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1. Introduction
2. Dysbiosis and the components
of the MetS
3. Probiotics and intestinal
microbiota modulation
4. Microbiota modulation with
probiotics and the components
of the MetS
5. Conclusion
6. Expert opinion
Review
The role of probiotics on each
component of the metabolic
syndrome and other
cardiovascular risks
Bruna Miglioranza Scavuzzi, Lucia Helena da Silva Miglioranza,
Fernanda Carla Henrique, Thanise Pitelli Paroschi,
Marcell Alysson Batisti Lozovoy, Andrea Name Colado Sima
˜o&
Isaias Dichi
†
†
University of Londrina, Department of Internal Medicine, Parana
´, Brazil
Introduction: Probiotics are defined as live microorganisms that when
administered in adequate amounts confer health benefits to the host. The
consumption of probiotics has gained increasing recognition from the scien-
tific community due to the promising effects on metabolic health through
gut microbiota modulation.
Areas covered: This article presents a review of scientific studies investigating
probiotic species and their effects on different risk factors of the metabolic
syndrome (MetS). This article also presents a summary of the major mecha-
nisms involved with gut microbiota and the components of the MetS and
raises the key issues to be considered by scientists in search of probiotics
species for treatment of patients suffering from this metabolic disorder.
Expert opinion: Probiotics may confer numerous health benefits to the host
through positive gut microbiota modulation. The strain selection is the most
important factor for determining health effects. Further studies may consider
gut microbiota as a novel target for prevention and management of MetS
components and other cardiovascular risks.
Keywords: dysbiosis, dyslipidemia, gut microbiota, inflammation, insulin resistance, obesity
Expert Opin. Ther. Targets [Early Online]
1. Introduction
Metabolic syndrome (MetS) is a complex disorder represented by a cluster of car-
diovascular risk factors associated with central fat deposition, abnormal plasma lipid
levels, elevated blood pressure (BP), insulin resistance (IR), a low-grade inflamma-
tory state and possibly intestinal dysbiosis [1-3]. Changes in eating habits and lifestyle
are undoubtedly the most important non-pharmacological factors for the preven-
tion and treatment of MetS and various nutritional therapies have been researched.
Among nutritional therapies to prevent MetS, the scientific literature has pointed
out the consumption of probiotic, prebiotic and symbiotic products.
The gastrointestinal tract is composed of several connected organs, which are
involved in nutrient conversion. This complex system has a well-known anatomical
architecture that is ~7 m long, comprising 300 m
2
surface area in adults. The
human large intestine has a bacterial flora with total numbers of 10
14
cells (ten times
the number of cells in the human body) and > 1000 species [4-6]. The main
functions of gut microbiota are metabolic, protective and trophic [7].
From the mouth to the colon, there is a complex microbiota, which is formed by
facultative and strict anaerobes, including streptococci, bacteroides, lactobacilli and
yeasts. The microbiome comprises nearly two million genes, making the collective
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bacterial genome vastly greater than the human genome. The
advent of high-throughput methodologies and the elaboration
of sophisticated analytic systems have facilitated the detailed
description of the microbial constituents of the human gut
as never before and are now enabling comparisons to be
performed between health and various disease states [5].
The intestinal mucosa forms a biochemical and physical
barrier between the host and the intestinal lumen. The intes-
tinal mucosa is composed of a mucous layer, a single layer of
intestinal epithelial cells (IECs) connected by adhesive struc-
tures known as tight junctions, as well as the lamina propria
and two thin layers of muscle tissue -- the muscularis mucosae.
The loss of the barrier function may lead to a systemic
immune activation [8].
Currently, it has also been recognized that this dynamic yet
stable ecosystem plays a role in conditions such as obesity and
type two diabetes (T2D) from infancy to ageing and that early
differences in fecal microbiota composition in children may
predict obesity in their adulthood [4,9-13]. The literature has
demonstrated different gut microbial compositions between
non-diabetics and adults with T2D, as well as between lean
and obese individuals, suggesting that gut microbial composi-
tion may affect the metabolism and energy storage [4,14-16].
A consensus definition of the term ‘probiotics’ was adopted
after a joint Food and Agricultural Organization of the
United Nations and World Health Organization expert con-
sultation. In October 2001, the Organization experts defined
probiotics as ‘live micro-organisms which, when administered
in adequate amounts, confer a health benefit on the host.’ The
original idea of the prebiotic concept (that can be translated in
‘prebiotic effects’) was defined as: ‘the selective stimulation of
growth and/or activity (ies) of one or a limited number of
microbial genus (era)/species in the gut microbiota that
confer(s) health benefits to the host.’ When probiotics and
prebiotics are used in combination, they are known as
symbiotics [17].
The consumption of probiotics has gained recognition
from the scientific community due to the promising health
effects and well-documented history of safe use. Thus, the
present review gathers recent and relevant literature involving
the consumption of probiotics and the components of the
MetS in humans.
