European Review for Medical and Pharmacological Sciences 2018; 22: 7588-7605

Probiotics, prebiotics and synbiotics

for weight loss and metabolic syndrome
in the microbiome era
R. FERRARESE1, E.R. CERESOLA2, A. PRETI2, F. CANDUCCI3

1
Microbiology Unit, Vita-Salute San Raffaele University, Milan, Italy
2
Microbiology Unit, University of Insubria, Varese, Italy
3
Microbiology Unit, Ospedale San Raffaele, Milan, Italy

Abstract. – OBJECTIVE: Excessive body fat sheets updated October Available from: http://
and the associated dysmetabolic consequences www.who.int/mediacentre/factsheets/fs311/en/).
affect both developed and emerging countries. Metabolic comorbidities more frequently asso-
An altered gut microbiota composition is an im-
portant environmental cause of these conditions. ciated with excessive abdominal body fat and
Clinical trials targeting gut microbiome compo- obesity are dyslipidemia, insulin resistance, hy-
sition or functions with pro or prebiotics to pro- pertension (the so-called Metabolic Syndrome),
mote a healthier profile are considered a promis- diabetes, cardiovascular diseases (CVD), but also
ing tool for excessive body weight treatment and cancer1-7.
prevention of dysmetabolic complications. However, despite the increased risk to develop
MATERIALS AND METHODS: We searched
PubMed and Cochrane Library using combinations
metabolic syndrome or CVD, recent data suggest
of probiotics/prebiotics and synbiotics with obesi- that not the body fat mass alone but a systemic
ty/weight loss/metabolic syndrome as the search state of increased subclinical low-grade inflam-
terms. Clinical studies and significant pre-clinical mation and local (in the adipose tissue) metabolic
results showing molecular mechanisms support- dysfunction may explain the pathogenic potential
ing clinical results were also discussed. of adipose tissue accumulation despite genetic or
RESULTS: Several studies in humans and in environmental causes8. It has been proposed that
animal models have elucidated biological mech-
anisms supporting the observed clinical efficacy metaflammation is a key feature of the metabolic
of selected probiotic and prebiotic compounds syndrome, where a leaky intestinal barrier allows
for weight management. Efficacy appears to be translocation of proinflammatory bacterial com-
species or strain-specific. Fibers such as inu- ponents (such as lipopolysaccharide released by
lin or galactomannan promote independent and gram-negative bacteria, LPS). Metaflammation
synergistic beneficial effects. promotes insulin resistance in the liver (even-
CONCLUSIONS: Diet supplementation with syn-
biotics prepared using selected strains (such as
tually leading to non-alcoholic steatohepatitis;
Lactobacillus gasseri strains) showed to exert NASH) and the release of various inflammatory
weight-reduction and anti-inflammatory activity in mediators from adipose tissues8,9.
large independent studies. Their administration, Among the environmental determinants of
together with galactomannan and/or inulin fibers, obesity and its comorbidities, the intestinal micro-
may increase weight management effects due to biota has recently been proposed to have a signif-
synergistic effect on short chain fatty acid pro- icant impact10. Its role in human energy balance
duction and microbiota ‘re-configuration’.
has been demonstrated and, in a co-evolutionary
Key Words perspective, it can be speculated that the increased
Probiotic, Prebiotic, Synbiotic, Microbiome, Meta- energy extraction from ingested food obtained
bolic syndrome, Weight. by virtue of the vast enzymatic armamentarium
of intestinal bacteria (especially for plant-derived
Introduction complex carbohydrates) is an advantage in condi-
tions of limited food availability11,12. Nowadays the
Excessive body fat and its metabolic conse- increased availability of food in Western countries
quences are worldwide epidemics affecting both and changes in the proportion of diet components
developed and emerging countries (Obesity and have markedly changed the composition of our
overweight: World Health Organization; fact- gut microbiota13-15. The main responsible for this

