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Cardiovascular benets of probiotics: a review of

Cite this: Food Funct., 2016, 7, 632
experimental and clinical studies
Ram Mohan Thushara, Surendiran Gangadaran, Zahra Solati and
Mohammed H. Moghadasian*

Received 1st October 2015,
Accepted 1st January 2016
DOI: 10.1039/c5fo01190f
www.rsc.org/foodfunction
The microbiota inhabiting the human gastro-intestinal tract is reported to have a signicant impact on the
health of an individual. Recent ndings suggest that the microbial imbalance of the gut may play a role in
pathogenesis of cardiovascular diseases (CVD). Therefore, several studies have delved into the aspect of
altering gut microbiota with probiotics as an approach to prevent and/or treat CVD. The World Health
Organization denes probiotics as live microorganisms that, when consumed in adequate amounts, have
a positive inuence on the individuals health. The present review focuses on strategies of human dietary
intervention with probiotic strains and their impact on cardiovascular risk factors like hypercholesterole-
mia, hypertension, obesity and type-2 diabetes. Accumulating evidence shows probiotics to lower low
density lipoproteins (LDL)-cholesterol and improve the LDL/high density lipoproteins (HDL) ratio, as well
as lower blood pressure, inammatory mediators, blood glucose levels and body mass index. Thus, pro-
biotics have the scope to be developed as dietary supplements with potential cardiovascular health
benets. However, there is not only ambiguity regarding the exact strains and dosages of the probiotics
that will bring about positive health eects, but also factors like immunity and genetics of the individual
that might inuence the ecacy of probiotics. Therefore, further studies are required not only to under-
stand the mechanisms by which probiotics may benecially aect the cardiovascular system, but also to
rule out any of their probable negative eects on health. The present review aims to critically appraise the
complexity of the available data with regard to the cardiovascular benets of probiotics.

Introduction in sucient amounts, have a beneficial impact on the health

It has been known for a long time that the normal microbiota
of the gastrointestinal (GI) tract has a significant impact on
the health of an individual. While the exact quantity, compo-
sition and functions of the healthy gut microbiota is not
clearly known, an increasing number of reports indicates that
dysbiosis (microbial imbalance) of the gut is implicated not
only in the pathogenesis of intestinal disorders, but also in the
extra-intestinal disorders such as, metabolic syndrome, cardio-
vascular disease (CVD) and obesity.1,2 Therefore, targeting the
gut microbiota as a strategy to prevent and/or treat a disease is
currently one of the most exciting topics of research. Emerging
evidence proposes that the modulation of gut microbiota with
probiotics might oer new possibilities of prophylaxis and/or
disease treatment.2,3
According to the World Health Organization (WHO) probio-
tics are defined as live microorganisms that, when consumed
Department of Human Nutritional Sciences, University of Manitoba, and the
Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface
Hospital research Centre, Winnipeg, MB, Canada. E-mail: mmoghadasian@sbrc.ca;
Fax: +1-204-237-4018; Tel: +1-204-478-1685
of the individual.4 The theory that certain microbes might
have a beneficial eect on the human body was first coined in
the early 1900s by the Nobel Prize winner Elie Metchniko,
while he was studying the longevity of Bulgarian peasants.5
There are increasing numbers of probiotic products being
made available to consumers, which include yogurt, other fer-
mented milk and food products as well as various forms of
dietary supplements. These products are usually prepared
using lactic acid bacteria of four general species; Lactobacillus
sp., Bifidobacterium sp., Enterococcus sp., and Streptococcus sp.,
although the probiotic bacteria type and composition varies
from product to product.6 Common probiotic yogurts often
contain one or two bacterial strains, such as Bifidobacterium
lactis and/or Lactobacillus acidophilus, whereas kefir, another
fermented milk product, contains many more strains. Accord-
ing to the literature, the human GI tract begins to colonize bac-
teria in infancy, and continues this process throughout the
lifespan.7,8 The adult GI tract contains 10 to 100 trillion micro-
organisms and the species vary from one person to the next
due to factors such as genetics, age, diet, and antibiotic
use.7,9,10 Another major factor aecting the composition of
bacteria in the human gut is the presence of fermentable

632 | Food Funct., 2016, 7, 632642 This journal is The Royal Society of Chemistry 2016

