimental evidence has found that pro-
interest associated with this publication and there has been
biotics might be able to improve intestinal barrier integrity
no significant financial support for this work that could have
and thereby alleviate increased intestinal permeability, and
influenced its outcome.
probably inhibit the release of harmful metabolites (i.e., LPS)
into the systemic circulation. Probiotics are also likely to
suppress the pathways related to the formation of TMA and Acknowledgements
TMAO. Specifically, the available research has underlined
the primary role of targeting the TMA/TMAO synthesis The authors wish to thank the staff of Cardiovascular Dis-
pathway as a likely practical therapeutic approach in treating eases Research Center, Department of Cardiology, Heshmat
CVDs complication progression; however, the exact conse- Hospital, School of Medicine, Guilan University of Medical
quences of probiotic administration on serum TMAO levels Sciences, Rasht, Iran for their kind support and cooperation.
are not yet clearly understood.
Further, probiotics appear to enhance inflammation by
suppressing the NF-kB signalling pathway and pro-
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The Effects of Probiotics On Inflammation

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Heart, Lung and Circulation (2022) 31, e45–e71 REVIEW

The Effects of Probiotics on Inﬂammation,

Dispersal of various agents, including hormones or neu-

Figure 1 Factors inﬂuencing intestinal microbiota composition and/or characteristics.

biological importance of TLRs as imperative signal trans- Aims of This Review

Number of Pooled Results of Probiotic and/or Synbiotic Reference

Number of Pooled Results of Probiotic and/or Synbiotic Reference

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