The articles included in this review were found in at least
130 Databases included in the Brazilian National Electronic
Library Consortium for Science and Technology and that
were published from 1998 to 2014. Studies were included if
they met the following criteria: 1) randomized, controlled
intervention trials with humans; 2) studied the effect of probi-
otics on waist circumference and/or body mass index, glucose
metabolism, blood lipids, BP, markers of inflammation and
other cardiovascular risk factors; 3) considered probiotic
products with a known amount of live bacteria from a given
strain. There were no restriction groups, but searches have
focused on texts written in English.
2. Dysbiosis and the components of the MetS
An alteration of gut microbial diversity and an imbalance
between the potentially harmful and beneficial intestinal
bacteria (e.g., increase in Firmicutes and reduction in the
abundance of Bacteroidetes), known as dysbiosis, has been
associated with several components of MetS, such as obesity
and IR, via modulation of inflammatory pathways [18-20].
The mechanisms linking these gut microbiota alterations
and metabolic changes are still a matter of debate; however,
it likely involves gut barrier alterations and low-grade inflam-
mation. High-fat, low-fiber and high-sugar diets have been
associated with a negative impact in gut activity and composi-
tion with a subsequent decrease in the barrier function [21-25].
Long-term overnutrition with macronutrients such as
saturated fats and carbohydrates can induce inflammation
through activation of toll-like receptor 4 (TLR-4) expressed
in the membrane of the IECs. Dietary products that are rich
in saturated fats, such as meats, contain significant amounts
of lipopolysaccharide (LPS), a major component from the
outer membrane of gram-negative bacteria that is known to
induce TLR-4 activation. TLR-4 stimulation induces
NF-kB-mediated inflammation, which has been related to
the development of IR [26].
Cani et al. [16] first demonstrated increased gut permeability
in mice after 4 weeks of a high-fat diet. This barrier disruption
is characterized by alteration of mucous thickness or tight
junction function and may allow the passage of microbial
components such as LPS to the systemic circulation, resulting
in metabolic endotoxemia and low-grade chronic inflamma-
tion that characterizes the MetS [18]. Elegant studies have
demonstrated that dietary fats may facilitate intestinal absorp-
tion of LPS. The mechanisms involved in LPS absorption
probably include paracellular leakage due to compromised
barrier function caused possibly by the saturated fats and
internalization by IECs and subsequent chylomicron
formation [27].
High LPS concentrations have been strongly associated
with the components of the MetS [28]. The lipopolysaccha-
ride-binding protein (LBP) is known to reflect LPS levels
Article highlights.
.Metabolic syndrome (MetS) has been associated with
intestinal dysbiosis.
.Probiotics may normalize intestinal microbiota
composition and improve gut barrier function.
.Microbiota modulation with probiotic strains have
shown to improve the components of the MetS.
.The physiological effects of probiotics are highly
strain-dependent.
.Probiotics consumed within fermented milk products
may have additional health benefits.
This box summarizes key points contained in the article.
B. M. Scavuzzi et al.
2Expert Opin. Ther. Targets (2015) 19(8)
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and activity and is considered a marker of subclinical endotox-
emia. Accordingly, elevated LBP concentrations have also
been was associated with obesity, MetS and T2D. LBP is a
protein that is involved in the transfer of the LPS molecule
to CD14, a protein found in the surface of most TLR-4-
expressing cells and that is required for TLR4 endocytosis [29].
It has been hypothesized that CD14 could modulate insulin
sensitivity in physiological conditions possibly via modulation
of inflammatory pathways. Correspondingly, CD14 knock-
out mice were remarkably resistant to inflammation induced
by LPS administration and high-fat feeding [30,31].
2.1 Inflammation and IR
There is evidence that chronic inflammation is triggered by
the binding of LPS and bacterial lipopeptides to toll-like
receptors, such as TLR-4 and that it negatively affects glucose
homeostasis [18,32,33]. In obese individuals, circulating fatty
acids (FA) concentration is frequently elevated. Under such
conditions, saturated FAs may also bind to and activate
TLR-4 [34,35]. These bound molecules may activate the c-Jun
NH2-terminal kinase (JNK) or the IkB kinase (IKK)/
NF-kB pathways and result in IR [33].
In a study to investigate the effects of Lactobacillus acidoph-
ilus NCFM on insulin sensitivity and LPS-induced inflamma-
tory response in human subjects, the authors found that LPS
triggered a systemic, though reversible, inflammatory response
that included an increase of TNF-a, IL-6 and IL-1 receptor
antagonist [36].
In early studies, Hotamisligil et al. [29] showed that TNF-a
could induce IR. Later investigations demonstrated the
involvement of other proinflammatory cytokines (e.g., IL-6),
chemokines (e.g., monocyte chemoattractant protein 1) and
several bioactive substances (e.g., leptin, resistin) on the
pathogenesis of IR [33]. Additionally, increased adiposity and
TNF-alevels decrease the expression of adiponectin, an
adipocyte-derived hormone with antiatherogenic, anti-
inflammatory and antioxidant capacity [36-41]. The decrease
of this adipokyne also correlates with IR [42].