Food & Function
Table 1 Criteria for the selection of probiotic bacteria for human
consumption
Characteristics References
Ability to withstand human digestion, including gastric 47
juices and bile
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Ability to adhere to intestinal wall 46
Antimicrobial activity 4, 5
Ability to reduce pathogen adhesion to intestinal wall 4, 6
Considerable shelf-life 57
Ability to stabilize intestinal microflora 5, 6
Non-pathogenic/non-toxic 57
materials in the intestinal tract, which are referred to as
prebiotics.11
In order to choose suitable probiotic bacteria for commer-
cial use, several criteria must be met. WHO suggests that in
order to provide health benefits, probiotics must be able to
endure human digestion, including gastric juices and bile,
and be capable of multiplying once they arrive in the GI tract.4
A complete list of necessary characteristics for commercially
available probiotic products can be found in Table 1.
Many beneficial eects have been attributed to the presence
of the Lactobacilli genera in the human GI tract. This species
of bacteria is commonly found in commercial probiotic pro-
ducts but unfortunately, very few people living in Western
societies have it in their colon; on the other hand, nearly the
entire populations of Africa and Asia do.8 Because of these
variations in colonized bacteria, specific strains of probiotics
may be beneficial to some people but not others, which is an
important factor to consider when conducting probiotic
research. The present article attempts to critically review how
human dietary interventions with probiotic strains can help to
reduce/prevent cardiovascular risk factors collectively associ-
ated with metabolic syndrome. These risk factors include
hypercholesterolemia, hypertension, obesity and type-2 dia-
betes (T2DM) (Fig. 1).
Fig. 1 A schematic representation depicting the risk factors of cardio-
vascular diseases and the potential probiotic microorganisms that are
reported to reduce the risk for each of these risk factors.
This journal is The Royal Society of Chemistry 2016
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Review
Hypocholesterolemic eects of
probiotics
Though cholesterol is an essential substance for cell function
and integrity, increased levels of blood cholesterol over a long
period may result in atherosclerosis, and is therefore con-
sidered a major risk for CVDs. In fact, the possibility of heart
attack is three times higher in individuals with hypercholester-
olemia as against those with normal blood lipid profiles.12 In
the 1970s, Mann discovered the lipid-lowering eects of fer-
mented milk products. He suggested that these eects were
due to the inhibition of cholesterol synthesis from acetate, a
precursor for acetyl coenzyme A.13 After this pioneering study
that reported the cholesterol-lowering eect of fermented milk
containing a wild Lactobacillus strain, numerous studies inves-
tigated the hypocholesterolemic eects of lactic acid bacteria
(LAB), particularly strains of Lactobacillus and Bifidobacterium.14
Many subsequent studies have been successful in repro-
ducing similar results, showing significant reductions in low
density lipoprotein (LDL) and total cholesterol with probiotic
consumption. Other studies have found increases in high
density lipoprotein (HDL) cholesterol, reduction in systolic
blood pressure (SBP), increases in antioxidant activity, and
influences on leptin regulation.10,15,16
In 2000, Agerholm-Larsen et al. conducted a randomized,
double-blind study on 70 overweight and obese adults using
three dierent probiotic yogurts; one contained Streptococcus
thermophilus and two strains of Lactobacillus acidophilus,
the second contained S. thermophilus and one strain of
L. rhamnosus, and the third yogurt contained S. thermophilus
and Enterococcus faecium (G). Two placebo groups were used;
one was given conventional yogurt and the other placebo
pills. Subjects treated with the third type of yogurt (G) for
8 weeks showed an 8.4% reduction in their LDL-cholesterol
concentrations, which the authors claim that it would parallel
to a decline in the risk of CVD by 2030% ( p < 0.05).17
A randomized, double blind, placebo-controlled sub-study was
conducted in Helsinki in 2008 to determine if the probiotic
Lactobacillus rhamnosus GG (LGG) would have an eect on the
lipidomic profiles of healthy adults.18 LGG was chosen for the
sub-study due to the fact that it was found to have the
highest anti-inflammatory potential in the authors previous
study. However, these researchers did not find statistically sig-
nificant dierences in the serum lipid levels of the partici-
pants post-intervention. While investigating the changes in
inflammatory variables, the researchers found a trend
towards decreased levels of the mediator lysophosphatidylcho-
line. This mediator is associated with angiogenesis, carcino-
genesis and is a major atherogenic lipid of oxidized LDL.
Lysophosphatidylcholine has also been associated with vascu-
lar inflammation and coronary atherosclerosis. Another
finding of this study was a reduction in sphingomyelin (SM),
a membrane sphingolipid and precursor of certain signaling
molecules such as ceramide and sphingosine. According to
Bismuth et al., SM has been found in significantly high
Food Funct., 2016, 7, 632642 | 633
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Review Food & Function

amounts in aortic plaque and is a major predictor of heart

Sadrzadeh-Yeganeh et al.26
Agerholm-Larsen et al.17
disease.19
Some of the mechanisms through which probiotics are

Schaafsma et al.25
thought to exhibit a hypocholesterolemic eect could be: bile

Kiessling et al.15
salts deconjugation by bile-salt hydrolase (BSH), bacterial cell
membrane assimilation of cholesterol, and short chain fatty

Author (s)
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acid (SCFA) production by probiotics. Among these, BSH

activity is an essential factor for colonization and therefore
considered a basic criterion for the selection of cholesterol-
lowering probiotics. For example, the LAB with BSH activities

14 were hypercholesterolemic
Normal healthy men (n = 30),

(n = 20) and females (n = 50),

years), among whom 15 were

overweight and obese males
are regarded as excellent candidates that meet this criterion.

normocholesterolemic and

90 female volunteers aged

29 healthy women, (1956
70 healthy, weight-stable,
It has been proposed that certain probiotic lactobacilli and
bifidobacteria enzymatically deconjugate bile acids leading to
their elevated rates of excretion. Therefore, cholesterol ( precur-

1855 years old,

3364 years old
Subject profile
sor of bile acids) is used up to synthesize bile acids so as to

1949 years
replace the ones lost during excretion, ultimately leading to a
drop in serum cholesterol levels.12 Numerous studies have
been conducted based on this principle. In a study by de
Rodas et al. hypercholesterolemia-induced pigs were used to

periods, 1st- control yogurt

investigate the hypocholesterolemic eect of a probiotic strain

yogurt for 11; 3rd- reverse

trial, placebo controlled

controlled double-blind

Randomized controlled
compliance-controlled,
two-way cross over trial

Cross-over study, three

L. acidophilus ATCC 43121, wherein a reduction in total blood

Randomized placebo-

Randomized, double-

yogurt for 18, control

of that in the second

for all; 2nd- probiotic
blind, placebo- and
cholesterol (11.8%) was observed ( p = 0.014).20 Further, Park
et al. also examined the cholesterol-lowering eect of

parallel study.
Trial design
L. acidophilus ATCC 43121 in hypercholesterolemic rats, and
showed that the probiotics supplementation reduced total

period.
serum cholesterol levels by 25% along with significant
reductions in very low density lipoproteins (VLDL), intermedi-
ate density lipoprotein and LDL-cholesterol levels (p < 0.05).21

HDL-cholesterol

cholesterol ratio
total cholesterol
and Total : HDL
LDL cholesterol

LDL cholesterol

LDL/HDL ratio
In another study conducted by Kiessling et al.15 in women, the levels by 5.4%

and improved
Reduction in

Reduction in

Decrease in
Increase in
hypocholesterolemic eect of yogurt containing probiotic
by 8.4%
Results

strains of L. acidophilus 145 and B. longum 913 was investigated.

