Probiotics and Prebiotics: Present Status and Future
Perspectives on Metabolic Disorders
Ji Youn Yoo
and Sung Soo Kim
Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Korea;
Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive
Oxygen Species and Biomedical Science Institute, School of Medicine, Kyung Hee University,
Seoul 02447, Korea
* Correspondence: email@example.com; Tel.: +82-2-961-0524
Received: 24 December 2015; Accepted: 11 March 2016; Published: 18 March 2016
Metabolic disorders, including type 2 diabetes (T2DM) and cardiovascular disease (CVD),
present an increasing public health concern and can signiﬁcantly undermine an individual’s quality
of life. The relative risk of CVD, the primary cause of death in T2DM patients, is two to four times
higher in people with T2DM compared with those who are non-diabetic. The prevalence of metabolic
disorders has been associated with dynamic changes in dietary macronutrient intake and lifestyle
changes over recent decades. Recently, the scientiﬁc community has considered alteration in gut
microbiota composition to constitute one of the most probable factors in the development of metabolic
disorders. The altered gut microbiota composition is strongly conducive to increased adiposity,
dysfunction, metabolic endotoxemia, systemic inﬂammation, and oxidative stress. Probiotics and
prebiotics can ameliorate T2DM and CVD through improvement of gut microbiota, which in turn
leads to insulin-signaling stimulation and cholesterol-lowering effects. We analyze the currently
available data to ascertain further potential beneﬁts and limitations of probiotics and prebiotics in the
treatment of metabolic disorders, including T2DM, CVD, and other disease (obesity). The current
paper explores the relevant contemporary scientiﬁc literature to assist in the derivation of a general
perspective of this broad area.
metabolic disorders; type 2 diabetes (T2DM); cardiovascular diseases (CVD); gut
microbiota; probiotics; prebiotics
Metabolic diseases, such as type 2 diabetes (T2DM) and cardiovascular diseases (CVD), present an
important social problem, considering the increasing morbidity rate in both developing and developed
countries. Over the last decade, dynamic changes in dietary macronutrient ingestion and lifestyle have
rapidly increased the prevalence of metabolic disorders. T2DM patients have a higher risk of CVD, the
primary cause of death. Recently, scientists and nutritionists have proposed that metabolic disorders
might result from an alteration in gut microbiota composition [
]. Bacteroidetes and Firmicutes
are dominant (>90% of the total microbial population) in human intestine and play a signiﬁcant
role in nutrient absorption, mucosal barrier fortiﬁcation, xenobiotic metabolism, angiogenesis, and
postnatal intestinal maturation. Diet controls the composition of these bacteria, which are crucial in
the development of metabolic disorders [3–7].
The term “probiotic” originates from the Greek word meaning “for life” [
]. In 1989, Fuller
deﬁned the term probiotic as “a live microbial feed supplement which beneﬁcially affects the host
animal by improving its intestinal balance” [
]. In 1995, Gibson et al. deﬁned prebiotics, on the other
hand, as “a non-digestible food ingredient that beneﬁcially affects the host by selectively stimulating
Nutrients 2016, 8, 173; doi:10.3390/nu8030173 www.mdpi.com/journal/nutrients
Nutrients 2016, 8, 173 2 of 20
the growth and/or activity of one or a limited number of bacteria in the colon” [
]. A long history of
human consumption of probiotics (particularly lactic acid bacteria and biﬁdobacteria) and prebiotics exists,
either as natural components of food or as fermented foods. In 76 B.C., the Roman historian Plinius
recommended the ingestion of fermented milk products to a patient who had gastroenteritis [
Probiotics and prebiotics began to blossom in the late 1800s and early 1900s. Subsequently, Metchnikoff
noticed health effects stemming from the alteration of the intestinal microbial balance, and he
proposed that the consumption of yogurt containing Lactobacillus would result in a decrease in
toxin-producing bacteria in the gut and an increase in the longevity of the host [
]. In 1900,
Tissier recommended the addition of biﬁdobacteria to the diet of infants suffering from diarrhea,
claiming that biﬁdobacteria superseded the putrefactive bacteria that caused the condition [
then, numerous scientists have noticed that bacteria in the colon produce many different types of
compounds that maintain both positive and negative effects on gut physiology, as well as other systemic
]. As an example, short-chain fatty acids (SCFAs) are produced by the fermentation
of bacteria, when the bacteria in the colon metabolize proteins and complex carbohydrates. These
SCFAs may decrease the risk of developing metabolic disorders due to the increasing demand of
cholesterol for de novo synthesis of bile acids [
]. Probiotics and prebiotics are considered to be
alternative supplements against metabolic disorders, as the manner of their action is thought to be
based largely on a modulation of the composition and function of the intestinal microbiota. Several
studies have shown that probiotics and prebiotics play an important role in the amelioration of T2DM
and CVD [
]. A number of researchers studied the potential of food-grade bacteria for treating
or preventing diabetes. The studies indicated that certain probiotics (L. lactis, biﬁdobacteria) secrete an
insulin analog and promote the expected biological effect on target adipocytes both in human and
in animal subjects [
]. Accumulating evidence suggests that supplementation of probiotics and
prebiotics could have preventative and therapeutic effects on CVD due to a reduction in total serum
cholesterol, low-density lipoprotein (LDL-cholesterol), and inﬂammation [
]. This highlights a
growing recognition of the role of probiotics and prebiotics in modulating the metabolic activities of
the human gut microbiota and regulating the immune system, in turn improving the host’s health.