2.2 Obesity and lipid metabolism
Backhed et al. [14] demonstrated that after conventionalization
of germ-free mice with a normal microbiota, there was an
increase in fat mass by 60% and IR, despite energy intake
reduction, and suggested that the gut microbiota affected
energy harvest from the diet and energy storage in the
host [14]. The authors also reported an increase in leptin levels
upon colonization and found it to be proportional to the
increase in body fat. After these findings, numerous studies
of human gut microbiome reported evidence of core differen-
ces between lean and obese individuals, reduced diversity of
microbiota in obese individuals and suggested that gut micro-
bial composition may affect metabolism and fat
storage [16,43,44].
Turnbaugh et al. [45] colonized the gut of germ-free mice
with microbiota from either obese or lean animals. The
authors demonstrated that animals colonized with obese
microbiota had an increased capacity to store energy from
the diet. Obesity was associated with higher proportion of
Firmicutes, whereas lean animals had a greater abundance of
Bacteroidetes. The authors also found that cecal concentra-
tions of short chain FAs (SCFAs) were lower in lean compared
to obese animals [45].
SCFAs are produced by intestinal fermentation of indigest-
ible carbohydrates and the main SCFAs are acetate, propio-
nate and butyrate. These substrates are absorbed and used as
an energy source to the host. SCFAs are also known to play
an important role in metabolism regulation; therefore, SCFAs
can act both as an energy substrate and as a metabolic
regulator [46,47].
SCFAs are converted to triacylglicerol, which is later stored
in adipocytes, through hepatic de novo lipogenesis. Several
mechanisms to explain the increased fat storage have been
postulated and they include: i) the suppression of the
fasting-induced adipose factor, also known as angiopoietin-
like protein 4, by gut microbiota results in an increase of
lipoprotein lipase activity, which enhances the storage of
triacylglicerol in adipocytes; ii) the inhibition of AMPK activ-
ity in the muscle, leading to reduction of mitochondrial FA
oxidation, which predisposes to obesity; and iii) SCFAs also
influence energy intake through the binding to G-protein
coupled receptors (free FA receptors 2 and 3) and leads to
modulation of glucagon-like peptides (GLP) and peptide-YY
(PYY). In turn, GLP-1 and PYY modulate the production
and release of digestive hormones that are responsible for
satiety [46,48-53].
Although the etiology of dyslipidemia is mostly genetic or
related to lifestyle (sedentary lifestyle with excessive intake of
saturated FA, trans FA and cholesterol), SCFAs produced by
microbiota fermentation may also play a role in the regulation
of blood lipids. The SCFA acetate is known to be a substrate
for cholesterol synthesis and could have the potential to
increase plasma cholesterol. Accordingly, Jenkins et al. [54]
studied the effect of colonic fermentation of a 25 g/day of
lactulose supplementation on serum lipids. After 2 weeks of
treatments, a significant increase of fasting serum total
cholesterol (TC), low-density lipoprotein (LDL) and apolipo-
proteins B was reported. The authors suggested that the
lipid-raising effect occurred due to an increase of serum
acetate concentrations. The effects of SCFAs on blood lipids
are still a matter of debate, but it is likely that the effect is
dependent on the propionate to acetate ratio.
2.3 Blood pressure
The number of studies linking gut dysbiosis and increase in
BP are very limited. However, BP may increase indirectly
due to obesity, elevated blood lipids and IR [55-58].
The main mechanisms linking dysbiosis and all the compo-
nents of MetS described in this topic have been summarized
and illustrated in Figure 1.
The role of probiotics on each component of the MetS and other cardiovascular risks
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3. Probiotics and intestinal microbiota
modulation
The modulation of the intestinal microbiota is one of the
potential beneficial health effects of probiotics, and numerous
research studies have documented that probiotics can alter gut
microbiota. The mechanisms and efficiency of probiotic
effects depend primarily on the interactions between the pro-
biotic microorganisms and either the microbiota of the host
or the immunocompetent cells of the intestinal mucosa [59,60].
Dysbiosis of intestinal microbiota has been associated with
a growing number of diseases. Recently, fecal microbiota
transplant from non-diabetic donors infused into the
duodenum of patients with the MetS improved their insulin
sensitivity, highlighting the broad potential of this interven-
tion [61]. Since modulation of the composition of intestinal
microbiota by probiotics was demonstrated to be possible,
this intervention could have the potential to counterbalance
intestinal dysbiosis and thus restore health.
Probiotics may play a beneficial role in several medical
conditions, including diarrhea, gastroenteritis, irritable bowel
syndrome, inflammatory bowel disease, cancer, infant
allergies, failure-to-thrive, hyperlipidemia, hepatic diseases,
Helicobacter pylori infections, and others [62].