It was found that the daily consumption of 300 g of the probio-
Studies showing hypo-cholesterolemic eects of probiotic yogurt products

tics yogurt resulted in the elevation of HDL-cholesterol level by

0.3 mmol L1 (p = 0.002) and the reduction in the ratio of LDL/
consumption

HDL cholesterol from 3.24 to 2.48 (p = 0.001).15 Sindhu and

450 mL
375 mL

Khetarpaul investigated the eects of a fermented food mixture

300 g

300 g
Daily

containing probiotic strains of L. casei (NCDC-19) and Saccharo-

myces boulardii and 1% dietary cholesterol on serum chole-
Colony forming

(conventional)
sterol levels in Swiss mice. The feeding of such a diet resulted
3.9 107 each

106107 each
units (CFU)

(probiotic)

in a drop in the total serum cholesterol and LDL-cholesterol

per gram

107108

106108

levels by 19% and 37%, respectively, as compared to controls.

However, HDL-cholesterol and triglyceride (TG) levels in serum
*

remained unaltered.22 Yet another study by Park et al. evi-

denced that diet-induced obese mice treated with the probiotic
Probiotic product

oligosaccharides

Synbiotic yogurt
Probiotic yogurt
Probiotic yogurt

strains L. curvatus HY7601 and L. plantarum KY1032 showed a

Probiotic and
conventional

significant reduction in plasma cholesterol level by 17% ( p <

with fructo-

0.05).23 More recently, Tsai et al. reported the hypocholesterole-

yogurt

mic eect of their LAB product PROBIOS-23 containing

*Information not available

strains of Lactobacillus rhamnosus, Bifidobacterium adolescentis

and Pediococcus acidilactici in hypercholesterolemic hamsters. It
Bifidobacterium lactis
Enterococcus faecium

acidophilus La5 and

was demonstrated that PROBIOS-23 showed a remarkable

longum and 1% of
and two strains of
Microorganisms

cholesterol-lowering eect (up to 22.88%, 25.53% and 56.96%

Bifidobacterium

oligo-fructose
Streptococcus
thermophilus
Lactobacillus

Lactobacillus

Lactobacillus

reductions in serum total cholesterol, triglycerides and LDL-C

acidophilus,
acidophilus

levels, respectively as compared to control ( p < 0.05).14

Table 2

One commercially available cholesterol-lowering probiotic

Bb12

product is Cardioviva, which has been approved by Health

634 | Food Funct., 2016, 7, 632642 This journal is The Royal Society of Chemistry 2016
 View Article Online

Food & Function Review

Canada as an over-the-counter diet supplement for cardio-

Kekkonen et al.18
Agerholm-Larsen

Swine model (Yorkshire barrows, n = 33) three de Rodas et al.20

Kiessling et al.15
vascular health benefits. It is also available in the USA and

Park et al.21

Park et al.23

Tsai et al.14
Europe. The product consists of 100 mg capsules, each con-
Author(s)

et al.17 taining 2 billion live bacterial cells of the strain Lactobacillus

reuteri NCIMB 30242. It has been reported that a daily intake
of the product (2 capsules per day) reduces LDL-cholesterol
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with a mean age of 42 years (range 2355) and

replicate trials of 8 pigs and one replicate trial

levels by 11.6% in hypercholesterolemic adults.24 Table 2 sum-

fat diet (n = 27, normal diet (ND group, n = 9)

(n = 20) and females (n = 50), 1855 years old

Healthy adults (n = 26, 14 females, 12 males)

Male C57BL/6J mice (n = 36), 4 weeks old. High-

29 healthy women, aged 1956 years. 15 of
marizes the cholesterol-lowering eects of some of the probio-
70 healthy, weight-stable, overweight and

of 9 pigs, weighing approximately 92 kg.

a mean BMI of 24 kg m2 (range 2030).
obese (25.0 < BMI < 37.5 kg m2) males

these were normocholesterolaemic and

14 women were hypercholesterolaemic
tic yogurt products and Table 3 summarizes the laboratory and
clinical trials.

Male Sprague-Dawley rats (n = 36)

Male hamsters 3-week-old, n = 50

Owing to a lot of varied outcomes of clinical studies on the
eect of probiotics on lipid metabolism, Cho and Kim very
recently published their report on meta-analysis of random-
ized controlled trials (RCT) that quantified prospectives of pro-
biotics in managing blood lipid levels. The study involved 30
Subject profile

RCTs with 1624 participants (828 in intervention groups and

796 in placebo groups). Subjects administered with probiotics
(Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus
plantarum, Lactobacillus helveticus, or Enterococcus faecium deli-
vered via milk, yogurt/cheese, or capsule/drink) showed
reduced total cholesterol and LDL-cholesterol compared to
A randomized, double blind,

controlled, cross-over study

control subjects by 7.8 mg dL1 (95% CI: 10.4, 5.2) and

Randomized, placebo- and

placebo-controlled 3-week
clinical intervention trial

7.3 mg dL1 (95% CI: 10.1, 4.4), respectively ( p < 0.05). They
compliance-controlled,

Randomized, Placebo

Randomized, Placebo

Randomized, Placebo

were not able to show any major eect of probiotics on HDL-

Placebo-controlled

Placebo-controlled

cholesterol or TG. Even the eect of probiotics on total chole-

parallel study.

Randomized,

Randomized,

sterol and LDL-cholesterol relied on several factors. It was

Trial design

controlled.

controlled

observed that significant eects were better for higher baseline

total cholesterol levels, prolonged treatment, particular probio-
tic strains as well as industrial sponsorships. Reflecting on the
limitations seen in this meta-analysis and previous clinical
in their LDL-cholesterol concentrations, which is parallel
S. thermophilus, E. faecium (G) showed an 8.4% reduction

No statistically significant dierence was observed in the

eect (up to 22.88%, 25.53% and 56.96% reductions) in

trials, the authors conclude that the existing clinical evidence

However decreased levels of the inflammatory mediator
serum lipid levels of the participants post-intervention.

reduction in plasma cholesterol level by 17% (p < 0.05)

serum total cholesterol, TG and LDL-cholesterol levels,

(P = 0.002) and the reduction in the ratio of LDL/HDL
significant reductions in very low density lipoprotein,
intermediate density lipoprotein and LDL-cholesterol