7588 Corresponding Author: Filippo Canducci, MD, Ph.D; e-mail: [email protected]

 Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome

change is the increased intake of fat (especially Probiotics are defined as live microorganisms
unsaturated fatty acids) and sugar, the reduction that confer a health benefit to the host when admin-
of plant-derived carbohydrates, the consumption istered in adequate amounts29. Bifidobacterium and
of processed food with wide usage of antimicrobial Lactobacillus strains are still the most widely used
preservatives and the antibiotic abuse (especially at probiotic genera included in many functional foods
younger ages). and dietary supplements. Next generation probiotics,
The recent availability of the next generation such as F. prausnitzii, A. muciniphila, or Clostridia
technology for the massive sequencing of nucleic strains, were shown to be present in the majority
acid extracted from human samples (sputum, feces, of people’s microbiota, but their relative reduction
biopsies, etc.) allowed us to reveal changes in the was associated with increased risk of suffering from
microbiome (when referring to data collected from immunometabolic diseases. However, in part due
microbiota sequencing), population and sometimes to complex large-scale production of strictly an-
even variation of very few bacterial species related aerobe bacteria, they are still lacking clinical trials
with increased weight accumulation and with met- to support their beneficial usage as supplements30.
abolic dysfunctions or systemic inflammation10,16-21. At the same time, the newly discovered or better
In fact, the gut microbiota has important physi- elucidated beneficial interactions with the host of
ologic functions that have direct impact on host commercially available probiotics preparation can
metabolism, gut mucosal barrier development and nowadays lead to a more scientifically robust and
both local and systemic immune functions4,22-26. evidence-based therapeutic or preventive approach
Targeting gut microbiota composition or metabolic for weight loss, to limit the metabolic consequences
functions with natural and safe compounds, such of obesity or to maintain and reinforce the efficacy
as pro or prebiotics, to promote a healthier “non- of weight reduction regimens.
obese” profile might, therefore, represent a promis-
ing tool for prevention and treatment of obesity and
correlated diseases. Indeed, a heterogeneous group Materials and Methods
of pioneer clinical trials and more recent molecular
metagenomic analyses of intestinal microbes have The selected studies were reviewed inde-
investigated these possibilities27. pendently by all four researchers. Any disagree-
Recently, the ISAPP consensus panel pro- ment between the investigators was resolved by dis-
posed a new definition of a prebiotic that better cussion. The following information were collected:
fits recent data obtained in the “microbiome probiotic strain used, study design, duration of
era”: “a substrate that is selectively utilized by intervention, sample size, subjects’ characteristics,
host microorganisms conferring a health bene- age, dose of probiotics/prebiotics and composition
fit”28. Today, even if new substances are known of the synbiotic preparation, the vehicle used and
to influence microbiota composition, fructans results of the intervention. The search was limited
(fructooligosaccharides (FOS), inulin) and galac- to human studies for the generation of Tables.
tans (galactomannan or other galactooligosaccha- Significant pre-clinical results obtained with the
rides) dominate this group of compounds. Their bacterial strains present in the probiotic/synbiotic
activity is mainly mediated through enrichment compound described in the selected clinical stud-
of Lactobacillus and/or Bifidobacterium species ies were also analyzed to identify molecular mech-
but possibly also through modulation of the me- anisms explaining clinical results. Studies with
tabolism of other beneficial microorganisms, probiotics that enrolled less than 50 subjects were
such as Akkermansia muciniphila, Faecalibac- not considered, nor those that were not randomized
terium prausnitzii or some Clostridia groups28. placebo-controlled trials. All results with possible
The metabolic activity of gut microbes directly impact on weight loss and dysmetabolic diseases
affects host energy homoeostasis and variations were reported (BMI, body weight, TC, LDL-C,
of microbiome composition are associated with triacylglycerol (TAG), inflammatory markers, the
obesity pathogenesis10. Part of these effects may homeostasis model assessment of insulin resis-
also be due to the fact that humans utilize not tance (HOMA-IR), etc.). We searched PubMed,
only glucose, long-chain fatty acids, and amino Cochrane Library, and EMBASE databases from
acids as energy sources, but also short chain fatty their inception through October 2017, using com-
acids (SCFA) produced by these beneficial organ- binations of probiotics/prebiotics and synbiotics
isms through fermentation of dietary fibers that with obesity or weight loss metabolic syndrome,
reach the anaerobic colon environment. lactobacilli as the search terms.

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 R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

Plant-Derived Prebiotics: Glucomannan duction, reduction of LDL cholesterol (about 20%

and Inulin-Type Fructans total reduction) and non-HDL cholesterol (almost
Not all fibers have the same efficacy and struc- 20-30% reduction) both in adults and children
tural characteristics. There are short-chain (oli- at all doses of KJM used (2.0-15.1 g/d). Several
gofructose) and long-chain (polyfructose, such as early and more recent investigations34 have also
inulin) fructans typically present in the plant roots shown that supplements containing glucomannan,
where they are used as energy pools31. Moreover, as stated in the EFSA claim promoted weight loss
their preferential degradation by host or bacterial and reduction of postprandial glycemia. Another
enzymes in the small or in the large intestine oligosaccharide with interesting activity and suf-
respectively, suggests that enrich our diet with ficient body of good quality literature is inulin.
prebiotics supplemented with specific type of Even if inulin has not obtained an official claim
fibers can be more beneficial than a generic life- for weight-loss management, recent meta-analyses
style recommendation to eat indistinctly more of randomized clinical trials that tested the effect
vegetables. Eating adequate amounts of fibers, es- of inulin-type fructans on serum triacylglycerols
pecially highly viscous plant-derived fibers such and other dysmetabolic parameters showed that
as glucomannan or inulin, was demonstrated to the intake of inulin or oligofructose was associated
reduce serum triacylglycerols in humans32. with a significant decrease (about 20 mmol/L) in
Among the plant-derived beneficial fibers, serum triacylglycerol concentrations in the vast
glucomannan (KJM), extracted traditionally majority of clinical trials (>80% of trials)35,36. No-
from the tuber root of Amorphophallus konjac, tably, as already observed with galactomannan,
has been used for centuries in Asia as a food the effects were not dependent on the condition of
source and beneficial healthy remedy33. Its safety the patients (lipid levels before supplementation).
profile was recently assessed by the Food and Most effective and safe dosage varies from 3 to
Drug Administration and Health Canada, and 10 g of fibers. Self-supplementation or ad libitum
was approved for general use by the European administration of larger doses of purified complex
Union (as E425). More interestingly, in 2010, fibers (more than 10/15 grams/daily) should be
the European Food Safety Authority (EFSA) ap- avoided to minimizes gastrointestinal discomfort
proved important health claims related to the and bloating, that are otherwise commonly as-
usage of glucomannan and reductions in body sociated side effects that often reduce patients’
weight, postprandial glycemia, and blood cho- compliance. The amount of reduction in serum tri-
lesterol concentrations (EFSA Panel on Dietetic acylglycerol (7 and 8%) is remarkable, considering
Products, Nutrition and Allergies. EFSA J 2010; that it is obtained in a few weeks of supplemen-
8: 1798). EFSA strictly require assuming at least tation (4-12) without difficult-to-follow changes
1 g three times daily to allow the above men- in dietary (reduction of carbohydrates, fats, etc.)
tioned approved claims. Similarly, Health Canada and behavioral strategies (exercise, etc.) (Table I).
also approved health claims for reductions in Moreover, because inulin fibers are not absorbed
cholesterol and postprandial glycemia related to in the small bowel, they have no effect on post-
glucomannan supplementation, thus confirming prandial blood glycaemia and, at the same time,
its beneficial metabolic function (Summary of their low-glycemic-index minimally stimulates
Health Canada’s assessment of a health claim cholesterol synthesis, thus lowering cholesterol
about a polysaccharide complex. Ottawa (Cana- blood concentrations37,38. Of note, short chain fatty
da): Bureau of Nutritional Sciences, Food Direc- acids (SCFA) produced during colon fermentation
torate, Health Products and Food Branch, Health of inulin or galactomannan fibers that reach the
Canada; 2016. 8. Summary of Health Canada’s colon almost unaltered, specifically bind a series
assessment of a health claim about a polysac- of orphan G protein-coupled receptors. In partic-
charide complex (glucomannan, xanthan gum, ular, the free fatty acid receptor 3 (FFA3/GPR41)
sodium alginate) and a reduction of the post-pran- that is expressed both in the intestine and sympa-
dial blood glucose response [updated May 2016]. thetic nervous system, recognize SCFA including
Ottawa (Canada): Bureau of Nutritional Scienc- propionate and butyrate, that trigger several folds
es, Food Directorate, Health Products and Food higher receptor activation compared to acetate39,40.
Branch, Health Canada; 2016.). Lack of this GPR41 receptor in mice causes lower
Several meta-analyses of large clinical trials31,34 energy expenditure and reduced glucose tolerance
confirmed that KJM can safely and effectively be compared to wild-type mice41,42. Other groups
used for cardiovascular diseases (CVD) risk re- have also shown that SCFA are directly involved

