Clinical Nutrition 40 (2021) 4915e4931

Contents lists available at ScienceDirect

Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

Effects of probiotics on body adiposity and cardiovascular risk markers

in individuals with overweight and obesity: A systematic review and
meta-analysis of randomized controlled trials
Karine Scanci da Silva Pontes a, Marcella Rodrigues Guedes a, Michelle Rabello da Cunha b,
Samanta de Souza Mattos b, Maria Ine ^s Barreto Silva c, d, Mario Fritsch Neves b,
Bianca Cristina Antunes Alves Marques b, e, Ma rcia Regina Simas Torres Klein c, *
a
Post-Graduation Program in Clinical and Experimental Pathophysiology, State University of Rio de Janeiro (UERJ), Av. Professor Manuel de Abreu, 444,
Terreo e Rio de Janeiro, RJ, 20550-170, Brazil
b
Department of Clinical Medicine, State University of Rio de Janeiro (UERJ), Av.Vinte e Oito de Setembro, 77 Sala 329, Rio de Janeiro, RJ, 20551-030, Brazil
c ~o Francisco Xavier, 524 e Pavilha
Department of Applied Nutrition, Nutrition Institute, State University of Rio de Janeiro (UERJ), Rua Sa ~o Joa
~o Lyra Filho, 12º
Andar, Bloco D, Rio de Janeiro, RJ, 20559-900, Brazil
d
Department of Applied Nutrition, Nutrition School, Federal University of the State of Rio de Janeiro (UNIRIO), Av. Pasteur, 296, Botafogo, 3º Andar, Rio de
Janeiro, RJ, 22290-250, Brazil
e
Department of Nutrition and Dietetics, National Cancer Institute (INCA), Av. Bina rio do Porto, 831, Rio de Janeiro, RJ, 20081-250, Brazil

a r t i c l e i n f o s u m m a r y

Article history: Background & aims: Evidence suggests that gut microbiota is a potential factor in the pathophysiology of
Received 21 April 2021 both obesity and related metabolic disorders. While individual randomized controlled trials (RCTs) have
Accepted 23 June 2021 evaluated the effects of probiotics on adiposity and cardiovascular disease (CVD) risk factors in subjects
with overweight and obesity, the results are inconsistent. Thus, this systematic review and meta-analysis
Keywords: aimed to evaluate the effects of probiotic supplementation on body weight, body adiposity and CVD risk
Probiotics
markers in overweight and obese subjects.
Microbiota
Methods: A systematic search for RCTs published up to December 2020 was conducted in MEDLINE (via
Obesity
Overweight
PubMed), EMBASE, Scopus and LILACS. Meta-analysis using a random-effects model was chosen to
Adiposity analyze the impact of combined trials.
Cardiovascular diseases Results: Twenty-six RCTs (n ¼ 1720) were included. Data pooling showed a significant effect of probiotics
in reducing body weight (MD:-0.70 kg; 95%CI:-1.04,-0.35 kg; P < 0.0001), body mass index (BMI) (MD:-
0.24 kg/m2; 95%CI:-0.35,-0.12 kg/m2; P ¼ 0.0001), waist circumference (WC) (MD:-1.13 cm; 95%CI:-1.54,-
0.73 cm; P < 0.0001), fat mass (MD:-0.71 kg; 95%CI:-1.10,-0.32 kg; P ¼ 0.0004), tumor necrosis factor-a
(MD:-0.16 pg/ml; 95%CI:-0.24,-0.08 pg/ml; P ¼ 0.0001), insulin (MD:-0.85mcU/ml; 95%CI:-1.50,-
0.21mcU/ml; P ¼ 0.010), total cholesterol (MD:-0.16 mmol/l; 95%CI:-0.26,-0.05 mmol/l; P ¼ 0.003) and
LDL (MD:-0.09 mmol/l; 95%CI:-0.16,-0.03 mmol/l; P ¼ 0.006) compared with control groups. There was a
significant decrease in body weight, BMI and WC in studies using both single and multi-bacterial species.
Decreases in body adiposity parameters were only observed in studies using a probiotic dose of 
1010 CFU and for 8 weeks duration.
Conclusions: The present meta-analysis suggests that probiotics consumption may be helpful for
improving body weight, body adiposity and some CVD risk markers in individuals with overweight and
obesity. The review was registered on PROSPERO (International prospective register of systematic re-
views): CRD42020183136.
© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