PROBIOS-23 showed remarkable cholesterol-lowering

to a decline in the risk of CVD by 20 30% (p < 0.05)

is not substantial enough to endorse probiotics as an alterna-

Daily consumption of the probiotics resulted in the
Reduction in total serum cholesterol levels by 25%,

Feeding of probiotics resulted showed a significant

Laboratory and clinical trials on hypo-cholesterolemic eects of probiotics

elevation of HDL-cholesterol level by 0.3 mmol L1

A reduction in total blood cholesterol (11.8%) was
lysophosphatidylcholine and sphingomyelin were

tive therapy to improve blood lipid profile; and urge for better
Subjects treated with the yogurt (G) containing

clinical trials with long follow-up periods to validate the eec-

respectively as compared to control (p < 0.05)

tiveness and safety of probiotics for lowering cholesterol

cholesterol from 3.24 to 2.48 (p = 0.001)

levels.27
Thus, in spite of all the alleged benefits from the human
clinical studies carried out in the past several years, a critical
conclusion cannot be given due to several factors such as, the
poorly elucidated mechanism for cholesterol removal, probio-
tics strain dependency, practicality of laboratory results in the
observed (p = 0.014)

in vivo systems, and discrepancies in the data of dierent

levels (p < 0.05).

eects on serum cholesterol levels.

observed.
Results

Anti-hypertensive eects of probiotics

Hypertension also plays a major role in the development of
adolescentis and Pediococcus
Lactobacillus rhamnosus GG

rhamnosus, Bifidobacterium

CVDs and has been closely linked with stroke, ischemic heart
L. rhamnosus, Enterococcus
Streptococcus thermophilus

L. acidophilus ATCC 43121

L. acidophilus ATCC 43121

PROBIOS-23 Lactobacillus
Lactobacillus acidophilus,

L. curvatus HY7601 and

disease and heart failure. Recent scientific reports point out

L. acidophilus 145 and

L. plantarum KY1032

that probiotics and their metabolites can be exploited to

Microorganisms

manage hypertension via mechanisms such as improving total

B. longum 913

cholesterol and LDL-cholesterol levels, reducing blood glucose

faecium (G).

acidilactici

levels and insulin resistance, and regulating the reninangio-

Table 3

tensin system.28 Few studies have demonstrated that probiotic

(LGG)

strains such as Lactobacillus casei, Streptococcus thermophilus,

This journal is The Royal Society of Chemistry 2016 Food Funct., 2016, 7, 632642 | 635

Review
L. plantarum and L. helveticus significantly reduce SBP.29 In a
human study, older hypertensive subjects were made to
consume a daily dose of 95 mL sour milk fermented with
L. helveticus and Saccharomyces cerevisiae. At the end of an
8 week trial period, it was found that the systolic and diastolic
blood pressure (DBP) decreased significantly by 14.1
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3.1 mmHg and 6.9 2.2 mmHg ( p < 0.01), respectively.30
There are also a number of studies on probiotics and their
interactions with the reninangiotensin system (RAS). RAS con-
sisting of the angiotensin-converting enzyme (ACE) plays a
major role in the regulation of blood pressure (BP). In RAS,
renin hydrolyses plasma angiotensinogen, liberating the in-
active angiotensin I, which in turn is converted to angiotensin II
by ACE. Angiotensin II can cause vasoconstriction and elevate
BP. Therefore, ACE inhibition is a key clinical target for BP
control.31 Fermentation is considered to be an eective way to
produce the bioactive peptides with ACE-inhibitory pro-
perties.32 A number of products that are fermented with
specific strains of microbes, e.g. fermented milk, cheese,
yogurt, and soymilk are reported to be good sources of ACE-
inhibitory peptides.33 Probiotics, that possess caseinolytic and
lactose hydrolyzing enzyme systems, thrive in milk products
and initiate fermentation, resulting in the generation of ACE-
inhibitory peptides.34 Therefore, intake of dairy products or
milk proteins along with the specific probiotics seems to be a
potential option to lower BP. A study by Korhonen reported
that Lactobacillus helveticus ferment milk protein casein to
release ACE-inhibitory antihypertensive tripeptides such as
Val-Pro-Pro and Ile-Pro-Pro.35 Ong and Shah demonstrated the
Cheddar cheeses fermented with probiotic strains of lacto-
cocci also release ACE-inhibitory peptides.36 Similarly,
Rhynen et al. reported that yogurt, cheese, and milk fermen-
ted with L. casei ssp. rhamnosus, L. acidophilus and bifidobac-
teria release ACE-inhibitory peptides.37 Similar studies were
performed in tofu-based medium (fermented with L. fermen-
tum and L. bulgaricus) and soy whey (fermented with
L. acidophilus) wherein the production of peptides with ACE-
inhibitory properties was demonstrated.38,39 In a study by
Aihara et al., powdered fermented milk (fermented with Lacto-
bacillus helveticus CM4) rich in ACE-inhibitory tripeptides (Val-
Pro-Pro and Ile-Pro-Pro) was assessed for its eect on hyperten-
sion. A randomized, placebo-controlled, double-blind study
was conducted on 40 subjects with highnormal BP (HN
group) and 40 subjects with mild BP (MH group). Each subject
was administered 6 test tablets (12 g) containing the powdered
fermented milk (test group) or the same amount of placebo
tablets ( placebo group). At the end of 4 weeks, a significant
decrease in DBP in the HN group was observed (i.e. 5.0 mmHg
(0.1, 9.9; p = 0.04) compared with the placebo group). There
was no significant change in SBP. In the MH group, SBP
decreased by 11.2 mmHg (4.0, 18.4; p = 0.003) and there was a
statistically non-significant decrease in DBP of 6.5 mmHg
(0.1, 13.0; p = 0.055) compared with the placebo group. Thus,
the authors concluded that the daily intake of the tablets con-
taining powdered fermented milk with L. helveticus CM4 in
subjects with highnormal BP or mild hypertension lowers
636 | Food Funct., 2016, 7, 632642
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Food & Function
elevated BP without any undesirable side-eects.40 Gmez-
Guzmn et al., probed the cardiovascular eects of probiotic
Lactobacillus fermentum CECT5716 (LC40), or L. coryniformis
CECT5711 (K8) plus L. gasseri CECT5714 (LC9) (1 : 1) in spon-
taneously hypertensive rats (SHR). Ten Wistar Kyoto rats
(WKY) and 30 SHR were arbitrarily allocated to 4 groups (n =
10): a control WKY group, a control SHR group, an LC40-
treated SHR group, and a K8/LC9-treated SHR group (at a dose
of 3.3 1010 colony forming units (CFU) per day in drinking
water). At the end of the 5 week treatment period a gradual
drop in SBP (13.4 1.9%, and 14.7 1.9% by LC40 and K8/
LC9, respectively, as against untreated SHR, p < 0.01) was
observed.41 In a study by Chen et al., the ACE-inhibitory
activity of fermented milk produced by 259 Lactobacillus helve-
ticus strains isolated from traditional Chinese and Mongolian
fermented foods was investigated. Among them, fermented
milk produced by strain H9 (IMAU60208) showed the highest
in vitro ACE-inhibitory activity (86.4 1.5%), and measurable
levels of Val-Pro-Pro (2.409 0.229 M) and Ile-Pro-Pro (1.612
0.114 M). The long-term (7 weeks) daily consumption of H9-
fermented milk induced a significant antihypertensive eect
on SHR, and the SBP and DBP were significantly lower, by 12
and 10 mmHg, respectively, compared to the control receiving
saline ( p < 0.05). Thereby, the study identified a novel probio-
tic L. helveticus strain from kurut (fermented yak milk)
sampled from Tibet (China), which has a potential to be deve-
loped as a functional food for managing BP.42
A recent systematic review by Khalesi et al. sought to eluci-
date the eects of probiotics on BP by meta-analysis of ran-
domized, controlled trials (included 9 trials). Intake of
probiotics led to a significant changed SBP by 3.56 mmHg
(95% CI, 6.46 to 0.66) and DBP by 2.38 mmHg (95% CI,
2.38 to 0.93) versus control groups ( p < 0.05). A higher
reduction was observed with combined as against single
species of probiotics, for both SBP and DBP. Trials using sub-
group analysis with baseline BP 130/85 mmHg compared
with <130/85 mmHg showed a more significant improvement
in DBP. A treatment period less than 8 weeks, as well as a daily
dose of probiotics less than 1011 CFU did not result in a sig-
nificant reduction in SBP or DBP. Thus the meta-analysis indi-
cates that the intake of probiotics may improve BP by a modest
level, with a probable significant eect when baseline BP is
elevated, with an intake of a combination of probiotics
species, a higher daily dosage (1011 CFU) for a prolonged
period (8 weeks). The authors also recommend future studies
investigating the eect of dierent products with dierent
species and doses to substantiate the results of this meta-ana-
lysis.28 Further, Mahboobi et al. conducted a RCT comprising
60 prediabetic patients (2565 years old), who were randomly
allocated to the intervention (receiving 500 mg probiotic cap-
sules, n = 30) or placebo control group (n = 30) for 8 weeks.
The probiotic capsules mainly contained Lactobacillus casei
(7 109 CFU), Lactobacillus acidophilus (2 109 CFU), Lacto-
bacillus rhamnosus (1.5 109 CFU), Lactobacillus bulgaricus
(2 108 CFU), Bifidobacterium breve (2 1010 CFU), Bifido-
bacterium longum (7 109 CFU), and Streptococcus thermophilus
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Food & Function Review