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Table I. Prebiotics.

Fiber Duration Population: M/F Study design Results Ref.

Oligofructose-enriched 16 weeks 42 subjects Single center, double blind, Reduced body weight z-score, percent Nicolucci et al100
  inulin (8 g/day) 24M/18F   placebo controlled   body fat, percent trunk fat, and serum

Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome
  level of interleukin 6

Low calorie diet + 12 weeks 59 female subjects Randomized, controlled, Reduced triglycerides and improved intake Tovar et al101
  Inulin 10 g   longitudinal   of micronutrients

Galacto-oligo-saccharide 12 weeks 45 subjects; Double blind, randomized, Decreased: fasting insulin, TC, TG, CRP, Vulevic et al102
  (5.5 g)   16M/29F   placebo controlled,   fecal calprotectin
 crossover

Inulin (10 g) 8 weeks 49 female subjects Randomized, triple blind Decreased: FBG, A1c, malondialdehyde; Gargari et al103
  controlled   Increased: antioxidant defense

Inulin (10 g) 8 weeks 49 female subjects Randomized controlled Reduction in FBS, HbA1c, total cholesterol, Dehghan et al104
  triglyceride, LDL-c, LDL-c/HDL-c ratio
  and TC/HDL-c ratio, increased HDL-c

Oligofructose-enriched 8 weeks 52 female subjects Triple-blind randomized Decreased fasting plasma glucose, glycosylated Dehghan et al47
  inulin (10 g)   controlled   hemoglobin, interleukin-6, tumor necrosis
  factor-a and plasma lipopolysaccharide

Glucomannan/Capsule 4 weeks 63 subjects Double-blind crossover, Reduced total cholesterol, LDL-C, Arvill et al105
  (0.43 g)   placebo controlled   triglycerides  and systolic BP

Glucomannan/Capsule 8 weeks 40 subjects; Randomized controlled Reduced plasma total cholesterol and LDL-C Martino et al106
  (2 g/d) 20M/20F

Glucomannan/Capsule 8 weeks 40 subjects; Randomized, double blind, Reduced total cholesterol and LDL-C Martino et al107
  (2 g/d) 19M/21F   six-arm parallel

Glucomannan/Capsule 8 weeks 60 subjects; Randomized, double blind Decrease of alpha-lipoprotein; increase Vido et al108
  (2 g/d) 33M/27F   of pre-beta-lipoprotein and triglycerides

Glucomannan/Capsule 8 weeks 42 subjects; Randomized, placebo Reduced body mass, fat mass, total cholesterol, Kraemer et al109
  (3 g/d) 22M/20F   double blind, crossover   and LDL-C

Glucomannan/Capsule 12 weeks 58 subjects; Double-blind, placebo Reduced total cholesterol and LDL-C Vasques et al110
 (1.5 g/d) 12M/46F  controlled

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 R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

in the so-called ‘gut-brain axis’, that affects host  • Increase bacterial fermentation in the colon
energy expenditure by directly up-regulating the and promote beneficial bacteria replication
activity of the sympathetic nervous system via and metabolic production of SCFA thus in-
GPR41 and enhancing body energy expenditure43. creasing the molar ratio of propionate to ac-
etate, that affect gut barrier integrity and
The biological mechanisms by which cholesterol metabolism45.
prebiotics, viscous plant-derived oligo-   • Inhibit or down-regulate liver lipogenic path-
saccharides, exert their health effects (Figure 1) ways through propionic acid production46.
Highly viscous soluble fibers exert their ac-  • SCFA production reduced translocation of
tivity in different districts of the gastrointestinal Gram-negative bacteria derived Lipopolysac-
tract and can affect host physiology and gut bar- charide (LPS) systemic metaflammation both
rier function directly or indirectly. in human and animal models47.
  • Delay gastric emptying, thereby affecting nu-   • SCFA production affects the secretion of gas-
trient kinetics and satiety44. trointestinal hormones such as regulation of
 • Enhance intestinal viscosity, that impairing incretin hormone GLP-1 and other gastroin-
the uptake of dietary cholesterol and reducing testinal peptides (the PYY satiety hormone for
bile acids reabsorption44. example)48,49.