* Corresponding author. Av 28 de Setembro, 87 e salas 363 and 361, Vila Isabel, Rio de Janeiro, RJ, Postal Code: 20551-030, Brazil. Fax: þ55 21 2334 2063.
E-mail addresses: [email protected] (K.S.S. Pontes), [email protected] (M.R. Guedes), [email protected] (M.R. Cunha), samantasmattos@gmail.
com (S.S. Mattos), [email protected] (M.I. Barreto Silva), [email protected] (M.F. Neves), [email protected] (B.C.A.A. Marques), marciarsimas@gmail.
com (M.R.S.T. Klein).

https://doi.org/10.1016/j.clnu.2021.06.023
0261-5614/© 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

1. Introduction accessed at https://www.crd.york.ac.uk/prospero/display_record.

php?ID¼CRD42020183136.
Cardiovascular diseases (CVDs) are the leading cause of death
worldwide. In 2019, CVDs were responsible for ~18.6 million deaths 2.2. Eligibility criteria
globally and by 2030 it is expected to account for >22.2 million
deaths [1,2]. Adults presenting with overweight or obesity are at Studies were included if they met the following inclusion
increased risk for CVDs, including atherosclerotic CVD, atrial fibril- criteria: (i) controlled, randomized, parallel or cross-over trials; (ii)
lation and heart failure [3]. Excessive body adiposity is characterized presence of a placebo or control group; (iii) enrollment of adults (18
by dysfunctional adipose tissue associated with inflammatory and years or older) with overweight or obesity defined according to
metabolic disturbances [4]. Individuals with overweight and obesity local standards for body mass index (BMI); (iv) use of probiotics as
frequently present with a cluster of CVDs risk factors, such as hy- the only active intervention, administered through powder/cap-
pertension, dyslipidemia, insulin resistance, type 2 diabetes, sys- sules or added to foods; (v) evaluation of body weight, body
temic inflammation and a prothrombotic state [5e7]. Therefore, it is adiposity, BP, metabolic profile, inflammatory markers and vascular
key that excessive body adiposity and its CVD risk factors be treated. parameters as outcomes; (vi) report of mean and standard devia-
Gut microbiota has been identified as a potential factor in the tion (SD) of outcome variables at baseline and post-treatment (or
pathophysiology of obesity and related metabolic disorders [8]. mean changes) for the intervention and the control group. Exclu-
Changes in the composition, diversity and richness of gut micro- sion criteria were: (i) review articles; (ii) protocol articles; (iii)
biota (dysbiosis) have been associated with obesity, hypertension, observational studies (cross-sectional, cohort or caseecontrol); (iv)
type 2 diabetes mellitus, dyslipidemia, and CVDs [9e13]. Some cell culture, in vitro or animal studies; (v) non-randomized and
mechanisms involved in CVD pathogenesis have been proposed, uncontrolled clinical trials; (vi) studies that did not use probiotics
including pathogen-associated molecular patterns (PAMPs), such as as an isolated intervention; (vii) RCTs involving: children, pregnant
lipopolysaccharide (LPS), which are recognized by host receptors or lactating women; subjects with gastrointestinal disorders, the
promoting chronic inflammation. In addition, the gut microbiome use of intragastric balloon and/or undergoing gastrointestinal sur-
produces metabolites, such as trimethylamine-N-oxide (TMAO), gery, including bariatric surgery; patients using drugs that may
short chain fatty acids (SCFA) and secondary bile acids, that have affect body weight and body composition; patients with diabetes,
also been linked to inflammation and CVD risk [14e16]. TMAO hypertension, heart disease, renal or hepatic dysfunction, non-
plasma levels present a positive dose-dependent association with alcoholic fatty liver disease, cancer, critical illness, autoimmune or
increased cardiovascular risk and mortality [17]. immunosuppressive diseases, thyroid disease, polycystic ovary
Restoring healthy gut microbial composition may potentially syndrome or metabolic syndrome; (viii) studies with insufficient
improve metabolic disorders and promote cardiovascular health data.
[10]. Approaches may include the use of probiotics, defined as “live
microorganisms that, when administered in adequate amounts, 2.3. Search strategy
confer a health benefit on the host’’ [18]. Probiotics can have
beneficial effects on reducing body weight, which in turn may A systematic search of studies published up to December 15,
promote better metabolic and vascular parameters [3]. Thus, the 2020 was conducted in the electronic bibliographic databases
positive effects of probiotics on CVD risk factors may potentially be MEDLINE (via PubMed), EMBASE, Scopus and VHL REGIONAL/LI-
more pronounced in individuals with excessive body adiposity. In LACS. Keywords and their synonyms were used to maximize the
recent years, some randomized controlled trials (RCTs) evaluated sensitivity of the search, and standard filters were applied to
the effects of probiotics on adiposity and CVD risk factors in over- identify studies. Detailed search strategies are available in the
weight/obese individuals, yielding inconsistent results [19e24], supplementary table (Table S1).
this is likely due to the heterogeneity in study design. To date few
meta-analyses of RCTs have been published about the effects of 2.4. Data collection
probiotics on body adiposity and have reported divergent results
[25e28]. Although a reduced number of meta-analyses analyzed The articles identified by the search strategy were organized in
the probiotics effects on glycemic control/insulin resistance [27], EndNote software. Duplicates were removed and a final library was
and lipid profile [27,29], none evaluated the effects of probiotics on prepared for further screening. Titles and/or abstracts of identified
other CVD risk factors, such as blood pressure (BP), vascular and studies were independently screened by two pairs of reviewers
inflammatory parameters, in individuals with overweight and to identify studies that potentially met the eligibility criteria
obesity. described above. The full text of these potentially eligible studies
Therefore, the primary aim of this systematic review and meta- was retrieved and evaluated. Eligibility disagreements between the
analysis of RCTs was to evaluate the effects of probiotic supple- two pairs of reviewers were discussed with a senior reviewer to
mentation on body weight and body adiposity in individuals with reach consensus.
overweight and obesity. The secondary aim was to evaluate the
effects of probiotics on CVD risk markers related to excessive body 2.5. Data extraction
adiposity in this group of individuals.
Data extraction included: (i) study identification and design
information including authors, year of publication, language,
2. Material & methods country, design, duration of the study and number of participants in
each group; (ii) characteristics of the study population including
2.1. Protocol and registration age and sex; (iii) characteristics of the probiotics including species/
strains, dosage and vehicle (dairy or powder/capsules); (iv) dietary
This review followed the Preferred Reporting Items for System- intervention (energy restriction); and (v) outcomes including body
atic Reviews and Meta-Analyses (PRISMA) statement [30] and the weight, BMI, waist circumference (WC), waist-to-hip ratio, fat mass,
protocol was registered in the International Prospective Register of abdominal fat area (total, visceral and subcutaneous), lipid profile
Systematic Reviews (PROSPERO) (CRD42020183136) and can be (total cholesterol and fractions and triglycerides), glucose
4916
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