We analyze the current knowledge of the molecular mechanisms by which probiotics and
prebiotics participate in host functions that affect the prevention and treatment of metabolic disorders,
including T2DM, CVD, and obesity. The current review focuses on the important functions of probiotics
and prebiotics through relevant contemporary studies to assist in the derivation of a general perspective
of this broad area.
2. Gut Microbiota Compositions and Metabolic Disorders
Interactions between the gut microbiota and the host’s overall health begin at birth, and the nature
of microbial diversity changes throughout the host’s life. The interaction of gut epithelial cells with
microbes and their metabolites is a key mediator of the cross-talk between the gut epithelium and other
cell types [
]. Additionally, this interaction assists in maturation of the intestinal epithelial layer, the
enteric nervous system, the intestinal vascular system, and the mucosal innate immune system. Human
gut microbiota are strongly involved in diverse metabolic, nutritional, physiological, and immunological
processes, and changes in the composition of the gut microbiota directly influence the host’s health [
Although early intestinal microbiota studies focused on only a minority of bacteria species and their
functions, recent researchers have discovered more than 1100 bacteria species and were able to analyse
their functional properties as related to certain disease states, such as T2DM, CVD, obesity and cancer,
because of the development of advanced techniques, such as DNA-based analyses [
]. In particular,
changes of gut microbiota composition are strongly associated with increased adiposity,
metabolic endotoxemia, systemic inflammation, and oxidative stress associated with T2DM .
Intestinal microbiota can affect host adiposity and regulate fat storage which, in some cases,
can contribute to obesity [
]. The change in intestinal microbiota and the reduced bacterial
diversity were also observed in obese conditions. For example, Ley et al. demonstrated a signiﬁcant
Nutrients 2016, 8, 173 3 of 20
relationship between gut microbiota composition and obesity. This study showed that the number
of Firmicutes increased while the number of Bacteroidetes decreased in obese mice compared to lean
]. Furthermore, other studies revealed that transplantation of microbiota from obese mice
into germ-free mice, despite reduced food intake, signiﬁcantly increased adipose tissues compared to
transplantation of microbiota from lean mice [
]. Larsen et al. also demonstrated that the proportions
of Bacteroidetes to Firmicuteswere signiﬁcantly and positively associated with reduction of glucose
tolerance. They showed that microbiome diversity was not different between T2DM and non-DM
patients, but the composition and function were different, including butyrate-producing bacteria
and opportunistic pathogens [
]. The change of these bacteria compositions increases susceptibility
to infections, immune disorders, inﬂammation, oxidative stress and insulin resistance, events that
are mediated by metabolic endotoxemia, which involves exposure to noxious intestinal products,
particularly lipopolysaccharides (LPS) [
]. LPS is a component of the gram-negative bacteria’s cell
wall. LPS binds to toll-like receptor-4 (TLR4) on endothelial cells, monocytes,and macrophages.
The reaction initiates an inﬂammatory response and oxidative stress, leading to the activation of
B and AP-1. These activations produce pro- inﬂammatory cytokines, chemokines, adhesion
molecules and reactive oxygen species (ROS), which can cause endothelial damage and dysfunction.
For example, trimethylamine N-oxide (TMAO) contributesto the development and progression of
cardiovascular disease and the early detection of myocardial injury [
]. TMAO, an oxidation product
of trimethylamine (TMA), is a relatively common metabolite of choline in animals [
]. Tang et al.
validated that increased TMAO levels are associated with increased risk of incidence of major adverse
cardiovascular events in a large independent clinical cohort (n = 4007). According to the study, people
in the highest quartile of circulating TMAO levels had a 2.5-fold increased risk of having a major
adverse cardiac event, when compared to those in the lowest quartile [
]. Furthermore, TMAO levels
were dose-dependently related to obesity and insulin resistance in animal studies [
]. Although the
mechanisms by which circulating TMAO promotes CVD are currently unclear, there is a possible
hypothesis of cardiovascular physiology. Expression of scavenger receptors (CD36 and SR-A1) on
macrophages and foam cell formation were increased by supplementation of TMAO in normal chow
diet mice [
]. Furthermore, supplementation of TMAO reduces reverse cholesterol transport in
macrophage, which would be predicted to advance atherosclerosis [
]. Although supplementation
of TMAO clearly inﬂuences multiple steps of both forward and reverse cholesterol transport, the
underlying molecular mechanisms behind these observations remain unclear. Therefore, further
study should be performed to elucidate how circulating TMAO levels are sensed to elicit pathological
responses and to explain mechanisms by which TMAO promotes CVD.
Numerous studies also support the theory that gut microbiota can inﬂuence host immune
functions. Gut microbiota cooperate with the host immune system through an extensive array of
signalling pathways, which involve many different classes of molecules and extend beyond the
immune system. These immune-mediated signalling processes are directly associated with chemical
interactions between the microbe and the host.
The deﬁnition of a probiotic is “a live microbial feed supplement which beneﬁcially affects the host
animal by improving its intestinal balance” [
]. The initial concept of probiotics originated from the
work of Metchnikoff at the beginning of the 20th century. Subsequently, Shaper et al. (1963) and later
Mann (1974) observed a reduction in serum cholesterol after consumption of copious amounts of milk
fermented with wild Lactobacillus and/or Biﬁdobacterium [
]. Probiotics have been investigated as a
potential dietary supplement that can positively contribute to an individual’s health [
]. These health
beneﬁts are not limited to the intestinal tract, but also include amelioration of systemic metabolic
disorders, such as T2DM and CVD.