Probiotics such as Lactobacilli and Bifidobacterium are mor-
phologically defined as Gram-positive, non-spore-forming,
anaerobic, aciduric, acidogenic, homofermentative or
heterofermentative microorganisms that have complex
nutritional requirements (carbohydrates, amino acids, pepti-
des, FA, salts, nucleic acids and vitamins) [63]. Even within
the same species of microorganisms, the physiological effects
of probiotics are highly strain-dependent. The variations in
outcomes between different studies appear to be due to choice
of probiotic strain, number of colony-forming units (CFU)
and length of the study.
Several strains of probiotics have been shown to improve
metabolic parameters such as hypertension, obesity, inflam-
mation, glucose homeostasis disorders and abnormal plasma
lipid levels, such as decrease of LDL concentration, reduction
of TC and an improvement in TC: high-density lipoprotein
(HDL) and LDL:HDL ratios [12,64-73]. The important
criteria, which have been put forward by FAO/WHO in the
selection of food probiotics include identification of strains
using state-of-the-art techniques, ability to tolerate gastric
juice and bile, maintenance of stability and, most impor-
tantly, proof to be safe and beneficial to the consumer.
A number of genera of bacteria are used as probiotics,
including Lactobacilli (L.), Bifidobacterium (B.), Pediococcus,
Leuconostoc and Enterococcus [74]. Amongst probiotics,
L. acidophilus NCFM/La5, L. casei subsp. casei,L. gasseri
SBT2055, L. helveticus, L. plantarum 299v, L. rhamnosus
GG, L. reuteri NCIMB, B. lactis Bb12 and others, have
human health efficacy data with desirable properties and
well-documented clinical effects on parameters of
MetS [36,67]. The main clinical effects of these strains were
Inadequate diet
(↑ Fat, ↑ Sugar, ↓ Fiber)
Changes in gut microbiota
composition
(e.g., ↓ Bacteroites, ↑ Firmicutes)
↑ Proportion of
proinflammatory bacteria
↑ Passage of microbial products (e.g., LPS)
to systemic circulation
↑ Gut permeability
Systemic and adipose tissue inflammation
↑ Proinflammatory cytokynes
(TNF-α, IL-6, and IL-1)
↓ Adiponectin expression
↑ Leptin levels
Insulin resistance ↑ Blood pressure
Short chain
fatty acids
↑ De novo
lipogenesis Obesity
↑ Energy
Storage
↓ GLP-1
↓ PYY
↓ Satiety
↑ Appetite
FIAF suppression by
gut microbiota
↑ LPL
activity
AMPK inhibition in
muscle
↓ Fatty acid oxidation
Figure 1. Mechanisms linking dysbiosis and the components of the metabolic syndrome.
FIAF: Fasting-induced adipose factor; GLP-1: Glucagon-like peptide 1. LPL: Lipoprotein lipase; LPS: Lipopolysaccharide; PYY: Peptide-YY.
B. M. Scavuzzi et al.
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body mass index and abdominal adiposity reduction,
diminished LDL and TC levels and decrease in BP [65,69,75,76].
The effects of probiotics are mediated by their role in nor-
malization of intestinal microbiota composition, immunomo-
dulation, and maintenance of gut barrier function. Three
main mechanisms have been proposed to explain the action
of probiotics. The first is the suppression of viable counts of
the pathogenic bacteria, which can occur by competition for
attachment surface and nutrients, as well as by production
of antibacterial compounds, such as AMPs, anti-microbial
peptide human-bdefensin 2, bacteriocins, acetic and lactic
acids. The second mechanism is by alteration of microbial
enzyme activities. SCFA and bacteriocins may reduce luminal
and fecal pH and decrease the activity of undesirable bacterial
enzymes. The third mechanism is by stimulation of host
immunity by increasing antibody levels (e.g., Immunoglobu-
lin A), and leukocyte and macrophages activity. Probiotics
also increase barrier function, inhibiting the invasion of
pathogenic microbial products [8,77].
With advancing knowledge of how probiotics interact with
the gut microbiome, there is an increasing interest in explor-
ing the effect of probiotics on specific elements of MetS in
humans.
4. Microbiota modulation with probiotics and
the components of the MetS
4.1 Probiotics and body weight
Kadooka et al. [75] performed a 12-week intervention study
with fermented milk containing Lactobacillus gasseri strain
SBT2055 (LG2055) in adults with large visceral fat areas.
The subjects consumed 200 g of fermented milk/day contain-
ing either 10
7
,10
6
or 0 (control) CFU of LG2055/g. The
authors found visceral adiposity reduction with LG2055
intervention to be dose-dependent and the average reductions
in abdominal visceral fat areas were 8.5% in the 10
7
dose
group and 8.2% in the 10
6
dose group. The control group
did not reduce abdominal visceral fat. The authors suggested
that LG2055 could enhance anti-inflammatory and
integrity-maintaining mechanisms of IECs and thus, contrib-
ute to reduced abdominal adiposity [75].