Figure 1. The biological mechanisms by which prebiotics exert their health effects. 1) Delay gastric emptying, thereby affect-
ing nutrient kinetics and satiety. 2) Enhance intestinal viscosity, that impairing the uptake of dietary cholesterol and reducing
bile acids reabsorption. 3) Increase bacterial fermentation in the colon and promote beneficial bacteria replication and metabolic
production of SCFA thus increasing the molar ratio of propionate to acetate, that affect gut barrier integrity and cholesterol
metabolism. 4) Inhibit or down-regulate liver lipogenic pathways through propionic acid production. 5) SCFA production re-
duced translocation of Gram-negative bacteria derived Lipopolysaccharide (LPS) systemic metaflammation both in human and
animal models. 5) SCFA production affects the secretion of gastrointestinal hormones such as regulation of incretin hormone
GLP-1 and other gastrointestinal peptides (the PYY satiety hormone for example).

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 Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome

Probiotics that indicate the species but not the strain as per
A major obstacle in defining the efficacy good-manufacturing guidelines. This may cause
of currently available probiotic preparations on under-supplementation of the beneficial strains or
weight control and metabolic syndrome treat- over-supplementation with bacteria with deleteri-
ment reside in the numerous confounding factors ous weight-gain consequences. Some strains are
that affect both the formulation and, most of the in fact more resistant than others to the indus-
time, also the study design. In fact, under the trial processing or at normal storage conditions
common definition of probiotics, several micro- (such as Streptococcus thermophilus). Thus, by
bial strains including yeasts or bacteria were the time the commercial preparations reach the
used. Unfortunately, even if bacteria present in shelf, the supplement may still contain a high
different products belong to the same genera or number of living microbes but with only one
species, they often have important strain-spe- or a few single species (personal observation).
cific phenotypic differences that may modulate Moreover, some products commercialized under
their beneficial activity50. Different amount of the same blend name, varied the strains quantity
viable bacterial cells in the available commercial and composition many times (even changing the
preparations were used, sometimes with poorly strains) over the years, thus affecting the scien-
standardized shelf-life (number of living bacterial tific reproducibility of previously obtained results
cell at time of expiration) determinations. Com- or any reliable conclusion.
mercial preparations often lack clear description In many cases probiotics were administered
of the relative representation of each strain when as fermented milk or yoghurt or cheese in hu-
bacterial blends are used. Similarly, different man trials not allowing a proper evaluation of
types of formulations, including capsules, sa- the number of living bacteria. Moreover, in this
chets, yoghurts etc. were used. Moreover, several case, products should more properly considered
comorbidities or co-factors (such as age, sex, au- synbiotic preparations, since they contain also
toimmune diseases, diabetes, etc.) today known prebiotic components that are fermented by the
to be independently associated with microbiota probiotic bacteria or by the host microbiota, that
alterations, were not always considered in the some authors or patients were not probably fully
exclusion criteria for patient’s enrolment nor were aware (milk oligosaccharides for examples, or
they eventually discussed in the analysis of re- other carbohydrates present in yoghurts or in
sults. However, and despite these biases, several fermented milks or skimmed milk powder ex-
meta-analyses and large review studies clearly cipients that may confer synergistic beneficial
suggest that some probiotic strains or synbiotic effects). In some cases, this bias was addressed by
formulations may exert a beneficial effect on using chemically ‘fermented’ yoghurt as placebo.
weight loss and on metabolic syndrome manage- For these reasons, these studies are discussed in
ment and may help to design improved probiotic the Synbiotic session.
or synbiotic formulations. Only very few prod- As an example, the administration for eight
ucts containing the probiotic strain alone or in weeks of L. acidophilus La5, B. lactis Bb12, and
blend were tested in sufficiently large clinical L. casei DN001 as yoghurt to patients with high
trials in order to promote weight loss, improve BMI, showed a reduction in BMI, fat percent-
lipid metabolism or reduce inflammatory markers age, and leptin level and also a reduction in the
in patients with metabolic syndrome (Table II). serum levels of inflammatory markers as well
The majority of results are negative regarding the as immunomodulation of PBMCs. The effect
weight loss effect, with a few of them showing was augmented if the supplement was associated
improved lipid or inflammatory markers (Table with weight-loss diet. The intake of a similar
II). This suggests that the beneficial effects are combination of bacteria, (L. acidophilus La5 and
species, or even strain dependent and cannot B. animalis subsp. lactis Bb12) in capsules, did
be ascribed indistinctly to all available com- not affect HOMA-IR, blood pressure, heart rate
mercial products. This seems especially true if nor the serum lipid concentrations in overweight
recent analyses will be confirmed, suggesting a adults52,53. This may suggest a critical role for
deleterious weight-gain effect caused by the ma- the presence of the prebiotic milk present in the
jority of probiotic preparations containing very yoghurt vehicle or to L. casei present in only one
commonly used Lactobacilli strains51. This may product. Researches54,55 that evaluated Lactoba-
represent an important issue for products con- cillus casei Shirota alone as probiotic in patients
taining probiotic blends or for those preparations with insulin resistance demonstrated that the only

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Table II. Probiotics.

Strain/vehicle (dosage) Duration Population: M/F Study design Results Ref.