Since probiotics have been recognized as a key health promoter thought to stem from the
modulation of host immune responses [
], earlier studies have mainly focused on the relationship
Nutrients 2016, 8, 173 4 of 20
between probiotics and immune diseases, such as atopic dermatitis and inﬂammatory bowel disease.
Intestinal bacteria, including Lactobacilli and Biﬁdobacterium, can cross the intestinal mucous layer
and stimulate phagocytic activities in the spleen or in other organs for many days [
responses of spleen cells to concanavalin A (a T-cell mitogen) and lipopolysaccharide (a B-cell mitogen)
were signiﬁcantly enhanced in mice supplied with Lactobacillus rhamnosus, Lactobacillus acidophilus, or
Biﬁdobacterium. Despite administration of these probiotics, the mice did not exhibit any signiﬁcant
increase in interleukin-4 production by spleen cells nor peripheral blood leucocytes. Instead, spleen
cells from mice that consumed these probiotics produced signiﬁcantly higher amounts of interferon-
response to stimulation with concanavalin A, compared to cells from the control animals .
Several studies have demonstrated that patients with T2DM have a signiﬁcantly lower number of
bacteria that produce butyrate when compared to healthy people. Larsen et al. showed an association
between T2DM and compositional changes in the intestinal microﬂora. In particular, they demonstrated
a considerably lower proportion of phylum Firmicutes and biﬁdobacteria in T2DM patients than
in non-diabetic individuals [
]. Interestingly, several studies have revealed that probiotics
and prebiotics might maintain the potential to improve lipid proﬁles, including the reduction of
LDL-cholesterol, serum/plasma total cholesterol, and triglycerides or increment of high-density
lipoprotein (HDL-cholesterol) in the context of treating CVD [
]. Previous studies have
proven that the administration of certain probiotics can promote short-chain fatty acids (SCFAs) that
alter secretion of incretin hormones and attenuate cholesterol synthesis .
A prebiotic was ﬁrst deﬁned as “a non-digestible food ingredient that beneﬁcially affects the host
by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon,
and thus improves host health” [
]. Subsequently, Roberfroid stated that “A prebiotic is a selectively
fermented ingredient that allows speciﬁc changes, both in the composition and/or activity in the
gastrointestinal microﬂora that confers beneﬁts upon host well-being and health.” [
]. Gibson et al.
examined three criteria, namely: (a) resistance to gastric acidity, hydrolysis by mammalian enzymes,
and gastrointestinal absorption; (b) fermentation by intestinal microﬂora; and (c) selective stimulation
of the growth and/or activity of intestinal bacteria associated with health and well-being [
the prebiotics that fulfill these three criteria are fructooligosaccharides, galactooligosaccharides, lactulose,
and non-digestible carbohydrates. The non-digestible carbohydrates include large polysaccharides (inulin,
resistant starches, cellulose, hemicellulose, pectins, and gums), some oligosaccharides that escape digestion,
and unabsorbed sugars and alcohols. Most prebiotics, including fructooligosaccharides and inulin, are
digested by bifidobacteria and stimulate the growth of their colonies. These bacteria influence homeostasis
of intestinal cells and inhibit the growth of pathogenic bacteria [56–58].
SCFAs, such as acetic acid, propionic acid, and butyric acid, are the essential end-products of
carbohydrate metabolism. Fermentation of carbohydrates represents a major source of energy for epithelial
cells in the colon [
]. SCFAs reduce the development of gastrointestinal disorders, cardiovascular
diseases, and cancers by inducing apoptosis (programmed cell death) [
]. Furthermore, prebiotics
could stimulate the immune system, produce Vitamin B, inhibit pathogen growth, and lower blood
ammonia. They also appear instrumental in promoting cell differentiation, cell-cycle arrest, and apoptosis
of transformed colonocytes by inhibiting the enzyme histone deacetylase and decreasing the transformation
of primary to secondary bile acids [
]. Moreover, SCFAs decrease glucagon levels in a dose-dependent
manner, improve glucose tolerance, and activate glucagon-like peptide1 (GLP-1), which can stimulate the
elevation of insulin production and increase insulin sensitivity [
]. Thus, administration of prebiotics
probably plays a regulatory role in modulating endogenous metabolism.
5. Effects of Probiotics and Prebiotics on T2DM
Over recent decades, an abundance of evidence has emerged to suggest a close link between T2DM,
CVD, and inﬂammation. Insulin plays an important role in the regulation of glucose homoeostasis
Nutrients 2016, 8, 173 5 of 20
and lipid metabolism. The failure of target organs to respond to the normal action of insulin is termed
insulin resistance, which in turn often results in compensatory hyperinsulinemia. This hyperinsulinemia
leads to an array of metabolic abnormalities thought to constitute the pathophysiologic basis of
metabolic syndrome which can lead to CVD and coronaryheart disease .