Although only few studies have investigated the effect of
probiotic strains in abdominal adiposity, several studies have
recognized that the composition of the gut microbiota has
an impact on energy homeostasis and have suggested that pro-
biotics have positive results on weight loss. However, it is
important to reinforce that the physiological effects of probi-
otics are highly strain-dependent. Million et al. [78] conducted
a comparative meta-analysis of studies considering the
effect Lactobacillus species on body weight in humans and
animals. The authors found that the species L.fermentum
and L.ingluviei were associated with weight gain in animals,
L.plantarum was associated with weight loss in animals and
L. gasseri was associated with weight reduction in animals
and humans [59].
Sanchez et al. [64] performed a 24-week intervention study
to investigate the impact of Lactobacillus rhamnosus
CGMCC1.3724 (LPR) on weight loss and maintenance in
obese men and women. The participants consumed two
capsules a day of either a placebo or a LPR formulation
(1.6 10
8
CFU of LPR/capsule). The authors found that
L. rhamnosus CGMCC1.3724 was associated with a reduction
in the abundance of the Lachnospiraceae family (phylum
Firmicutes) in women. The Lachnospiraceae family is a group
that is more abundant in the obese microbiota. The women in
the intervention group had significant weight loss after
12 weeks with the association of probiotic supplementation
and an energy-restricted diet. The women who received the
probiotic supplementation continued to lose body weight
and fat mass during the 12 weeks weight-maintenance period
where there was no diet restriction. However, the placebo
group gained weight. These results suggest that changes in
gut microbiota composition may help to lose weight and
maintain weight loss. They also indicated that the health
effects are also influenced by the host gender [64].
The mechanisms involved in body weight reduction are
not clear, but studies point to the reduction of adipocyte
size, inhibition of adipogenesis and suppression of energy
intake [59-67,74,75,77-82].
4.2 Probiotics and blood lipids
Guo et al. [83] conducted a meta-analysis of randomized
controlled trials to evaluate the effects of probiotics on blood
lipids. The authors found evidence that probiotics decrease
concentrations in LDL and TC in subjects with normal,
borderline high and high cholesterol levels [83].
Although the mechanisms involved in the cholesterol-
lowering effect are not clearly understood, it is accepted that
blood lipids are affected by: i) probiotics containing bile salt
hydrolase (BSH) (e.g., lactobacilli and bifidobacteria) increase
bile acid deconjugation, which suppresses cholesterol absorp-
tion in the enterohepatic circulation. Inhibition of the enter-
ohepatic circulation leads to the synthesis of more bile acid,
which utilizes circulating cholesterol; ii) probiotics bind and
incorporate cholesterol to their cell membrane, decreasing
the intestinal cholesterol pool available for absorption; and
iii) probiotics produce SCFAs such as propionate, which
reduces cholesterol synthesis by inhibiting hydroxymethylglu-
taryl CoA reductase (HMG-CoA reductase), a rate-limiting
step of the cholesterol synthesis pathway [84-86].
One proposed mechanism to explain HDL increase after
probiotic treatment is the reduction in serum triglyceride
(TG) levels. In hypertriacylglycerolemic states, HDL particles
exchange cholesterol for TG with LDL and very LDL and
become TG-rich. The TG-rich HDL particles are more
rapidly catabolized in the liver than normal HDL particles.
Therefore, reduction in serum levels of TG often observed
in probiotic treatments may indirectly lead to an increase in
serum HDL levels [87].
The role of probiotics on each component of the MetS and other cardiovascular risks
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Besides the cholesterol-lowering effects caused by probiot-
ics, when probiotics are consumed through dairy products,
there can be an additional decrease in cholesterol levels,
probably due to the presence of milk matrix components
such as calcium and magnesium [12].
4.3 Probiotics, glucose homeostasis and
inflammation
Firouzi et al. [88] conducted a review of studies in animals
and humans that considered the impact of probiotics on
parameters of glucose homeostasis. Sixteen out of seventeen
studies in animals, and three out of four studies in humans,
found significant improvements in at least one glucose
homeostasis-related parameter [88].
The mechanism by which gut microbiota modulation
improves IR has been associated to an increase in hepatic
natural killer T-cell number and a reduction in inflammatory
signaling [89]. One of the possible mechanisms to induce a
decrease in inflammatory signaling is through PPARgagonist
activation. Conjugated linoleic acid is produced by some
species of Lactobacilli (e.g., acidophillus, plantarum, paracasei
and casei) and has the potential to act as a PPARgagonist,
which up-regulates adiponectin, down-regulating inflamma-
tion, adiposity and improving IR by blocking suppression of
glucose transporter type 4 [26].
Studies evaluating probiotic intake and markers of inflam-
mation are scarce and the results are controversial. Gøbel et al.