L. salivariusLs-33/Capsule 12 weeks 50 obese adolescents Double-blind, randomized, Increase in ratios of Bacteroides, Larsen et al59
 (1010 CFU)   placebo controlled   Prevotellaceae and Porphyromonas

L. salivariusLs-33/Capsule 12 weeks 50 adolescents with Double-blind, randomized, No effect Gobel et al58

 (1010 CFU)   obesity: 22M/28F   placebo controlled

R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

Bifidobacteria, Lactobacilli, 6 weeks 60 overweight subjects Randomized, placebo controlled Improvement in lipid profile, insulin Rajkumar et al56
 and S. thermophiles/Capsule   sensitivity and decrease in CRP
 (112.5x109 CFU)

L. paracaseiN19/Sachet 6 weeks 58 obese post- Single-blind, randomized, No effect Brahe et al60

 (9.4x1010 CFU)   menopausal women   parallel group

B. longum BL999 16 weeks 112 subjects: Multicentric: prospective, Weight gain; daily weight gain Chouraqui et al111
 (1.3x108 CFU)   54M/58F   double blind, reference   on 4 months (g/d)
L. rhamnosus LPR   controlled, randomized
  (6.45x10 CFU)/100 mL
  formula from powder

L. salivarius CECT5713 24 weeks 80 subjects: Monocentric: prospective, Weight gain on 6 months (g) Maldonado et al112
 (2x106 CFU/g) on formula 39M/41F   double blind, placebo
  controlled, randomized

L. acidophilus ATCC4962 1 week 800 newborns subjects Two centers: Weight gain; weight gain at one month Robinson et al113
  and ATCC4963   prospective, randomized
 (>5x108 CFU), 1 ml to
  each quart of formula

Hydrolyzed casein formula 16 weeks 188 subjects: Multicentric: prospective, Growth and tolerance; weight gain (g/d) Scalabrin et al114
 with L. rhamnosus strain GG 94M/94F   double blind, randomized
 (108 CFU/g of formula powder)

L. rhamnosus strain GG 24 weeks 120 subjects; Multicentric: prospective, Growth and fecal flora on 6 months Vendt et al115
  ATCC53103/Formula 60M/60F   double blind, randomized
 (1x107 CFU)

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 Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome

parameter that was clearly ameliorated was in- • Increase in sympathetic nerve activity65.
sulin sensitivity index, but gut permeability was • Suppression of fat deposition via increased
unfortunately increased despite lack of increased expression of angiopoietin-like 4, a circulating
LPS translocation. Other studies tested the effect inhibitor of lipoprotein lipase66,67.
of a blend containing bifidobacteria, lactobacilli, • Induction of transcriptional activation of fatty
and Streptococcus thermophilus (as capsules) in acid β-oxidation-related genes in the liver and
overweight subjects. The mixture had a signifi- muscle68,69.
cant improvement in their lipid profiles, reducing • Inhibition of the transcription of fatty acid
triacylglycerols, total cholesterol, and LDL-C lev- synthase in the liver70,71.
els with beneficial effect on high-density lipopro- • Improve insulin sensitivity and glucose toler-
tein cholesterol levels and on insulin sensitivity ance through SCFA production and reduction
as well as on inflammatory markers (C-reactive of LPS translocation72-74.
protein, CRP)56. Other randomized, double-blind, • Improvement of the gut barrier function,
placebo-controlled studies in overweight and through SCFA production and immunomod-
obese subjects designed to evaluate the effects of ulation of gut immune cells75.
an Enterococcus faecium strain (that unfortunate- • Modulate the gene expression profile in PB-
ly is a pathobiont, an opportunistic microbe that MCs and intestinal immune cells of ROR-gt
can cause infections in humans) and two strains (down-regulated) and FOXP3 (up-regulated)
of Streptococcus thermophilus supplemented as transcription factors, dampening inflamma-
yoghurts, showed a beneficial effect on cardio- tion and promoting immunomodulation76.
vascular risk factors including reduction in body • Regulation of appetite77.
weight, blood pressure and LDL-C57. Negative
results were also obtained by Gobel et al58 with Synbiotics
Lactobacillus salivarius Ls-33 on inflammation When the probiotic strains are used in com-
biomarkers and several dysmetabolic parameters bination with prebiotics, the final product can
associated with metabolic syndrome in a popula- correctly be described as synbiotic if an in-
tion of adolescents with obesity. These data are in creased synergistic health benefit is obtained78.
agreement with more recent findings59 obtained Some trials were conducted with synbiotics to
in a similar population of obese adolescents that investigate their combined effects on weight loss
showed no effects on weight reduction after 12 and maintenance in obese adults or children.
weeks of supplementation with L. salivarius Ls- Used preparations contained mainly lactobacilli,
33. Other studies showed that L. paracasei F19 more frequently including L. rhamnosus (CG-
did not modulate any markers associated with MCC1.3724 strain), L. plantarum, L. paraca-
metabolic dysfunctions ((HOMA-IR), C-reactive sei F19, L. acidophilus La5 and B. animalis
protein, and lipid profile) when compared with subsp. Lactis Bb12 together with oligo-fructose
the placebo60. and inulin fibers (Table III). Some studies used
complex blends of probiotics (5 or more strains)
The biological mechanisms by which and different amounts of inulin-type fructans.
some probiotic strains exert their health Despite some discrepant results, supplementation
effects (Figure 2) with synbiotics appears to confer clear beneficial
 • Competitive adherence to the mucosa and effects on waist circumference, on BMI, VFA
epithelium with proinflammatory microbes61. and hip circumference in overweight or obese
• Regulation of the gut associated lymphoid people (Table III). In women, but not in men, L.
immune system through intestinal cell pat- rhamnosus CGMCC1.3724 + inulin supplemen-
tern recognition receptors, (toll-like recep- tation allowed to obtain a significantly higher
tors and nucleotide-binding oligomerization weight loss than in the placebo group after the
domain-containing protein-like receptors) or first 12 weeks, with a parallel modification of gut
through the release of metabolites or immu- microbiota79. The synbiotic induced weight loss
nomodulating peptides62. was also associated with reductions in visceral
• Bile-acid deconjugation by some lactobacilli fat mass and circulating leptin concentrations. In
strains, thus reducing lipid absorption and obese children, the intake of synbiotics resulted
calories intake63. in a significant reduction in the BMI z-score,
• Induction of lipolysis via production of waist circumference, TC, LDL-C and TAG as
trans-10, cis-12-conjugated linoleic acid64. well as reduction of total oxidative stress serum