Moreover, an excess accumulation of visceral fat leads to insulin resistance. In addition, this
excess causes a chronic low-grade inﬂammation characterized by increased macrophage inﬁltration and
pro-inﬂammatory adipokine production. Pro-inﬂammatory adipokines obstruct the insulin-signaling
pathway in peripheral tissues and promote the development of insulin resistance [
]. These data
indicate that T2DM is associated with a state of chronic low-level inﬂammation that leads to the
development of CVD. The molecular and cellular underpinnings of obesity-induced inﬂammation and
the signaling pathways at the intersection of metabolism and inﬂammation contribute to T2DM and
SCFAs maintain important functions in T2DM patients. Interestingly, some studies have found
that the number of SCFAs producing bacteria were signiﬁcantly lower in people with T2DM. These
SCFAs not only bind to G-protein coupled receptors (GPCRs), but also cause the exhibition of various
biological effects. For example, SCFAs promote secretion of GLP-1, one of the major incretin hormones
primarily synthesized by entero-endocrine L-cells. This hormone inhibits glucagon secretion, decreases
hepatic gluconeogenesis, improves insulin sensitivity, and enhances central satiety, resulting in
weight loss [
]. Furthermore, some evidence indicates that SCFAs may directly prevent low-grade
inﬂammatory response, as bacteria actively translocate from the intestines into the mesenteric
adipose tissue (MAT) and the blood. Amar et al. proved that certain probiotics (e.g., Biﬁdobacterium
animalis subsp. lactis 420) could reverse the low-grade inﬂammatory response by reducing mucosal
adherence and bacterial translocation of gram-negative bacteria from the Enterobacteriaceae. As a result,
probiotics may attenuate adipose tissue inﬂammation and several features of T2DM . Asemi et al.
demonstrated the effects of oral supplements of probiotics on metabolic proﬁles, high sensitivity
C-reactive protein (hs-CRP), and oxidative stress in T2DM. In this randomized, placebo-controlled, and
parallel designed study, they utilized an oral supplement comprising seven viable and freeze-dried
strains: Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus rhamnosus, Lactobacillus bulgaricus,
Biﬁdobacterium breve, Biﬁdobacterium longum, and Streptococcus thermophilus. The test subjects ingested
the supplement for eight weeks. The results indicated that the consumption of multi-probiotics led to
a meaningful reduction in fasting plasma glucose compared to the placebo group .
Additionally, probiotics could promote antioxidation in T2DM patients. Erythrocyte superoxide
dismutase, glutathione peroxidase activities, and total antioxidants increased in the group
supplemented with probiotic yogurt compared to the control group [
]. Administration of Lactobacillus
acidophilus and Lactobacillus casei with dahi (yogurt in the Indian subcontinent) significantly suppressed
streptozotocin (STZ)-induced oxidative damage in pancreatic tissues by inhibiting the lipid peroxidation
and nitric-oxide formation [
]. Yadav et al. also demonstrated that administration of the probiotic dahi
in the diet significantly delayed the onset of glucose intolerance, hyperglycemia, hyperinsulinemia, and
dyslipidemia, and decreased oxidative stress in high fructose-induced diabetic rates .
In contrast, few papers demonstrated that probiotics fail to maintain signiﬁcant effects on the lipid
proﬁles of T2DM patients. One of these studies concluded that supplementation of probiotics failed to
cause signiﬁcant changes in total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides (TG),
TG/LDL, or LDL/HDL ratios, following eight weeks of intervention [
]. Additionally, Lewis et al.
showed that lactobacillus acidophilus administered to 80 hypercholesteraemic volunteers for six weeks
failed to produce any signiﬁcant effects of probiotics on serum blood lipid [
]. Although some
studies showed no beneﬁts of probiotics on serum lipids, numerous animal or human studies have
demonstrated the beneﬁts of probiotics and prebiotics. Hence, further studies are required to improve
our knowledge of, and eliminate uncertainties regarding, probioticsand prebiotics (Tables 1 and 2).
Nutrients 2016, 8, 173 6 of 20
Table 1. Characteristics of the included animal studies.
and Dose (Per Day)
Rice bran (10
Decreased serum total cholesterol
Increase ∆6-desaturase activity and
serum arachidonic acid
Fukushima et al.,
B. lactis Bb-12,
B. longum Bb-46
Buffalo milk yoghurt
Decreased total cholesterol
Increasedfecal excretions of bile acids
Abd El-Gawad et al.,
Probiotics L. plantarum PH04 Mice
Decreased total cholesterol and TG
Increased fecal lactic acid bacteria
Nguyen et al.,
L. lactis biovar
Rats Dahi 15% (150g/kg) 8 weeks
Decreased glucose intolerance,
dyslipidemia and oxidative stress
Yadav et al.,
L. acidophilus NCDC14,
L. casei NCDC19
(73 ˆ 10
Inhibition of insulin depletion, lipid
peroxidation and nitrite formation
Yadav et al.,
Probiotics B. animalis lactis 420 Mice
Decreased glucose intolerance, tissue
inﬂammation, insulin resistance and
Amar et al., 2011 [
Prebiotics Inulin Rats 5% 4 weeks
Decrease LDL-C, total cholesterol,
Liver lipid and TG concentrations
Increased HDL-C, and faecal
excretions of bile acids
Kim et al., 1998 
Abbreviations: Biﬁdobacterium (B), lactobacillus (L), streptococcus (S), colony forming units (CFU), tab (tablet), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein
(HDL-C), triglycerides (TG).