metabolism (fasting glucose and insulin, glycated hemoglobin and 3. Results

homeostasis model assessment (HOMA-IR)), inflammatory bio-
markers (C-reactive protein (CRP), tumor necrosis factor a (TNF-a), 3.1. Studies selection
interleukin (IL)-1, IL-6, interferon gamma and adiponectin), leptin,
ghrelin, LPS, lipopolysaccharide binding protein (LPB), TMAO, BP, The initial database search yielded 1471 potentially relevant
flow-mediated dilation (FMD), pulse wave velocity (PWV), vascular articles, after removing duplicates, 1142 remained for further
cell adhesion molecule (VCAM) and intercellular adhesion mole- screening. Inappropriate study design, drug, population, type of
cule (ICAM). Two pairs of authors independently evaluated the publication or outcome led to the exclusion of 1084. Fifty-eight
included trials and extracted data based on a standardized extrac- papers were eligible for full text evaluation among which 32
tion form. Cases of disagreement were resolved by discussion and were excluded for the following reasons: no control group, the
consensus. For studies reporting multiple interventions and dura- same Clinical Trials record published in two different journals,
tion of follow-up, extracted data was based on the highest dose, drug, population, type of publication, outcome, type of data and
largest number of probiotic species/strains, and longest follow-up. language. Therefore, 26 RCTs (n ¼ 1720), published as 29 papers
For studies reporting insufficient or incomplete data the corre- [19e22,24,35e58] were included in this meta-analysis (Fig. 1).
sponding authors were contacted requesting any necessary addi-
tional data, and when provided, were included.
3.2. Characteristics of the studies