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 R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

Figure 2. The biological mechanisms by which probiotics exert their health effects. 1) Competitive adherence to the mucosa and ep-
ithelium with proinflammatory microbes. 2) Regulation of the gut associated lymphoid immune system through intestinal cell pattern
recognition receptors (toll-like receptors and nucleotide-binding oligomerization domain-containing protein-like receptors) or through
the release of metabolites or immunomodulating peptides. 3) Bile-acid deconjugation by some lactobacilli strains, thus reducing
lipid absorption and calories intake. 4) Induction of lipolysis via production of trans-10, cis-12-conjugated linoleic acid. Increase in
sympathetic nerve activity. 5) Suppression of fat deposition via increased expression of angiopoietin-like 4, a circulating inhibitor of
lipoprotein lipase. 6) Induction of transcriptional activation of fatty acid β-oxidation-related genes in the liver and muscle. 7) Inhibition
of the transcription of fatty acid synthase in the liver. 8) Improve insulin sensitivity and glucose tolerance through SCFA production
and reduction of LPS translocation. 9) Improvement of the gut barrier function through SCFA production and immunomodulation of
gut immune cells. 10) Modulate the gene expression profile in PBMCs and intestinal immune cells of ROR-gt (down-regulated) and
FOXP3 (up-regulated) transcription factors, dampening inflammation and promoting immunomodulation. 11) Regulation of appetite.

levels suggesting an overall protection against longum, L. bulgaricus and fructo-oligosaccha-

CVD risk factors80,81. Patients with insulin resis- rides, in a study with 52 adults over 28 weeks,
tance supplemented with synbiotic capsules (sev- demonstrated that synbiotic supplementation
en strains plus fructo-oligosaccharide) showed a dampened NF-kB and reduced TNF-a produc-
significant improvement of fasting blood sugar tion. This observation suggests that the reduction
and insulin resistance as compare with the pla- of pro-inflammatory cytokines, such as tumor ne-
cebo group82. Recently, a randomized study on crosis factor (TNF), may have improved insulin
the use of a synbiotic that contains five probiotics resistance and reduced hepatic inflammatory cell
(L. plantarum, L. delbrueckii spp. bulgaricus, recruitment observed in metabolic syndrome and
L. acidophilus, L. rhamnosus, B. bifidum and NASH85. Two L. gasseri strains supplemented in
inulin) over 6 months in adult patients with synbiotic preparations (SBT2055 and BNR17 in
NASH was associated with a significant decrease yoghurt, fermented milk or with skimmed milk
in IHTG83,84. The evaluation of supplementation powders) have shown significant anti-obesity effects
with a synbiotic containing L. casei, L. rhamno- in independent well-designed clinical trials with
sus, S. thermophilus, B. breve, L. acidophilus, B. medium to low risk of biases in study design86-88.

7596
Table III. Synbiotics.

Strain/vehicle (dosage) Duration Population: M/F Study design Results Ref.

L. rhamnosus CGMCC1.3724/ 36 weeks 125 obese subjects: Double-blind, randomized, Weight loss and reduction in leptin. Sanchez et al79
  Capsule (1.6x108 CFU) 48M/77F   placebo controlled   Increase in Lachnospiraceae

Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome
L. casei, L. rhamnosus, S. thermophilus, 8 weeks 70 children and Randomized, triple-masked Decrease in BMI z-score and waist Safavi et al80
  B. breve, L. acidophilus, B. longum,   adolescents with   controlled   circumference
  L. bulgaricus, and FOS   high BMI
L. acidophilus, L. rhamnosus, 4 weeks 77 obese children Open-label, randomized, Changes in anthropometric Ipar et al81
  B. bifidum, B. longum,   controlled study   measurements. Decrease in TC,
  E. faecium, and FOS LDL-C
L. gasseri SBT2055/Yoghurt 12 weeks 87 subjects with high Multicenter, double-blind, Reduction in BMI, abdominal VFA. Kadooka et al88
  (5x1010 CFU/g) BMI: 59M/28F   randomized, placebo controlled   Increase in adiponectin levels
L. gasseri SBT2055/Yoghurt 12 weeks 210 adults with large Multicenter, double-blind, parallel Reduction in BMI, waist, abdominal Kadooka et al87
 (108 CFU/g) VFA: 105M/105F   group randomized controlled   VFA and hip circumference
L. gasseri BRN17/Capsule 12 weeks 57 subjects: Randomized, double blind, Body weight, BMI e waist and Jung et al93
 (10 CFU); filler powder
10
22M/35F   controlled   hip circumferences decreased in
  (50% trehalose, 25% skim   test group
  milk and 25% FOS)
L. acidophilus, L. casei, L. rhamnosus, 8 weeks 54 patients with Double-blind, randomized, Increased HOMA-IR and TGL plasma Asemi et al116
  L. bulgaricus, B. breve, B. longum, T2D (35-70 years)   placebo controlled   level: reduced CRP in serum
  S. thermophilus, (109 CFU)
  and 100 mg FOS
L. sporogenes/Bread 8 weeks 81 patients Double-blinded, randomized, Significant reduction in serum insulin Tajadadi-Ebrahimi
 (1x108 CFU) and Inulin/   with T2D   controlled   levels, HOMA-IR, and homeostatic   et al117
  Bread (0.07g/1 g)   model assessment-cell function
L. sporogenes/Bread 8 weeks 78 patients Double-blinded, randomized, Decrease in serum lipid profile Shakeri et al118
 (1x108 CFU) and   with T2D:   controlled   (TAG, TC/HDL-C) and
  Inulin/Bread (0.07g/1 g)   15M/63F   increase in HDL-C levels
L. casei, L. rhamnosus, S. thermophilus, 30 weeks 52 adult Double-blind, randomized, Inhibition of NF-kB and Eslamparast et al82
  B. breve, L. acidophilus, B. longum,   individuals   placebo controlled   reduction of TNF-a
  L. bulgaricus, and FOS/   with NAFLD:
  Capsule (2x108 CFU)   25M/27F
Bofutsushosan herb + DUOLAC7 8 weeks 50 female subjects Randomized, double blind, Increased HDL, increased B. Lee et al119
  (L. acidophilus, L. plantarum,   placebo controlled   Breve, B. Lactis, B. rhamnosus,
  L. rhamnosus, B. lactis, B. longum,   B. Plantarum
  B. breve, S. thermophiles)
  (5x109 CFU)
Inulin 1.08 g + L. sporogenes 6 weeks 62 subjects: Randomized, double blinded, Decreased hsCRP: Asemi et al120
  (2.7x10 CFU)
8
19M/43F   crossover controlled   increased GSH, Uric acid

Continued

7597
Table III. Synbiotics.

Strain/vehicle (dosage) Duration Population: M/F Study design Results Ref.

FOS 2.5 g + B. longum W11 24 weeks 66 subjects: Randomized, double blind, Decreased LDL, CRP, TNF-α, LPS, Malaguarnera et al121
  (5x109 CFU)   33M/33F placebo controlled   Steatosis
L. acidophilus La5, B. lactis 8 weeks 75 subjects with Double-blind, randomized, Changes in gene expression Zarrati et al76
  Bb12, and L. casei DN001/   high BMI   placebo controlled   in PBMCs as well as BMI,
  Yoghurt (108 CFU/g)   fat percentage and leptin levels
E. faecium, two strains 8 weeks 70 overweight and Double-blind, randomized, Reduction in body weight, systolic BP, Agerholm-
 of S. thermophiles/Yoghurt   obese subjects:   placebo and compliance   LDL-C, and increase on fibrinogen   Larsen et al57
 (6x107 – 1x109 CFU/g)  20M/50F  controlled, parallel  levels

R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

L. acidophilus La5, B. animalis 6 weeks 156 overweight Double-blind, randomized, Reduction in fasting glucose Ivey et al52,53
  subsp. Lactis Bb12/Yoghurt-   adults:   parallel study   concentration and increase
  capsule (3x109 CFU)   96M/60F   in HOMA-IR
L. acidophilus La5 and B. lactis 6 weeks 60 patients Double-blinded, randomized Reduced fasting blood glucose Ejtahed et al122
  Bb12/Yoghurt (7.23x10 and   with T2D:   controlled   and antioxidant status
6

 6.04x106 CFU/g)   23M/37F

L. acidophilus La5 and B. lactis 6 weeks 60 patients with T2D: Double-blinded, randomized TC and LDL-C improvement Ejtahed et al123
 Bb12/Yoghurt  23M/37F  controlled
L. acidophilus La5 8 weeks 72 patients Double-blinded, randomized, Reduced serum levels of ALT, Nabavi et al124
  and B. breve subsp.   with NAFLD:   controlled   ASP, TC, and LDL-C
 lactis Bb12/Yoghurt  33M/39F
Lactobacillus curvatus (2.5×109 12 weeks 95 subjects: Double blind, Placebo Body weight, BMI, waist circumference Jung et al125
  CFU) and L. plantarum   34M/61F   controlled, randomized   and subcutaneous fat mass decreased
 (2.5×109 CFU)/powder containing   in test group
  1.24 g of cellulose, 0.5 g of lactose,
  0.06 g of blueberry flavoring
L. amylovorus CP1563/Powder 12 weeks 200 subjects: Randomized, double blind, Body fat percentage, visceral fat Nakamura et al126
  (skim milk, citrate, flavors,   100M/100F   placebo controlled   area and whole-fat area
  sweeteners, soybean polysaccharide,   decreased in test group
  food emulsifier and 200 mg of
  L. amylovorus)
S. thermophilus, L. acidophilus, 8 weeks 101 subjects: Randomized, double blind, Reduced LDL-cholesterol, Chang et al127
  B. infantis/Yoghurt (109-1010 CFU)   31M/70F   placebo controlled, parallel   body weight and BMI
L. acidophilus L-1/Yoghurt 2 weeks 78 subjects: Monocentric; prospective, Lipid profile and body weight change; De Roos et al128
 (5x109 to 3x1010 CFU d)   22M/56F   double blind, randomized   weight change difference (kg)
L. acidophilus La1 and 6 weeks 90 female subjects prospective, double blind, Lipid profile; weight change (kg) Sadrzadeh-
  Bifidobacterium. lactis Bb12/   randomized   Yeganeh et al129
  Yoghurt (4x107 CFU)