(1.5 1010 CFU). At the end of the treatment period, the probiotic

Mahboobi et al.43
Gmez-Guzmn
supplementation did not induce any significant alterations in

Aihara et al.40

Chen et al.42
Hata et al.30
Author(s) total cholesterol, LDL-cholesterol, HDL-cholesterol, TG, TG/
LDL and LDL/HDL ratios. After adjusting for possible confoun-

et al.41
ders, HDL-cholesterol was significantly lowered in the placebo
group versus probiotic group. Percent change in SBP was sig-
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nificantly dierent in the probiotic group versus placebo group

A total of 36 hypertensive subjects

40 subjects with high-normal BP

(HN group) and 40 subjects with

Wistar Kyoto rats (WKY) (n = 40)

spontaneously hypertensive rat

spontaneously hypertensive rat

(3.10 2.22 vs. 3.24 1.96, p = 0.01), however this signifi-
cance did not subsist after confounders were adjusted ( p >

Wistar Kyoto rats (WKY)

0.05). Therefore, the authors proposed the necessity for more

60 prediabetic patients
mild BP (MH group).

selectively inbred for

selectively inbred for

powerful experiments in this area with a higher sample size
and probiotic dosage, as well as the control of potential con-
aged 4086 years

(2565 years old)

Subject profile

founders.43 Table 4 summarizes the anti-hypertensive eects

of some of the probiotics.
models

models
Regardless of extensive mechanistic data and promising
results from in vitro and animal studies, the potential eect of
probiotic bacteria on hypertension in humans remains uncer-
A randomized, placebo

tain and therefore needs further investigation.

Randomized, Placebo

placebo-controlled,
double-blind study

placebo-controlled

placebo-controlled

controlled trial
A randomized,

A randomized,

A randomized,

Probiotics and weight management

Trial design

controlled

Obesity is a global epidemic, and is considered a major risk

factor for CVD because of its association with other comorbid-
ities such as altered cardiovascular structure and function,
confounders, HDL-cholesterol was significantly lowered in
the placebo group versus probiotic group. (3.10 2.22 vs.
observed (i.e. 5.0 mmHg (0.1, 9.9; P = 0.04); no significant

statistically non-significant decrease in DBP of 6.5 mmHg

LC40 and K8/LC9, respectively, at the end of the 5 weeks,

(0.1, 13.0; p = 0.055) compared with the placebo group.