The 26 studies were controlled and randomized clinical trials

2.6. Quality assessment
published between 2000 and 2020 from Denmark [19,36], Poland
[35,48,53,55,56], United States of America [37,45], Iran [20,24,38,
Review authors independently assessed the risk of bias of each
39,47,58], Finland [21,53], Japan [22,40,50,57], Australia [41,42], Ko-
study using the Cochrane risk of bias tool for randomized trials (RoB
rea [43,44,46], United Kingdom [49], Slovenia [51] and India [52].
2.0) [31]. Disagreements were resolved by discussion and
One study was unblinded [51], three studies were single-blind
consensus with a senior reviewer. Methodological quality assess-
[35,36,47] and the remaining were double-blind. Two studies had
ment included seven domains: (i) random sequence generation
a crossover design [37,51] and the others had a parallel design. The
(selection bias); (ii) allocation concealment (selection bias); (iii)
studies’ populations consisted of subjects with overweight and/or
blinding of participants and personnel (performance bias); (iv)
obesity, according to BMI values, without associated comorbidities.
blinding of outcome assessment (detection bias); (v) incomplete
At baseline mean BMI varied from 26.6 to 37.5 kg/m2 and mean age
outcome data (attrition bias); (vi) selective reporting (reporting
from 31.78 to 65.4 years. The sample size ranged from 30 to 220
bias); and (vii) other sources of bias (funding declaration). Each
participants. Six studies included only females [20,36,38,47,48,
domain was classified into three categories: low risk of bias, high
53,55]. Probiotics vehicle included fermented yogurt or milk
risk of bias or unclear risk of bias. The overall quality of individual
[19,22,24,35,39,41,42,47,57,58], sachet [21,36,45,48,53e56], capsule
studies was considered good if it was low risk for more than 2
[37,41,42,44,49,50,52], powder [40,43,46] or kefir [20,38,51]. The
domains, fair if it was low risk for 2 domains, and weak if it was low
studies administered either one [21,22,36,37,40,44e46,50,54,57],
risk for less than 2 domains.
two [19,35,39,41e43,47], three [24,58] or four or more [48,49,
51e53,55] probiotic species. The lowest daily dose of probiotic was
2  107 CFU/day [47] and the highest was 1  1011 CFU/day [22]. The
2.7. Statistical analysis
intervention duration varied from three weeks [45,51] to six months
[21,49,54]. Eleven [20,24,35,38,39,44,46,47,57,58] studies performed
Mean and SD changes in outcome variables (from baseline to
dietary intervention (energy restriction). The characteristics of the
post-treatment) in the intervention and the control group of all
included RCTs are listed in Table 1.
selected studies were used for the meta-analysis. For studies
reporting standard error (SE) instead of SD, the SD was estimated by
(SD ¼ SE x √n), n is the number of participants. For studies 3.3. Risk of bias
reporting 95% confidence intervals (CI), the SD was estimated by
(SD ¼ √n x (upper limit e lower limit)/3.92). For studies that did not All selected articles were assessed for risk of bias, as per the
report SD, SE or 95% confidence interval of the mean change, the SD Cochrane recommendations and the methodological quality of all
was estimated based on the baseline and post-intervention SD [32]. studies was considered good. Figure 2 shows the distribution of the
The results of the meta-analysis were expressed using a risk of bias according to each category and domain specified in the
random-effects model, with standardized mean differences for Cochrane collaboration tool for randomized trials. Evaluation of the
continuous variables with 95% CI and two-sided P values for each studies showed that for almost all the domains, a low risk of bias
outcome. The heterogeneity between the studies was assessed was the most frequent category: random sequencing generation
using the I2 statistic (range: 0e100%), and defined as low (25%), (63%), blinding of participants and personnel (85%), blinding of
moderate (26e74%) and high (75%) [33]. Subgroup analyses were outcome assessment: self-reported outcomes (93%), blinding of
performed for outcomes of body weight and body adiposity if the outcome assessment: objective measures (89%), incomplete
number of studies were at least 10 and were based on probiotic outcome data (89%), and selective reporting (93%). Only one study
intervention (vehicle, number of species and dose), duration of the [47] had a high risk in the blinding domain. It was a single blinded
study and association with dietary intervention (energy restric- study, in which the evaluator was not blinded and performed a
tion). Publication bias was assessed for outcomes with at least 10 dependent evaluator outcome. In the allocation concealment
studies using visual inspection of funnel plots and quantitatively domain, in some studies (44.5%), there was inadequate information
using egger's test. All data analyses were carried out using Review about the random sequence generation process. For those with
Manager (RevMan) software version 5.4 [34] and STATA12.0 soft- inadequate description of concealment, such the use of sealed,
ware (StataCorp LP). P values < 0.05 were considered statistically opaque envelopes and numbered in sequence, these studies were
significant. classified as unclear risk of bias.

4917
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 1. PRISMA flow diagram of study.