Nutrients 2016, 8, 173 7 of 20
Table 2. Characteristics of the included human studies.
and Dose (Per Day)
Probiotics L. acidophilus L1, Human
4 weeks Decreased total cholesterol
Anderson et al.,
Probiotics B. longum BL1 Human/Rats
100 mL/3 ˆday
Decreased total cholesterol,
LDL-C and TG
Xiao et al.,
Probiotics L. acidophilus LA-1 Human
(3 ˆ 10
HDL-C, LDL-C, TG
Lewis et al.,
Probiotics L. fermentum Human
tablet/2 ˆ day
(2 ˆ 10
HDL-C, LDL-C, TG
Simons et al.,
Probiotics L. casei subsp. casei. Human
Yogurt 100 g/day and
Decreased total cholesterol
Fabian et al.,
L. rhamnosus LC705,
(2 ˆ 10
HDL-C, LDL-C, TG
Hatakka et al.,
L. acidophilus La5,
B. lactis Bb12
Yogurt 300 g/day
(2 ˆ 10
Decreased total cholesterol
Ejtahed et al.,
L. acidophilus La5,
B. lactis Bb12
(2 ˆ 10
Decreased fasting blood
glucose levels and HbA
activities and total
Ejtahed et al.,
(14 ˆ 10
Decreased serum hs-CRP
Increased plasma total GSH
Prevention of a rise in
fasting plasma glucose
Asemi et al.,
Nutrients 2016, 8, 173 8 of 20
Table 2. Cont.
and Dose (Per Day)
Positive effects on systolic
LDL-C, HDL-C TG,
Mahboobi et al.,
Prebiotics Inulin Human
Decreased total cholesterol
Increased breath H2
excretion and fecal
Brighenti et al.,
Prebiotics Inulin Human
One pint of vanilla ice
cream (20 g/pint)
Decreased total cholesterol
Causey et al.,
Abbreviations: Biﬁdobacterium (B), lactobacillus (L), streptococcus (S), colony forming units (CFU), tab (tablet), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein
(HDL-C), triglycerides (TG).
Nutrients 2016, 8, 173 9 of 20
6. Effect of Probiotics and Prebiotics on CVD
Cardiovascular disease (CVD) affects blood vessels and/or the heart. CVD primarily stems
from hypercholesterolemia and dyslipidemia. Particularly, a high level of LDL-cholesterol is most
commonly associated with CVD. CVD represents the most prevalent cause of death in T2DM patients.
The relative risk of CVD is two to four times higher in T2DM patients than in non-diabetic people.
The most common lipid pattern in people with CVD consists of increased triglyceride-rich lipoproteins,
high levels of LDL-cholesterol, and low levels of HDL-cholesterol.
Healthy nutrition and lifestyle intervention constitute important parts of managing CVD.
Hypercholesterolemia patients may avoid the use of cholesterol-lowering drugs by practicing dietary
control or through administration of probiotics and/or prebiotics. Health food supplements, such
as probiotics and prebiotics, can modulate gut health and regulate the immune system through gut
microbiota. Persuasive studies have shown that well-established probiotics and/or prebiotics possess
hypocholesterolaemic effects in humans and animals. Nguyen et al. demonstrated that total serum
cholesterol and triglycerides were signiﬁcantly reduced in hypercholesterolaemic mice that ingested
Lactobacillus plantarum PH04 [
]. Moreover, some studies supportedthatbuffalo milk yogurt and
soymilk yogurt containing Biﬁdobacterium Bb-12 or Biﬁdobacterium longum Bb-46 were highly effective in
decreasing the concentration of total cholesterol by 50.3%, LDL- cholesterol by 56.3%, and triglycerides
by 51.2% compared to the levels of the control group [
]. Anderson et al. completed a similar
study, but they utilized a different probiotic called Lactobacillus acidophilus L1. They showed that daily
consumption of 200 g of yogurt containing Lactobacillus acidophilus after each dinner contributed to a
signiﬁcant reduction in serum cholesterol concentration compared to the placebo group [
study indicated that the combination of bacteria strains more effectively reduced total cholesterol and
liver cholesterol compared to individual bacteria strains. The supplied mixed-bacteria and Lactobacillus
acidophilus groups exhibited a 23%–57% decrease of cholesterol concentrations in the liver compared to
the control group. Additionally, cholesterol concentration in the supplied mixed-bacteria group was
lower than in single-bacteria supplemented groups .
Prebiotics may lead to hypocholesterolemia via two different mechanisms. First, lower cholesterol
absorption is caused by enhanced cholesterol excretion via feces. The other mechanism is the
production of SCFAs upon selective fermentation by intestinal bacterial microﬂora [
]. Causey et al.
concluded that a daily intake of 20 g of inulin (longer-chain prebiotics, containing 9–64 links per
saccharide molecule, fermented more slowly) signiﬁcantly reduced serum triglycerides compared to
the control group. They also found that serum LDL-cholesterol decreased and serum HDL-cholesterol
increased following the administration of inulin compared to the control group [
]. Another study
showed that when normolipidemic individuals consumed 18% of inulin on a daily basis without any
other dietary restrictions, total plasma cholesterol and triacylglycerols decreased by
7.9% ˘ 5.4%
7.8%, respectively. Glucose tolerance tests demonstrated that inulin signiﬁcantly enhanced
breath H2 excretion (IAUC test 280
40; placebo 78
h), as well as fecal concentration
of Lactobacillus-lactate [
]. Thus, inulin may possess lipid-lowering potential in normolipidemic
people, possibly mediated by mechanisms related to colonic fermentation. The addition of inulin
in the diet of rats induced higher excretions of fecal lipids and cholesterol compared to that of
rats in the control group. This increased level of excretion is attributed primarily to reduced
cholesterol absorption [
]. Other prebiotics, such as oligodextrans, lactose, resistant starches and their
derivatives, lactoferrin-derived peptides, and N-acetylchitooligosaccharides have also been identiﬁed
as maintaining hypocholesterolaemic effects in people with T2DM who are at high risk of developing
Although numerous studies have documented the cholesterol-lowering effects of probiotics
and/or prebiotics in both
experiments, the effects remain controversial. Hatakka et al.