hypertension, type-2 diabetes, chronic inflammation and dysli-

A gradual drop in SBP (13.4 1.9%, and 14.7 1.9% by

3.24 1.96, p = 0.01), however this significance did not

Probiotic supplementation after adjusting for possible
3.1 mmHg and 6.9 2.2 mmHg (p < 0.01) respectively

pidemia.44 Recent findings suggest that the gut microbiota

Single oral dose of H9- fermented milk significantly
change in SBP. In the MH group, SBP decreased by
A significant decrease in DBP in the HN group was
The SBP and DBP decreased significantly by 14.1

subsist after confounders were adjusted (p > 0.05).

could play an imperative role in regulating weight and may be

11.2 mmHg (4.0, 18.4; p = 0.003) and there was a

p < 0.01 as against untreated SHR) was observed

accountable for obesity in some people.45,46 The gut micro-

attenuated the SBP, DBP and mean BP of SHR

biota is thought to participate in regulation of the absorption

of carbohydrates and lipids, by fermenting substrates passing
through the colon.47 The dierence in the microbial compo-
sition of the gut in obese versus lean persons is a topic of
immense scrutiny and debate. For instance, several studies
have testified the increased ratio of Firmicutes to Bacteroidetes
in obese mice as against lean mice; however, these results are
not suciently verified in human studies.48 It has also been
Probiotics that may be useful as anti-hypertensive agents

observed that the reduction of bifidobacteria in the gut of

obese individuals may lead to elevated levels of lipopoly-
saccharides in plasma, which in turn triggers the production
Results

of proinflammatory cytokines.49 A prolonged state of inflam-

mation increases the risk of insulin resistance.19 These obser-
vations suggest that the consumption of probiotics in order to
Lactobacillus fermentum CECT5716 (LC40), or
L. coryniformis CECT5711 (K8) plus L. gasseri

restore resilient microbiota and reduce inflammation may rep-

L. acidophilus, L. rhamnosus, L. bulgaricus,
L. helveticus and Saccharomyces cerevisiae

resent a novel tool in the management of obesity.29 Few other

Lactobacillus helveticus CM4 (powdered

Prebiotic capsule-Lactobacillus casei,

studies report that it may not be the state of obesity that

directly aects the composition of gut microbiota but the high
Lactobacillus helveticus strain H9

Bifidobacterium breve, B. longum,

fat diet consumed by the individual.5052 It was also reported

Streptococcus thermophilus

that when an obese person who has a higher Firmicutes :

CECT5714 (LC9) (1 : 1)

Bacteroidetes ratio alters his/her diet to include less fat, this

ratio is reversed. Ley et al. studied the fecal gut microbiota in
fermented milk)
Microorganisms

12 obese human subjects for a year, randomly allocating them

to either a fat-restricted or carbohydrate-restricted low-calorie
diet. Before diet therapy, obese participants had fewer Bacter-
Table 4

oidetes ( p < 0.001) and more Firmicutes ( p = 0.002) than lean

control participants. Following weight loss, the relative pro-

This journal is The Royal Society of Chemistry 2016 Food Funct., 2016, 7, 632642 | 637
 View Article Online

Review Food & Function

Stenman et al.57
portion of Bacteroidetes increased while the Firmicutes

Sanchez et al.54
decreased; irrespective of the diet, but the findings correlated

Park et al.23

Savcheniuk
Lee et al.55
Author(s)
only with the percentage of lost weight. Thus it is not clear

et al.56
why obese people have more Firmicutes and therefore
additional work is needed to better elucidate the cause-and-
eect association between gut microbiota and obesity.53
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absence of pregnancy, breast-feeding or

old. High-fat diet (n = 27, normal diet The study by Sanchez examined the eect of Lactobacillus
Male C57BL/6J mice (n = 36), 4 weeks

Obese men and women (1855 years;

n = 20, (females n = 10, males n = 10)

rhamnosus CGMCC1.3724 (LPR) supplementation on weight

Newborn Wistar rats, in each group

menopause stable body weight no

Male C57Bl/6J mice, 8 weeks old,

loss in obese men and women in a double-blind, placebo-con-
trolled, randomised trial over 24 weeks. Each subject was
administered 2 capsules per day of either LPR formulation (1.6
smoking, drug or alcohol

108 CFU) or a placebo. Each group underwent moderate

energy restriction for the first 12 weeks followed by 12 weeks
of weight maintenance. After the first 12 weeks and after 24
Subject profile

weeks, there was no significant mean weight loss when all the
subjects were considered. However, the mean weight loss in
n = 9)

women in the LPR group was significantly higher than that in

women in the placebo group ( p = 0.02) after the first 12 weeks.
The LPR group women lost weight and fat mass continuously
controlled, randomized trial

represented by both sexes,

during the weight-maintenance period, whereas opposite

All groups were equally
Double-blind, placebo-
Randomized, Placebo

Randomized, Placebo

changes were seen in the placebo group. LPR-induced weight

Placebo controlled

loss in women was also associated with the increase in the

number of bacteria of the Lachnospiraceae family in feces.
Trial design

Thus the study showed that the LPR formulation aided a

controlled

controlled

gender-dependent weight loss.54 Table 5 summarizes some of

the studies that reported the anti-obesity eects of probiotics.
A recent systematic review and meta-analysis by Park and
No significant mean weight loss when all the subjects

Bae assessed the data from clinical trials that have tested the
reduced weight gain and improved glucose tolerance.
than that in women in the placebo group (p = 0.02)

Treatment with B. lactis 420 significantly decreased

fat mass in obese and diabetic mice as observed by
were considered. However, the mean weight loss in

Conjugated linoleic acid produced by L. rhamnosus

resulted in significant reduction in total body and

eectiveness of probiotics as a treatment for weight loss. Only

women in the LPR group was significantly higher

multiprobiotic to glutamate-induced obese rats

Daily oral administration of 2.5 mL kg1 of the

4 of the studies were included in the RCTs that compared the

accumulation in diet-induced obese mice was

PL60 produced showed anti-obesity eects in

Reduction in both body weight gain and fat

therapeutic eectiveness of probiotics with a placebo. It was

observed that the meta-analysis of these data did not show any
significant eect of probiotics on body weight and BMI (body
weight, n = 196; mean dierence, 1.77; 95% CI, 4.84 to 1.29;
visceral adipose tissue weight.