[10] investigated the effect of L. salivarius Ls-33 on a series of
biomarkers related to inflammation and MetS. High-
sensitivity C-reactive protein (hs-CRP), IL-6 and TNF-a
were evaluated. The authors found no evidence of any benefi-
cial effect on inflammatory markers [10]. Andreasen et al. [32]
studied the effect of L. acidophilus NCFM on the systemic
inflammatory response. The authors found that this probiotic
strain did not affect the systemic inflammatory response
(C-reactive protein, TNF-a, IL-6 and IL-1 receptor antago-
nist) [36]. In contrast, Asemi et al. [90] studied the effect of a
multispecies probiotic supplement containing L. acidophilus,
L. casei, L. rhamnosus, L. bulgaricus, Bifidobacterium breve,
Bifidobacterium longum and Streptococcus thermophiles on hs-
CRP in diabetic patients. The authors found a significant
decrease in serum hs-CRP levels [90]. Barreto et al. [12]
performed a randomized controlled trial to compare the influ-
ence of fermented milk with L. plantarum and non-fermented
milk (control) on the classical parameters related to the MetS
and other parameters related to cardiovascular risk. The
authors found a significant decrease in IL-6 both in control
(p = 0.032) and intervention (p = 0.001) groups [12].
4.4 Probiotics and BP
In a recent systematic review and meta-analysis of randomized
controlled trials, Khalesi et al. [91] concluded that probiotics
moderately reduce BP. The authors found evidence that
BP reduction is greater when the intervention lasts
for > 8 weeks, when the daily dose of probiotic consumption
is greater than (or equal to) 10
11
CFU, and amongst individ-
uals with elevated BP. The study also suggests a greater
BP-lowering effect when multiple species of probiotics are
consumed [91].
Although the number of studies investigating the role of
gut microbiome on BP regulation is sparse, some authors
have demonstrated an influence of SCFAs on BP.
Mortensen et al. [92] found that SCFA acetate, propionate
and butyrate could produce a vasorelaxant effect in isolated
human colonic resistance arteries [92]. More recently,
Pluznick et al. [93] documented an acute decrease in BP after
propionate administration on wild-type mice. The authors
found that olfactory receptor 78 (Olfr78), an Olfr expressed
in the kidney and short-chain FA receptor GPR-41 respond
to SCFA propionate. Propionate stimulates the expression of
Olfr78, which elevates BP mediated by renin secretion but
conversely, propionate also causes a decrease in BP through
GPR41. The authors concluded that SCFA affects BP
through both receptors [93].
When probiotics are consumed with dairy products, a sig-
nificant reduction of BP may occur [91]. The BP lowering
ability of dairy products has been related to the release of
bioactive peptides that have an ACE inhibitory effect.
Different strains of probiotic microorganisms release different
bioactive peptides, which can be either more potent or less
potent in the ACE inhibitory activity [94]. BP decrease may
also be a result of the reduction of blood lipids, body weight
and IR [55-58].
The main mechanisms associated with improvements of all
components of MetS through probiotic consumption
described in this topic have been summarized in Figure 2.
Table 1 summarizes examples of human trials considering
probiotic intake and its effects on components of the MetS.
4.5 Probiotics and other cardiovascular risk factors
Barreto et al. [12] performed a randomized controlled trial to
evaluate the influence of fermented milk with L. plantarum
in the classical parameters related to MetS and other
parameters related to cardiovascular risk. The authors found
a significant decrease in homocysteine levels and associated
it to increased folate intake, naturally present in milk, and
the capacity of L. plantarum to synthesize folate [12].
Bukowska et al. [95] also performed an intervention
study with L. plantarum. There was a significant decrease
in levels of TC, LDL and fibrinogen after 6 weeks of
intervention. The authors associated the reduction of
fibrinogen levels to the reduction in cholesterol levels and
hypothesized that it could be due to: i) modulation of
the immune response; and ii) suppression of hepatic
synthesis of fibrinogen by lowering serum levels of free
FA promoted by propionate production during intestinal
fermentation [95].
B. M. Scavuzzi et al.
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5. Conclusion
Evidence is now accumulating that a diet rich in probiotics
might confer numerous benefits to the metabolic health of
the host through positive gut microbiota modulation and is
thus a novel target to be further studied and considered for
the prevention and management of all MetS components.
Considering that the effects of probiotics are strain-
dependent, the strains to be used for the management of the
MetS must be selected based on clinically established health
benefits and safety records. Overall, the studies show that
several probiotic strains have a favorable effect on at least
one component of the MetS in intervention studies.