3.4. Effects of probiotics on body weight, BMI and body adiposity CI ¼ 14.47, 4.91 cm2; P < 0.0001), visceral (MD ¼ 6.24 cm2; 95%
CI ¼ 8.94, 3.54 cm2; P < 0.00001) and subcutaneous
Seventeen studies (n ¼ 1215) reported body weight changes. (MD ¼ 3.46 cm2; 95%CI ¼ 6.55, 0.38 cm2; P ¼ 0.03) abdominal
Data pooling showed a significant effect of probiotic use in reducing fat area. There were non-significant heterogeneity for total (I2 ¼ 0%,
body weight of overweight/obese subjects (MD ¼ 0.70 kg; 95% P ¼ 0.64), visceral (I2 ¼ 0%, P ¼ 0.97) and subcutaneous (I2 ¼ 41%,
CI ¼ 1.04, 0.35 kg; P < 0.0001), with a moderate heterogeneity P ¼ 0.17) abdominal fat area (Fig. 4C, D, E).
(I2 ¼ 70%, P < 0.00001) (Fig. 3A). Seventeen studies (n ¼ 1224) re- Subgroup analyses were performed for body weight, BMI, WC
ported BMI and overall the meta-analysis showed significant dif- and fat mass (Table 2). A significant decrease in body weight and WC
ference between probiotic and control groups (MD ¼ 0.24 kg/m2; after probiotic supplementation was observed in studies using both
95%CI ¼ 0.35 kg/m2, -0.12; P ¼ 0.0001) with a moderate hetero- dairy and capsule/powder as the vehicle of probiotics. Whereas BMI
genic data (I2 ¼ 55%, P ¼ 0.003) (Fig. 3B). Thirteen studies (n ¼ 926) and fat mass decreased significantly only in studies using non-dairy
reported WC. Data pooling detected significantly reduced WC post vehicles. There was a significant decrease in body weight, BMI and
probiotic intervention (MD ¼ 1.13 cm; 95% CI ¼ 1.54, 0.73 cm; WC in studies using both single and multi-bacterial species, while
P < 0.0001), with no significant heterogeneity (I2 ¼ 33%, P ¼ 0.12) fat mass decreased significantly only in studies with a single pro-
(Fig. 3C). Five studies (n ¼ 395) reported waist-to-hip ratio. Probiotic biotic specie. Only in studies using a dose of probiotics 1010 CFU
administration led to a significant reduction in waist-to-hip ratio and lasting 8 weeks was there a significant decrease in all pa-
(MD ¼ 0.01; 95%CI ¼ 0.01, 0.01; P < 0.00001), with non- rameters of body adiposity. The effects on body weight and WC
significant heterogeneity (I2 ¼ 24%, P ¼ 0.26) (Fig. 3D). Fat mass differed according to the use of dietary intervention. Only in studies
and fat percentage were reported in 13 (n ¼ 705) and 8 (n ¼ 460) without dietary intervention was there a significant decrease in
studies, respectively. Probiotic treatment significantly reduced fat body weight. Decreases in BMI only occurred is studies with dietary
mass (MD ¼ 0.71 kg; 95%CI ¼ 1.10, 0.32 kg; P ¼ 0.0004) and fat intervention. WC and fat mass decreased significantly in studies
percentage (MD ¼ 0.66%; 95%CI ¼ 1.05, 0.27%; P ¼ 0.001) with a both with and without dietary intervention (Table 2).
moderate heterogeneity (I2 ¼ 55%, P ¼ 0.009; I2 ¼ 46%, P ¼ 0.07;
respectively) (Fig. 4 A, B). 3.5. Effects of probiotics on inflammatory biomarkers
Total, visceral and subcutaneous abdominal fat area were re-
ported in 4 (n ¼ 350), 5 (n ¼ 445) and 4 (n ¼ 350) studies, Nine studies (n ¼ 649) reported CRP level. Data pooling showed
respectively. Pooled data showed that probiotic consumption lea- a non-significant effect of probiotic use in reducing CRP
ded to significant decrease in total (MD ¼ 9.69 cm2; 95% (MD ¼ 0.45 mg/l; 95%CI ¼ 0.99, 0.08 mg/l; P ¼ 0.10), with a high
4918
 Table 1

K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al.

Characteristics of the randomized controlled trials included in systematic review.
Author Design Population Baseline characteristics (Probiotic/control) Sample Probiotic Duration Control group Dietary Main outcomes
Year, size (PB/C) (weeks) intervention
BMI (kg/m2) Age (years) Sex Vehicle Strains Dose (CFU)
Location
%F