refuted the purported hypocholesterolaemic effect of probiotics, and reported that the administration
of Lactobacillus rhamnosus LC705 failed to inﬂuence blood lipid proﬁles in 38 men with mean cholesterol
levels of 6.2 mmol/L after a four-week treatment period [
]. Lewis et al. argued that the administration
Nutrients 2016, 8, 173 10 of 20
of Lactobacillus acidophilus failed to affect any serum lipid changes [
]. Furthermore, Simonsa et al.
showed that a supplement of Lactobacillus fermentum failed to signiﬁcantly change plasma total
cholesterol, LDL-cholesterol, HDL-cholesterol, or triglycerides [
]. Although many studies suggest
that probiotics can favorably alter serum lipids, some human studies examining the beneﬁts of
probiotics on serum lipids have shown conﬂicting results. This may bedue to the possibility that
different delivery systems may affect the experiment result. The human studies, which used capsules
probiotics, did not show signiﬁcant changes inserum lipids compared to fermented bacteria product.
A study assumed that sufﬁcient time was not available for the freeze-dried probiotic capsule to become
metabolically fully activated before being ﬂushed into the colon. They thought that fermented dairy
products can be metabolically active when ingested, whereas freeze-dried probiotic capsules cannot
because the small intestinal transit is relatively short [
]. Furthermore, during the intervention,
the human studies could not control for an individual’s life style, including dietary intake, whereas
animal studies could, which may be one of the possible reasons for the apparent lack of effect.
Therefore, further researches are required to unequivocally establish the potential role ofprobiotics in
the management of metabolic disorder (Tables 1 and 2).
7. Others (Obesity)
Obesity causes low-grade inﬂammation and an altered composition of the gut microbiota.
Some studies have attempted to identify correlations between the composition of the microbiota
and the occurrence of inﬂammation and metabolic alterations in individuals with obesity [
The low-grade systemic inﬂammation in the obese phenotype is attenuated by peptides produced in
the gut. The composition of gut microbiota affects synthesis of these peptides. One such protein is
the serum amyloid A3 protein (SAA3). The gut microbiota serve to regulate SAA3 expression in the
adipose tissue [
]. Expression of this peptide was considerably higher in the adipose tissue and
colon of mice colonized with a normal gut microbiota from a healthy wild-type mouse when compared
with germ-free mice [
]. Collectively, these ﬁndings suggest that the gut microbiota modulate the
biological systems that regulate the availability of nutrients, energy storage, fat mass development, and
inﬂammation in the host, each of which is associated with the obese phenotype [
]. Signiﬁcantly, the
number of biﬁdobacteria is inversely correlated with fat mass, glucose intolerance, and LPS level [
Furthermore, inulin-type fructans affect gut ecology and stimulate immune cell activity. They also
decrease weight gain and fat mass in obese individuals [96–98].
8. Molecular Mechanisms of Action
Several hypotheses have been presented to explain how the mechanistic actions of probiotics and
prebiotics, including the improvement of gut microbiota, the stimulation of insulin signaling, and the
lowering of cholesterol, ameliorate the T2DM and CVD condition. Among the molecular mechanisms,
the current paper focuses on SCFA receptors and bile-salt hydrolase (BSH) that are associated with
regulation of insulin secretion, fat accumulation, and cholesterol levels.
Recently, two orphan GPCRs, GPR41 (known as FFAR3) and GPR43 (known as FFAR2), were
found to be receptors for SCFAs, including acetate, propionate, and butyrate. FFAR2 is primarily
activated by acetate and propionate, whereas FFAR3 is more often activated by propionate and
]. Both receptors are mainly expressed in L cells, which are located along the length of
the intestinal epithelium and respond directly to luminal signals [
]. FFAR2 and FFAR3 stimulate
the release of GLP-1 and peptide YY (PYY), which improve insulin secretion. The expression levels of
GLP-1 and PYY are often reduced in individuals with T2DM. Therefore, enhancement of GLP-1 and
PYY secretion from intestinal L cells could result in beneﬁcial effects in people with T2DM.
Several studies have shown that a deﬁciency of FFAR2 decreases SCFA-induced secretion of GLP-1
, and enhances insulin resistance. The injectable GLP-1 mimetics are associated
with good blood glucose control and a decreased incidence of hypoglycemia [
]. In addition,
FFAR2 regulates energy metabolism via promotion oﬂeptin secretion, adipogenesis, and inhibition of
Nutrients 2016, 8, 173 11 of 20
lipolysis in adipose tissue and adipocytes [
]. Obesity is frequently observed in FFAR2-deﬁcient
mice on a normal diet, while overexpressed FFAR2 in adipose tissue mice remain lean, even though the
mice are fed a high-fat diet. Isoproterenol-induced lipolysis is inhibited by SCFSs in a dose-dependent
manner in mouse 3T3-L1 derived adipocytes [
]. Kimura et al. concluded that FFAR2 activation
by SCFAs suppressed adipose-speciﬁc insulin signaling in white adipose tissues, and thus led to the
inhibition of fat accumulation .