p = 0.26; BMI, n = 154; mean dierence, 0.77; 95% CI, 0.24 to

1.78; p = 0.14). However, the authors claim that the low
diet-induced obese mice.

number of RCTs included, the total sample size, and the meth-
Probiotics that may help with body weight management

odological quality of the primary studies were not satisfactory

to depict a conclusive report. Thus, more meticulously
designed RCTs are needed to substantially analyze the eect of
observed.

probiotics on body weight management.58 Thus, in spite of

Results

numerous promising findings, more extensive investigations

are necessary to clearly comprehend both the cause-and-eect
relationship between gut microbiota of diverse composition
spp., Lactococcus, Propionibacterium genera
bacteria of Bifidobacterium, Lactobacillus

and the propensity to be obese or lean and to evaluate whether

Lactobacillus rhamnosus CGMCC1.3724

Multiprobiotic containing 14 probiotic

Bifidobacterium animalis ssp. lactis 420

altering the gut microbiota could aid in sustainable body

Lactobacillus curvatus HY7601 and

weight management.
Lactobacillus plantarum KY1032

Lactobacillus rhamnosus PL60

Anti-diabetic eects of probiotics

Microorganisms

Diabetes mellitus has gained epidemic proportions world over.

It is a chronic condition characterized by either the bodys
inability to produce an adequate amount of insulin or the
Table 5

reduced eectiveness of insulin. It is regarded as a risk factor

for CVD because type 2 diabetes mellitus (T2DM) patients have

638 | Food Funct., 2016, 7, 632642 This journal is The Royal Society of Chemistry 2016
 View Article Online

Food & Function Review

increased rates of cardiovascular morbidity and mortality.59

Al-Salami et al.67

Hulston et al.69
Ejtahed et al.16
Moroti et al.68
Accumulating evidence suggests that the consumption of high

Yadav et al.66
fructose and high fat diet may lead to chronic inflammatory

Author(s)
conditions, which not only induces insulin resistance, but also
disrupts the normal gut microbiota.60 To this end, many
studies have proposed strategies to alter the gut microbiota
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with probiotics in order to deal with T2DM. Probiotics are not

Wistar rats (aged 23 months, weight

placebo group and 10 for symbiotic

Probiotic (n = 8) or a control (n = 9)
only shown to restore the microbial balance of the gut but are

Healthy human subjects (n = 17);

Human volunteers (n = 20, 10 for
considered as eective supplements to the existing insulin

64 subjects, aged 3060 years

resistance therapies.

group), aged 50 to 60 years

The anti-inflammatory eect of Lactobacillus reuteri and the

Male albino Wistar rats

anti-oxidant and anti-inflammatory eects of L. plantarum are
among studies by which the impact of probiotics on the man-

Subject profile
agement of diabetes has been investigated.61,62 Few other

350 50 g)
studies suggest that the oral or diet supplementation of heat-
killed cells of L. casei decreased the plasma glucose concen-
tration and incidence of T2DM.6365 Further, Yadav et al.
reported that the feeding of probiotic dahi (yogurt) containing

blind, placebo-controlled

blind, controlled clinical

108 strains of L. acidophilus and L. casei delayed the onset of

A randomized, double-
Randomized, placebo-

Randomized, placebo-

blind controlled study

Randomized, double-

Randomized, double-
glucose intolerance, hyperglycemia, hyperinsulinemia, dyslipi-
demia, and oxidative stress in fructose-induced T2DM rats.

controlled study

controlled study
Therefore, the authors concluded that consumption of the

Trial design
probiotic yogurt might reduce the risk of T2DM.66 A study by
Al-Salami et al. evidenced that pre-treatment with a probiotic

study

trial
concoction of L. acidophilus, Bifidobacterium lactis and
L. rhamnosus decreased blood glucose concentrations and
enhanced the bioavailability of gliclazide, a drug used to treat

10% (p < 0.05) and whole-body insulin sensitivity decreased by 27%

was maintained in the probiotic group (4.4 (SE 0.8) and 4.5 (SE 0.9)
over-eating, respectively, p < 0.05. Glucose AUC values increased by
non-insulin-dependent T2DM in alloxan-induced T2DM rats.67

(p < 0.05) in the control group, whereas normal insulin sensitivity

concentrations and enhanced the bioavailability of gliclazide, an

(p < 0.01), hemoglobin A1c and malondialdehyde (p < 0.05) and

Fasting plasma glucose levels increased in the 4th week (control

Treatment with a probiotic concoction decreased blood glucose

group: 5.3 (SE 0.1) versus 5.6 (SE 0.2) mmol l1 before and after
A study by Moroti et al. reported that the daily intake of a

increased erythrocyte superoxide dismutase and glutathione

Decline in blood glucose levels by 38.89% in T2DM subjects

Probiotic yogurt significantly lowered fasting blood glucose

peroxidase activities and total antioxidant status (p < 0.05).

symbiotic shake containing strains of L. acidophilus and
Delayed the onset of glucose intolerance, hyperglycemia,

B. bifidum, and fructo-oligosaccharides, was associated with a

hyperinsulinemia, dyslipidemia, and oxidative stress in

decline in blood glucose levels by 38.89% in T2DM subjects

before and after overeating, respectively (p > 0.05).