6. Expert opinion
The connection between gut microbiota imbalance, inflam-
mation and its role in the pathogenesis of the components
of the MetS has been increasingly recognized. This interven-
tion is of particular interest since it has the potential to signif-
icantly improve all parameters of the MetS at once. However,
to date, the number of human intervention studies consider-
ing the effect of probiotics on every component of the MetS
is very limited and often contradictory. The conflicting results
may be due to differences in study design and probiotic strain
selected. Therefore, there is great research potential in this
field, as very little has been established specially regarding
the mechanisms of action involved and the information on
intervention characteristics such as effective probiotic strain,
duration, and dose required to achieve health benefits.
The key finding in this area is that microbiota modulation
with probiotics may improve metabolic parameters and that
the metabolic effects of probiotic are strain-dependent. There-
fore, when searching for a specific clinical response, the strain
should be carefully selected based upon scientific evidence of
efficacy. The strain selection is the most important factor for
determining the health effects, for example, when an addi-
tional reduction of cholesterol levels is needed, the strains
selected should be BSH-active.
The strain that has shown favorable and significant
improvements for most components of the MetS in the stud-
ies selected for this review was L. plantarum. However, most
studies considered only one metabolic parameter and there-
fore, it is very possible that other strains have a more favorable
impact on the metabolic risk factors overall. Therefore, more
in-depth studies are needed in order to conclude which strains
will be the most promising for metabolic improvements.
Unfortunately, the limited number of trials that consider
every component of the MetS and specific probiotic strains
make it difficult to suggest a microorganism (or a combina-
tion of strains) that is more likely to yield better clinical
improvements. This is also a promising field to be studied.
↓ Lipogenesis
Microbiota modulation
with probiotics
Restore gut microbiota
composition balance
(e.g., ↑ Bacteroites, ↓ Firmicutes)
↓ Proportion of
proinflammatory bacteria
↓ Passage of microbial products
to systemic circulation
↓ Gut permeability
↓ Systemic and adipose tissue
inflammation ↓ Insulin resistance ↓ Blood pressure
Short chain fatty acids
(e.g., propionate)
↓ Obesity
↓ Energy
storage
↑ GLP-1
↑ PYY
↑ Satiety
↓ Appetite
↓ Adipogenesis
↓ Adipocytes size
↓ Adipocytes number ↓ Blood lipids
↑ Cholesterol binding/incorporation
to probiotic cells
↓ Cholesterol
absorption
↑ Bile acid
deconjugation
↑ Bile acid synthesis using circulating cholesterol
↓ Cholesterol
absorption
Figure 2. Mechanisms linking gut microbiota modulation with probiotics and improvements in components of the metabolic
syndrome.
GLP-1: Glucagon-like peptide 1; PYY: Peptide-YY.
The role of probiotics on each component of the MetS and other cardiovascular risks
Expert Opin. Ther. Targets (2015) 19(8) 7
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The majority of studies considering the effects of probiotics
on metabolic health are very recent, most of which started to
be published around 2005. Therefore, very little is known
about which strains produce more effects on the components
of the MetS, the dose needed for each strain and the mini-
mum treatment period, since alteration of the gut microbiota
composition is probably gradual. The health effects are also
likely affected by the host characteristics, such as ethnicity,
gender and age.
Most studies selected for this review reported a positive
impact on the components of the MetS. The overall daily
dose of probiotic bacteria ranged from 10
6
to 10
10
CFU
consumed in capsules or within fermented dairy products.
The intervention period ranged from 3 to 24 weeks. These
studies indicate that significant results can be achieved in a rel-
atively short period and without a major change in dietary
habits.
Additional health benefits may occur when probiotics are
consumed in fermented dairy products, as milk alone also
has the potential to improve the components of the MetS
due to its complex matrix. For example, microorganism-
fermented dairy products may contain ACE inhibitory
peptides that contribute to BP reduction by decreasing the
production of angiotensin II.
It is also important to mention that the improvements in
metabolic parameters are more significant when probiotic
consumption is made within a balanced diet. Considering
that a diet rich in fat and sugar, and poor in fiber leads to
an alteration of barrier function and of the gut microbiota
composition, the limitation of using probiotics is that
improvements will likely be maintained only if there is a life-
long adherence to a balanced diet or continuous probiotic
consumption.
Medical organizations such as the World Gastroenterology
Organization; the European Society for Pediatric Gastroenter-
ology, Hepatology and Nutrition; and the North American
Society for Pediatric Gastroenterology, Hepatology, and
Nutrition have begun to suggest probiotics for clinical use
in the treatment of various clinical conditions, such as
antibiotic-associated diarrhea and irritable bowel syndrome.
Therefore, it is likely that the scientific findings, which associ-
ate probiotics and metabolic health, will be translated into
clinical recommendations considering the history of safe use
of many strains and the increasing body of evidence of health
benefits.
A promising area to be studied is how early gut coloni-
zation affects metabolic diseases in adulthood and meta-
bolic health (e.g., detailed information on the impact of
Table 1. Examples of human studies considering probiotics and components of metabolic syndrome.
Study/strain Population Duration Daily intake Effect Ref.