Similarly, Samuel et al. demonstrated that germ-free mice with or without FFAR3 were colonized
by speciﬁc microbes. The results showed that PYY levels were decreased in FFAR3-deﬁcient mice,
indicating that the secretion of PYY from the intestine was regulated by SCFA-induced FFAR3
Moreover, FFAR3 is abundantly expressed in sympathetic ganglia. Inoue et al. showed that
SCFA-induced FFAR3 activation resulted in increased heart rate and energy expenditure through
sympathetic activation. Notably, the effects were not observed in FFAR3-deﬁcient mice. FFAR3
also directly promotes noradrenalin release from sympathetic neurons [
]. In contrast, FFAR3
suppresses energy expenditure and produces
-hydroxybutyrate in the liver during starvation. Thus,
sympathetic activity is regulated by SCFA-induced FFAR3, thereby maintaining energy balance.
Additional research has indicated that SCFAs are involved in the regulation of hepatic cholesterol
], as demonstrated via
experiments of the liver of germ-free mice. The liver
metabolism of germ-free and colonized mice differs considerably, possibly due to the increased inﬂux
of SCFAs into the liver of colonized mice [
]. The increased levels of stored triglycerides in the
liver and the increased production of the triglyceride transporters were observed in colonized mice.
Increased triglyceride synthesis in the liver of colonized mice was associated with reduced expression
of fasting-induced adipose factors, or angiopoietin-like 4 (ANGPTL4), in the small intestine. ANGPTL4
inhibits circulating lipoprotein lipase (LPL), which regulates the cellular uptake of triglycerides
in adipocytes [
]. ANGPTL4 is also a downstream target gene of peroxisome proliferator
activated receptors (PPARs), the agonists of which are widely utilized for the treatment of T2DM
and CVD [
mainly plays an important role in hepatic fatty acid oxidation, whereas
constitutes the master regulator of adipogenesis [
]. Moreover, research has indicated that
overexpression of ANGPTL4 in the liver leads to decreased activation of LPL and increased plasma
triglyceride levels [
]. Interestingly, ANGPTL4 is susceptible to regulation by the gut microbiota [
Germ-free ANGPTL4-deﬁcient mice gained considerably more fat mass and body weight compared
to colonized mice during high-fat feeding, indicating that ANGPTL4 directly mediates microbial
regulation of adiposity in mice [
]. Thus, ingestion of SCFAs-producing probiotics could increase
inﬂux of SCFAs into the liver, leading to regulation of ANGPTL4 (Figure 1).
SCFA-producing bacteria primarily produce acetate, butyrate, and propionate, which leads to
increased FFAR2 and FFAR3 activation. These enhancements of FFAR2 and FFAR3 not only promote
noradrenalin release, but also increase heart rate and energy expenditure for energy homeostasis.
SCFAs are involved in increased leptin secretion, adipogenesis, and the inhibition of lipolysis in
adipose tissues. In the intestine, SCFAs enhance the secretion of PPY and GLP-1. Moreover, an
improvement of triglyceride synthesis occurs due to an inﬂux of SCFAs into the liver, which leads to
decreased ANGPTL4 activation in the intestines. In addition, SCFA-producing bacteria regulate the
suppression of ANGPTL4, an inhibitor of LPL, which promotes increased lipid clearance.
Enzymatic deconjugation of bile acids by bile-salt hydrolase (BSH) has been proposed as
an important molecular mechanism in cholesterol-lowering effects. Researchers evaluated BSH’s
cholesterol-lowering effect utilizing Lactobacillus plantarum 80 and Lactobacillus reuteri, whereupon it
was shown that the enzyme responsible for bile-salt deconjugation in enterohepatic circulation can
be detected in probiotics indigenous to the gastrointestinal tract [
]. Bile consists of conjugated
bile acids, cholesterol, phospholipids, bile pigment, and electrolytes. Synthesized in the liver, bile
is stored at high concentrations in the gallbladder between meals. After food intake, it is released
into the duodenum. Bile works as a biological detergent that emulsiﬁes and solubilizes lipids for
digestion. BSH catalyzes the hydrolysis of glycine or taurine conjugated primary bile acids to create
Nutrients 2016, 8, 173 12 of 20
deconjugated bile acids. The deconjugated bile acids are less soluble and less efﬁciently reabsorbed
than their conjugated counterparts, leading to their elimination in the feces [
]. Deconjugation of
bile salts can lead to a reduction in serum cholesterol either by increasing the demand for cholesterol
for de novo synthesis of bile acids to replace those lost in feces or by reducing cholesterol solubility
and, thereby, absorption of cholesterol through the intestinal lumen [
]. Figure 2 shows the
mechanism of enzymatic deconjugation of bile acids by bile-salt hydrolase (BSH).
increased FFAR2 and FFAR3 activation. These enhancements of FFAR2 and FFAR3 not only
promote noradrenalin release, but also increase heart rate and energy expenditure for energy
lipolysis in adipose tissues. In the intestine, SCFAs enhance the secretion of PPY and GLP‐1.
which leads to decreased ANGPTL4 activation in the intestines. In addition, SCFA‐producing
Enzymaticdeconjugationofbile acids by bile‐salthydrolase(BSH)hasbeenproposed as an
important molecular mechanism in cholesterol‐lowering effects. Researchers evaluated BSH’s
the duodenum. Bile works as a biological detergent that emulsifies and solubilizes lipids for
of bile salts can lead to a reduction in serum cholesterol either by increasing the demand for
solubility and, thereby, absorption ofcholesterol
through the intestinal lumen [121,123]. Figure 2
Figure 1. Molecular mechanisms of short-chain fatty acid (SCFA) receptors.