7598
 Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome

Lactobacillus gasseri strains are probiotic lactic levels86,97. Other mechanisms demonstrated in
acid bacteria isolated from the gastrointestinal animal models probably involve increased energy
tract or sometimes from the vagina of healthy expenditure and improved glucose tolerance by
subjects. L. gasseri SBT2055 strain was exam- synbiotic L. gasseri supplementation98.
ined in two studies86-88 using a cohort of Japa-
nese adults with large visceral fat areas (VFA).
The participants received increasing amounts of Conclusions
L. gasseri SBT2055 for 12 weeks. The results
showed a reduction in body mass index (BMI), In the pre-microbiome era, almost none of
waist, abdominal VFA and hip circumferences. the trials were designed to identify the molecu-
In obese individuals, the difference was clinical- lar mechanisms underlying the beneficial effects
ly relevant since an average weight loss of 6 kg observed in humans supplemented with pre/pro/
(3-6%) was obtained in overweight patients in a synbiotic preparations on weight loss and metabol-
few weeks86-88. ic syndrome dysmetabolism. Nevertheless, more
Both studies with L. gasseri strains observed recent studies on human and animal models have
decreased visceral fat. This is an important in part elucidated several biological mechanisms
achievement since visceral fat is associated with supporting their usage in these clinical conditions.
insulin resistance, cardiovascular risk and dia- Future studies attempting to demonstrate a bene-
betes mellitus86,87. In vitro and preclinical data ficial role for synbiotics in clinical trial will have
suggest that these genera of Lactobacilli strains to evaluate accurately the gut microbiota compo-
suppress lipogenic gene expression and accu- sition and functions to confirm already described
mulation of lipids in adipose cells89,90. This is mechanism of actions or to identify new benefi-
also in agreement with Kawano et al91 findings cial microbe-host interactions affecting local and
that demonstrated, in rats, that L. gasseri strain systemic inflammation and metabolic pathways.
SBT2050 reduced gut permeability in mice fed Characterization of baseline microbiome compo-
with high fat diet, thus possibly ameliorating gut sition in patients’ enrolled in future clinical trial
barrier function and reducing bacterial trans- may help to understand the individual responses to
location and the associated low-grade systemic synbiotic supplementation and may indeed guide
inflammation86,92. L. gasseri BRN17 was also to more effective weight-management treatments
associated with weight loss in humans (even if and results interpretation. Some results obtained
not statistically significant) and with reduced in early studies appear indeed controversial, but
adipose tissue accumulation under a carbohy- several reasons may explain some discrepancies.
drate-rich diet in animal models72,93-95. Lacto- In fact, heterogeneous amounts of bacterial cells,
bacillus gasseri BNR17 has recently received complex mixtures of bacteria strains and different
the South Korean FDA approval as functional dosages of prebiotic fibers were used (Tables I-III).
ingredient for body fat reduction93. Other authors In fact, the weight control activity appears to be
showed that LG2055 supplementation decreases a species or even a strain-specific characteristic
lymphatic triacylglycerols (TAG) absorption, in- and some probiotic strains such as L. acidophilus,
creases fecal fatty acid excretion in animal mod- L. ingluviei, L. fermentum and delbrueckii (and
els and decreases postprandial TAG absorption probably other endogenous Lactobacillus species
in humans. This may be explained in part by the that increase in obese patients) were linked to a
strong bile salt hydrolase (BSH) activity of some paradoxical significant weight-gain effect both in
lactobacilli, including L. gasseri strains, that may animal or human studies51. Therefore, diet sup-
help to reduce bile-acid re-adsorption63. Bile salts plementation only with synbiotics, prepared us-
are conjugated with glycine or taurine in the liver ing selected strains (such as Lactobacillus gasseri
and stored in the gall bladder and released into strains) that showed to exert weight-reduction and
the small intestine where they help to absorb anti-inflammatory activity in large independent
lipids96. The BSH enzyme hydrolyzes conjugated correctly designed studies, together with galacto-
bile salts into a deconjugated form that is much mannan and/or inulin fibers, may exert more pow-
less soluble and thus not absorbed by intestinal erful anti-obesity effects due to synergism in SC-
cells. Elimination of deconjugated bile salts, re- FA production and microbiota ‘re-configuration’.
sults in de novo synthesis of bile acid from cho- Novel synbiotics may reduce insulin resistance,
lesterol in the liver, thereby lowering both lipid cardiovascular risk and type-2 diabetes develop-
absorption from the bowel and serum cholesterol ment through VFA reduction. Better-designed syn-

7599
 R. Ferrarese, E.R. Ceresola, A. Preti, F. Canducci

biotics may promote not only weight loss but they   6. Dolpady J, Sorini C, Di Pietro C, Cosorich I, Ferra-
rese R, S aita D, Clementi M, C anducci F, Falcone M.
may also help to maintain the beneficial results of
Oral probiotic VSL#3 prevents autoimmune dia-
weight reduction regimens through the promotion betes by modulating microbiota and promoting in-
of a persistently healthier microbiota composition. doleamine 2,3-dioxygenase-enriched tolerogen-
Obese-type gut microbiota, in fact, induces neuro- ic intestinal environment. J Diabetes Res 2016;
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host behavior showed that microbiota composi- Burioni R. Cross-reacting antibacterial auto-an-
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Acknowledgments  12. De Filippo C, C avalieri D, Di Paola M, R amazzotti
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of University and Research and by the Italian Ministry of L ionetti P. Impact of diet in shaping gut microbiota
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Conflict of Interests  13. Bibbò S, Ianiro G, Giorgio V, Scaldaferri F, M asucci L,
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