Agerholm-Larsen DB, PC Healthy overweight 30.0/30.0 38.6/39.4 75/64 16/14 Yogurt S. thermophilus ~9  109 8 Yogurt fermented with No BW, BMI, WHR, BF, LIP, BP
2000 [19], Denmark and obese adults L. acidophilus delta-acid-lactone
10
30.2/30.0 37.9/39.4 72/64 14/14 S. thermophilus ~9  10
L. rhamnosus
30.1/30.0 37.8/39.4 75/64 16/14 E. faecium ~27  109
S. thermophilus
Banach SB, PC Obese 35.6/34.2 34.9/34.2 63/67 27/27 Yogurt L. acidophilus LA5 and ND 12 Only diet Yes BW, BMI, BF
2020 [35], Poland B. lactis BB12
Brahe 2015(36), Denmark SB, PC Obese women (Post-M) 34.2/34.3 31.4/58.5 53/47 18/16 Sachet L. paracasei F19 9.4  1010 6 Maltodextrin No LIP, GLU, INS, HOMA-IR, LPS,
IL-6, TNF-a, CRP
Culpepper 2019 [37], DB, PC, CO Health obese adults 36.2/36.1 56.0/53.6 100/73 18/60 Capsule B. subtilis R0179 2.5  109 6 Potato starch and No LIP, GLU, INS, HOMA-IR
USA 36.1/36.1 53.4/53.6 67/73 24/60 L. plantarum HA119 5  109 stearate
35.9/36.1 51.3/53.6 56/73 18/60 B. lactis B94 5  109
Fathi 2016 [38] and 2017 DB, PC Healthy overweight or 29.5/28.9 35.2/37.0 47/53 18/20 Kefir ND ND 8 Low-fat dairy products Yes BW, BMI, WC, LIP
[20], obese women (Pre-M)
Iran
Hajipoor et al. DB, PC Obese 36.3/34.6 40.9/35.37 71/81 28/31 Yogurt L. acidophilus LAB5 and 8  109 10 Low-fat yogurt Yes BF, LIP
2021 [39], B. lactis BB12
Iran
Hibberd DB, PC Healthy overweight or 30.9/31.0 49.1/48.3 72/72 25/36 Sachet B.animalislactis 420 1  1010 24 Microcrystalline No BW, BMI, WHR, BF, LIP, GLU,
2019 [21], obese adults cellulose HbA1C, INS, CRP
Finland
Higashikawa 2016 [40], DB, PC Healthy overweight 26.8/27.4 52.5/52.8 62/65 21/20 Powder P.pentosaceus LP28 1  1011 12 Dextrina No BMI, WC, BF, LIP, GLU,
Japan HbA1C, INS, HOMA-IR, LEP,
ADIP
Ivey 2014(41) and 2015(42), DB, PC Overweight 30.8/30.8 64.7/65.4 41/43 39/40 Yogurt and capsule L. acidophilus LA5 and 3  109 6 Milk and capsule No LIP, GLU, HbA1C, INS,
Australia B. animalislactis BB12 HOMA-IR, BP
4919

Kadooka 2010 [22], Japan DB, PC Healthy overweight 27.5/27.2 48.3/49 33/32 43/44 Fermented milk L.gasseri SBT2055 LG2055 1  1011 12 Fermented milk No BW, BMI, WC, WHR, BF, AF,
ADIP
Kim 2017 [43], South Korea DB, PC Overweight 26.6/27.1 ND ND 32/34 Powder L. curvatus HY7601 and 1  1010 12 Crystalline cellulose, No BW, BMI, BF, AF
L. plantarum KY1032 lactose, and blue berry
flavouring agent.
Kim DB, PC Overweight and obese 28.2/28.6 37.9/38.1 77/53 30/30 Capsule L. gasseri BNR17 1  1010 12 Maltodextrin, Yes BW, BMI, WC, WHR, BF, AF,
2018 [44], South Korea crystalline cellulose, LIP, GLU, HbA1C, INS,
and magnesium HOMA-IR, TNF-a, CRP, LEP,
stearate. ADIP
Krumbeck 2018 [45], DB, PC Obese 34.6/36.4 44.7/43.9 64/77 14/17 Sachet B. adolescentis IVS1 1  109 3 Lactose No BW, BMI, WC, LP, GLU, BP
USA 37.5/36.4 43.9/43.9 86/77 B. lactis BB12 1  109
Lim DB, PC Overweight and obese 28.0/28.5 46.4/47.2 75/70 47/48 Powder L. sakei CJLS03 1  1010 12 Powder Yes BW, BMI, WC, BF, AF,
2020 [46], Korea HbA1C, INS, HOMA-IR, BP
7
Madjd SB, PC Healthy overweight 32.1/32.1 32.2/31.8 100/100 44/45 Yogurt L. acidophilus LA5 and 2  10 12 Yogurt Yes BW, BMI, WC, LIP, GLU,
2016 [47], and obese women (Pre- B. lactis BB12 HbA1C, INS, HOMA-IR
Iran M)
Majewska 2020 [48], Poland DB, PC Obese women 36.6/36.1 55.2/58.7 100/100 25/25 Sachet B .bifidum W23, B. lactis 1  1010 12 ND ND LIP, TNF-a
W51, B. lactis W52, L
.acidophilus W37, L. brevis
W63, L. casei W56,