Cholesterol is utilized as the precursor for synthesis of new conjugated bile acids, and the
and/or prebiotics. Key issues in this field are safety and efficacy. Currently, some probiotics
secondary bile acids in the enterohepatic circulation, which in turn could increase the risk of
or colorectal cancer . Lithocholic acid (LCA) is a secondary bile acid primarily
The genetic interactions between ingested probiotics and the native intestinalmicrobeshave
by DNA may be enhanced upon the ingestion of bacteria, leading to genetic rearrangements. In
Figure 2. bile-salt hydrolase (BSH) effects on lowering cholesterol by probiotics.
Nutrients 2016, 8, 173 13 of 20
Cholesterol is utilized as the precursor for synthesis of new conjugated bile acids, and the
activation of BSH by probiotics catalyzes primary bile acids to create deconjugated bile acids that are
less soluble and less efﬁciently reabsorbed in the intestine and liver. Decongugated bile acids also
contribute to the elimination of cholesterol in the feces.
9. Future Prospects
studies have been conducted utilizing an array of probiotics
and/or prebiotics. Key issues in this ﬁeld are safety and efﬁcacy. Currently, some probiotics
(Lactobacillus, Biﬁdobacterium) and prebiotics (inulin, oligofructose) do not require approval from
the FDA and are present in our daily dietary intake. Although the safety of probiotics and prebiotics
for food application has been conﬁrmed by several legal authorities worldwide, few studies have been
conducted regarding incidences of bloating, ﬂatulence, and high osmotic pressure, which can lead to
gastrointestinal discomfort [
]. Furthermore, the effects could vary depending on the individual
and the type of food containing the prebiotics or probiotics. Probiotics and prebiotics are believed to
be safe for oral consumption due to their relatively low capacity to cause adverse effects. However,
no standard safety guidelines currently exist for oral administration of probiotics and prebiotics in
human cases. Therefore, individual probiotics and prebiotics should be evaluated at speciﬁc dosages
to ascertain potential adverse reactions.
Although BSH was shown to be beneﬁcial, it may lead to an increase in potentially cytotoxic
secondary bile acids in the enterohepatic circulation, which in turn could increase the risk of cholestasis
or colorectal cancer [
]. Lithocholic acid (LCA) is a secondary bile acid primarily formed in the
intestines by the bacteria. Trauner et al. and Beilke et al. showed that administration of LCA and its
conjugates to animals causes intrahepatic cholestasis. In humans, abnormal bile acid composition,
especially an increase in LCA, was found in patients suffering from chronic cholestatic liver disease or
cystic ﬁbrosis [
]. However, most studies argued mainly for the beneﬁts rather than the adverse
effects of BSH from probiotics and/or prebiotics.
The genetic interactions between ingested probiotics and the native intestinal microbes have also
constituted a topic of interest. The genetic materials can be exchanged via three mechanisms, including
transduction, conjugation, and transformation. The transformation of intestinal microﬂora by DNA
may be enhanced upon the ingestion of bacteria, leading to genetic rearrangements. In addition, the
transmission of antibiotic-resistantgenes among beneﬁcial bacteria and harmful pathogens could be
associated with a complex microﬂora colony in the gastrointestinal tract. This transmission can, in
turn, lead to the evolution of antibiotic-resistant probiotics and the potential emergence of resistant
Metabolic disorders are undoubtedly associated with an increased risk of morbidity and mortality.
In our study, we sought to evaluate the effect of probiotics and prebiotics in the context of metabolic
disorders. Intestinal microbiota may play an important role in the pathogenesis of T2DM and CVD by
inﬂuencing body weight, pro-inﬂammatory activity, and insulin resistance. The scientiﬁc community,
in general, accepts that the gut microbiota composition and function can be regulated via probiotics
and prebiotics. Numerous studies have indicated that probiotics and prebiotics affect T2DM and
CVD by changing gut microbiota, regulating insulin signaling, and lowering cholesterol. However,
elucidating the interactions between intestinal microbiota and ingested probiotics continues to present
Some of the proposed mechanisms and experimental evidence speciﬁcally targeting
cholesterol-lowering effects remain equivocal. Therefore, more speciﬁc and thoroughly designed
trials are required to improve our knowledge and eliminate uncertainties. This will, in turn, provide
a deeper understanding of the underlying mechanisms and enable us to conduct a more optimal
safety assessment prior to the consumption of probiotics and prebiotics by humans. Moreover, no
Nutrients 2016, 8, 173 14 of 20
standard safety guidelines currently exist regarding the oral administration of probiotics and prebiotics
in human cases. Therefore, individual probiotics and prebiotics should be carefully evaluated in order
to determine potential adverse reactions. Future studies are required to increase our understanding of
the complex interplay between intestinal and ingested microbiota.
This work was supported by the National Research Foundation of Korea (NRF), and the
grant was provided by the Korean government (MEST) (No. 2011–0030072).
Author Contributions: Ji Youn Yoo and Sung Soo Kim conceived, designed, and drafted the manuscript.
Conﬂicts of Interest: The authors declare no conﬂict of interest.
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