A DB, RPCT to assess the
cholesterol-lowering clinical
efficacy and safety of
microencapsulated Lactobacillus
reuteri NCIMB 30242
supplemented in a yogurt
formulation
114 healthy hypercholesterol-
emic adult men and women,
18 -- 74 years
2-week
washout,
2-week
run-in,
6-week
treatment
1.15
10
CFU Microencapsulate L. reuteri
yoghurt consumption
decreased LDL, total cholesterol
and non-high-density
lipoprotein cholesterol
[65]
A multicenter, DB, RPCT to
evaluate the effects of the
probiotic L. gasseri
SBT2055 (LG2055) - originated
from the human gut - on
abdominal adiposity, body
weight and other body measures
87 healthy adults (59 men/
28 women) with BMI of
24.2 -- 30.7 kg/m
2
and
abdominal visceral fat area
(81.2 -- 78.5 cm
2
)
12 weeks 200 g of FM
containing
10
7
and 10
6
CFU of
LG2055/g
LG2055 consumption
promoted a significant
reduction in abdominal
adiposity, BMI, waist and hip
circumference
[75]
A DB, RPCT parallel pilot study
to evaluate the effects of a
hypocaloric diet supplemented
with a probiotic cheese with
L. plantarum on obese
hypertensive patients
25 obese hypertensive
patients
3 weeks 50 g cheese.
Containing
110
9
CFU/g
The hypocaloric diet
supplemented with a probiotic
cheese helped to reduce
arterial blood pressure
[76]
A randomized, prospective,
parallel-group intervention study
to investigate whether
supplementation of probiotics
(L. rhamnosus GG, ATCC 53
103 and Bifidobacterium lactis
Bb12) with dietary counseling
affects glucose metabolism
256 pregnant women (mean
age of 30 years)
Entire preg-
nancy and
12 months
postpartum
1 capsule
with 10
10
CFU/day
Combined dietary counselling
and probiotics intervention
yielded improved glucose
metabolism and insulin
sensitivity
[96]
BMI: Body mass index; CFU: Colony forming units; DB: Double blind; FM: Fermented milk; LDL: Low-density lipoprotein; RPCT: Randomized placebo controlled
trial; TC: Total cholesterol.
B. M. Scavuzzi et al.
8Expert Opin. Ther. Targets (2015) 19(8)
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formula milk on long-term gut composition) and how the
microbiota is altered due to ageing or to different diseases.
Studies comparing the effects of different strains and possi-
bly combining them for optimum results are warranted.
The mechanisms of action have mostly been demonstrated
in animal models and remain to be confirmed in human
trials. Thus, in the next few years, the role of the micro-
biota composition on overall health will hopefully become
clearer.
Future intervention studies should preferably include stool
analysis to verify changes in stool composition (e.g., choles-
terol, SCFA, microorganisms). Studies should also include
measures of circulating LPS and markers of inflammation,
which would help to explain results and make associations
with the mechanisms of action.
Currently available scientific evidence is sufficient to sup-
port the study of dietary intake of probiotics in patients
with the MetS and with a normal immune system. This inter-
vention may broaden the area of non-medication strategies to
be employed to ameliorate the components of the MetS,
which currently include healthy nutrition and regular physical
activity.
Declaration of interest
The authors have no relevant affiliations or financial involve-
ment with any organization or entity with a financial interest
in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, con-
sultancies, honoraria, stock ownership or options, expert testi-
mony, grants or patents received or pending, or royalties.
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Affiliation
Bruna Miglioranza Scavuzzi
1
MSc,
Lucia Helena da Silva Miglioranza
2
PhD,
Fernanda Carla Henrique
3
MSc,
Thanise Pitelli Paroschi
3
MSc,
Marcell Alysson Batisti Lozovoy
4
PhD,
Andrea Name Colado Sima
˜o
4
PhD &
Isaias Dichi
†5
MD PhD
†
Author for correspondence
1
University of Londrina, Health Sciences
Graduate Department, Post Graduate Program in
Health Sciences, Rua Robert Koch n. 60,
Londrina, Parana
´, Brazil
2
University of Londrina, Department of Food
Science and Technology, Rodovia Celso Garcia
Cid (PR 445), Km 380, Londrina, Parana
´, Brazil
3
University of Londrina, Food Science and
Technology Graduate Department, Post
Graduate Program in Food Science, Rodovia
Celso Garcia Cid (PR 445), Km 380, Londrina,
Parana
´, Brazil
4
University of Londrina, Department of
Pathology, Clinical and Toxicological Analysis,
Rua Robert Koch n. 60, Londrina, Parana
´, Brazil
5
University of Londrina, Department of Internal
Medicine, Rua Robert Koch n. 60, Londrina,
Parana
´, Brazil
Tel: +55 43 33712332;
Fax: +55 43 33715100;
E-mail: dichi@sercomtel.com.br
B. M. Scavuzzi et al.
12 Expert Opin. Ther. Targets (2015) 19(8)
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