Clinical Nutrition 40 (2021) 4915e4931

L. salivarius W24, Lc. lactis
W19 and Lc. lactis W58.
Michael DB, PC Overweight and obese 29.1/29.0 45.3/46.5 60/61 110/110 Capsule L. acidophilus CUL60, 5  1010 24 Microcrystalline No BW, BMI, WC, LIP, BP, CRP
2020 [49], L. acidophilus CUL21, cellulose
United Kingdom L. plantarum CUL66,
B. bifdum CUL20 and
B. animalislactis CUL34
Minami DB, PC Overweight adults 27.7/27.6 45.4/45.6 93/93 40/40 Capsule B. breve B3 2  1010 12 ND No LIP, GLU, HbA1C,CRP
2018 [50], Japan
Pra
znikar 2020 [51], UB, PC, CO Asymptomatic ND ND ND 28/28 Kefir L. parakefiri, L. kefiri, L. ND 3 Milk No BW, BF, LIP, GLU, CRP, ADIP
Slovenia overweight kefiranofacien sssp.
kefirgranum, Kl. marxianus,
(continued on next page)
 Table 1 (continued )

K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al.

Author Design Population Baseline characteristics (Probiotic/control) Sample Probiotic Duration Control group Dietary Main outcomes
Year, size (PB/C) (weeks) intervention
BMI (kg/m2) Age (years) Sex Vehicle Strains Dose (CFU)
Location
%F

K. exígua and
R. kratochvilovae
Rajkumar 2014 [52], DB, PC Healthy overweight ND ND ND 15/15 Capsule B.longum, B. infantis, B. breve, 112.5  109 6 Microcrystalline ND LIP, GLU, INS, CRP
India and obese adults L.acidophilus, L.paracasei, cellulose
L.delbrueckiibulgaricus,
L.plantarum, and
S.salivariusthermophilus
Skrypnik 2019 [53], Poland DB, PC Obese women (Post-M) 35.6/36.8 56.0/60.5 100/100 23/24 Sachet B. bifidum W23, B. lactis 1  1010 12 ND No BF, CRP
W51, B. lactis W52,
L. acidophilus W37, L. brevis
W63, L. casei W56,
L. salivarius W24, Lc.
lactisW19, and Lc. lactis W58
Stenman 2016 [54], Finland DB, PC Overweight and obese 30.9/31.0 49.1/48.3 72/72 25/36 Sachet B. animalislactis 420 1  1010 24 Microcrystalline No BW, BMI, WC, IL-6,CRP
cellulose
 ska 2018 [55,56],
Szulin DB, PC Obese women (Post-M) 36.6/36.1 55.2/58.7 100/100 23/24 Sachet B. bifidum W23, B. lactis 1  1010 12 Maize starch and No BW, BMI, WC, BF, AF, LIP,
Poland W51, B. lactis W52, maltodextrins GLU, INS, HOMA-IR, BP, IL-6,
L. acidophilus W37, L. brevis TNF-a
W63, L. casei W56,
L. salivarius W24, Lc. Lactis
W19, and Lc. lactis W58.
Takahashi 2016 [57], Japan DB, PC Healthy overweight 26.8/26.9 46.9/46.9 33/40 69/68 Fermented milk B. lactis GCL2505 ~8  1010 12 Fermented milk No BW, BMI, WHR, AF
and obese
10
Zarrati DB, PC Overweight and obese 33.8/33.9 36/36 ND 25/25 Yogurt L. acidophilus LA5, B. lactis 6  10 8 Yogurt Yes BMI, WC, WHR, BP
2013 [58], BB12 and L. casei DN001
Iran
Zarrati DB, PC Overweight and obese 32.7/31.7 36/36.3 ND 26/30 Yogurt L. acidophilus LA5, B. lactis 6  1010 8 Yogurt Yes BW, BMI, WC, BF
2019 [24], BB12 and L. casei DN001
4920

Iran

BMI: Body mass index; PB: Probiotic; C: Control; F: Female; CFU: Colony-forming units; DB: Double-blind; SB: Single-blind; UB: Unblinded; PC: Placebo controlled; CO: Crossover; Post-M: Postmenopausal; Pre-M: Premen-
opausal; ND: Not discriminated; S: Streptococcus; L: Lactobacillus; E: Enterococcus; B: Bifidobacterium; P: Pediococcus; Lc: Lactococcus; K: Kazachstania; Kl: Kluyveromyce; R: Rhodosporidium; BW:Body weight; WC: Waist
circumference; WHR: Waist-to-hip ratio; BF: Body fat, AF: Abdominal fat; LIP: Lipid profile; GLU: Glucose; HbA1C: Glycated hemoglobin; INS:Insulin; HOMA-IR: Homeostasis model assessment; BP: Blood pressure; LPS:
Lipopolysaccharide; IL-6: Interleukin 6; TNF-a: Tumor necrosis factor a; LEP: Leptin; ADIP: Adiponectin.