( p < 0.05).68 Since it is known that oxidative stress is a key in
the pathogenesis and progression of T2DM, and that probiotic
foods have been reported to possess anti-oxidative properties,
Ejtahed et al. probed the eects of probiotic and conventional
Probiotics that help in the management of diabetes mellitus

yogurt on antioxidant status and blood glucose in T2DM

patients (64 subjects, 3060 years old, assigned to 2 groups in
a randomized, double-blind, controlled clinical trial).16 Probio-
fructose-induced T2DM rats

tic yogurt containing Lactobacillus acidophilus La5 and Bifido-

bacterium lactis Bb12 was given to the intervention group
(300 g d1) and conventional yogurt was given to the control
anti-diabetic drug

group (300 g d1). At the end of a 6 week trial period, probiotic

yogurt significantly lowered fasting blood glucose ( p < 0.01)
(p < 0.05)

and hemoglobin A1c ( p < 0.05) and increased erythrocyte

Results

superoxide dismutase and glutathione peroxidase activities

and total antioxidant status ( p < 0.05) compared to the control
group. The serum malondialdehyde concentration also signifi-
L. acidophilus and B. bifidum

Lactobacillus acidophilus La5

108 strains of L. acidophilus

cantly decreased compared to the baseline value in both

Lactobacillus casei Shirota
Bifidobacterium lactis and

and Bifidobacterium lactis

groups ( p < 0.05). Thus it was shown that intake of probiotic

yogurt improved fasting blood glucose and antioxidant status
Microorganisms

in T2DM patients.16 In yet another clinical study, Hulston

L. acidophilus,

L. rhamnosus

et al. probed the eect of probiotic supplementation with

and L. casei

Lactobacillus casei Shirota (LcS) on diet-induced insulin resistance.

Table 6

Healthy human subjects totaling 17 were randomly assigned to

Bb12

(LcS)

a probiotic (n = 8) or a control (n = 9) group. The probiotic

This journal is The Royal Society of Chemistry 2016 Food Funct., 2016, 7, 632642 | 639

Review
group was given LcS-fermented milk drink twice daily for 4
weeks, whereas the control group received no supplemen-
tation. After following a normal diet for first 3 weeks, they
were given a high-fat (65% of energy), high-energy (50%
increase in energy intake) diet for the final week. Body weight
increased by 0.6 (SE 0.2) kg in the control group ( p < 0.05) and
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by 0.3 (SE 0.2) kg in the probiotic group ( p > 0.05). Fasting
plasma glucose levels increased in the 4th week (control group:
5.3 (SE 0.1) versus 5.6 (SE 0.2) mmol l1 before and after over-
eating, respectively, p < 0.05), whereas fasting serum insulin
concentrations were maintained in both groups. Glucose AUC
values increased by 10% ( p < 0.05) and whole-body insulin
sensitivity decreased by 27% ( p < 0.05) in the control group,
whereas normal insulin sensitivity was maintained in the pro-
biotic group (4.4 (SE 0.8) and 4.5 (SE 0.9)) before and after
overeating, respectively ( p > 0.05). Thus, the authors suggest
that probiotic supplementation could potentially prevent diet-
induced metabolic diseases such as T2DM.69
A recent RCT meta-analysis study by Kasiska and Drze-
woski evaluated the ecacy of probiotics to modify selected
cardiometabolic risk factors in T2DM subjects. The parameters
that were considered included fasting plasma glucose (FPG),
insulin concentration, insulin resistance, hemoglobin A1c
(HbA1c), as well as the levels of total cholesterol, TG, LDL- and
HDL-cholesterols, and C-reactive protein (CRP). Eight trials
with 438 individuals were chosen for the meta-analysis. The
results demonstrated a significant eect of probiotics on low-
ering HbA1c levels (standardized mean dierence [SMD],
0.81; CI, 1.33 to 0.29, P = 0.0023; I2 = 68.44%; p = 0.0421
for heterogeneity) and HOMA-IR (SMD, 2.10; CI 3.00 to
1.20, p < 0.001; I2 = 82.91%; p = 0.0029 for heterogeneity).
However, no significant eect was seen on FPG, insulin, and
CRP levels as well as the lipid profile. Thus, the authors
suggest that probiotic supplementation might improve meta-
bolic control in T2DM subjects to some extent.70 Table 6 sum-
marizes the studies on anti-diabetic eects of probiotics.
Therefore, on the basis of the outcome of a limited number
of studies, it is not yet the right time to conclusively have a say
on the ecacy of probiotic therapy in T2DM. The assessment
of probiotic ecacy on a larger human population is extremely
multifarious due to many confounding factors such as diet,
endotoxin content of ingested food, frequency of food intake,
physical activity, glucose metabolism, insulin and other
gut hormones. Hence, there is a need for more powerful
and better metabolic clinical studies on a larger human
population.
Comments and conclusions
A regular and adequate consumption of probiotics may
produce a number of health benefits including reducing cardi-
ovascular risk factors. Probiotics have been shown to lower
LDL-cholesterol, and improve the LDL/HDL ratio as well as
lower blood pressure and inflammatory mediators, blood
glucose levels and BMI. All of these markers have been shown
640 | Food Funct., 2016, 7, 632642
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Food & Function
to individually or in combination participate in pathogenesis
of CVD. Though the health benefits of fermented food pro-
ducts was known to mankind from time immemorial, the
importance of the probiotics and their beneficial influence on
the gut microbiota was realized only in the recent times. Scien-
tific developments in dierent fields including bioinformatics,
metabolomics, metagenomics and metatranscriptomics have
provided convincing evidence pertaining to the role of gut
microbiota in human health and disease.71 Altering the gut
microbiota with probiotics with the intention of reinstating
the resilient microorganisms seems to be a promising area in
nutrition research.
In conclusion, probiotics seem to be safe dietary sup-
plements with many health benefits. In a report from WHO
(2001), it has been included that there have been no acute
negative eects associated with the consumption of probio-
tics.4 Therefore, probiotic products are becoming one of the
fast-selling over-the-counter diet supplements and functional
foods.72 Although probiotics were primarily studied for their
impact on gastrointestinal function, emerging data suggest
benefits from probiotics in other body systems including the
cardiovascular system. Thus far, a significant number of both
human and animal studies suggest cholesterol lowering pro-
perties of probiotics when the right bacteria are consumed
appropriately and adequately. The studies on anti-hyperten-
sion, anti-diabetic and anti-obesity eects of probiotics seem
promising as well. Additional studies are needed to under-
stand the mechanisms by which probiotics may beneficially
impact various aspects of cardiovascular function. There is
also an immense scope for research on how probiotics could
be incorporated into food through newer techniques such as
microencapsulation and cell immobilization.73
Acknowledgements
Dr Moghadasians research program is supported by the
Natural Sciences and Engineering Research Council of Canada
(NSERC).
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