Clinical Nutrition 40 (2021) 4915e4931

K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 2. Risk of bias and risk of bias summary.

level of heterogeneity (I2 ¼ 84%, P < 0.001) between the studies studies, respectively. Probiotic treatment led to a significant change
(Fig. 5A). As one of these studies was considered an outlier [36], we in TNF-a (MD ¼ 0.16 pg/ml; 95%CI ¼ 0.24, 0.08 pg/ml;
excluded this study from the analysis and observed a significance P ¼ 0.0001), and to a non-significant change in IL-6 (MD ¼ 0.05 pg/
decrease in the overall effect (MD ¼ 0.68 mg/l; 95% ml; 95%CI ¼ 0.28, 0.39 pg/ml; P ¼ 0.75), adiponectin (MD ¼ 0.04
CI ¼ 1.12, 0.24 mg/l; P ¼ 0.003), with a moderate heterogeneity mcg/ml; 95%CI ¼ 0.43, 0.36 mcg/ml; P ¼ 0.85) and leptin
(I2 ¼ 74%, P < 0.001). TNF-a, IL-6, adiponectin and leptin were re- (MD ¼ 0.30 ng/ml; 95%CI ¼ 3.86, 4.46 ng/ml; P ¼ 0.89) with a
ported in 4 (n ¼ 191), 3 (n ¼ 142), 4 (n ¼ 122) and 2 (n ¼ 101) non-significant heterogeneity among included trials (I2 ¼ 11%,

4921
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 3. Forest plots of the effect of probiotics on body weight (A), body mass index (B), waist circumference (C) and waist-to-hip ratio (D). Agerholm-Larsen 2000 a, Streptococcus
thermophilus and Lactobacillus acidophilus group vs. placebo group; Agerholm-Larsen 2000 b, Streptococcus thermophilus and Lactobacillus rhamnosus group vs. placebo group;
Agerholm-Larsen 2000 c, Streptococcus thermophilus and Enterococcus faecium group vs. placebo group; Krumbeck 2018 a, Bifidobacterium adolescentis group vs. placebo group;
Krumbeck 2018 b, Bifidobacterium lactis group vs. placebo group.

P ¼ 0.34), (I2 ¼ 57%, P ¼ 0.10), (I2 ¼ 31%, P ¼ 0.23) and (I2 ¼ 72%, 3.6. Effects of probiotics on glucose metabolism
P ¼ 0.06), respectively (Fig. 5 B, C, D, E).
As IL-1, interferon, ghrelin, LPS, LPB, TMAO, FMD, PWV, VCAM Thirteen studies (n ¼ 977) reported fasting glucose. Data pool-
and ICAM were evaluated each one in only one study or presented ing showed a non-significant effect of probiotic use in glucose
insufficient data it was not possible to perform a meta-analysis of levels (MD ¼ 0.07 mmol/l; 95%CI ¼ 0.26, 0.13 mmol/l; P ¼ 0.52),
such variables. with a high level of heterogeneity (I2 ¼ 92%, P < 0.00001) (Fig. 6A).
4922
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 4. Forest plots of the effects of probiotics on fat mass (A), percentage body fat (B), total abdominal fat area (C), subcutaneous abdominal fat area (D) and visceral abdominal fat
area (E). Agerholm-Larsen 2000 a, Streptococcus thermophilus and Lactobacillus acidophilus group vs. placebo group; Agerholm-Larsen 2000 b, Streptococcus thermophilus and
Lactobacillus rhamnosus group vs. placebo group; Agerholm-Larsen 2000 c, Streptococcus thermophilus and Enterococcus faecium group vs. placebo group.

Ten studies (n ¼ 776) reported fasting insulin. Probiotic use 3.7. Effects of probiotics on lipid profile
significantly reduced fasting insulin (MD ¼ 0.85 mcU/ml; 95%
CI ¼ 1.50, 0.21 mcU/ml; P ¼ 0.010), with non-significant het- Eighteen studies (n ¼ 1429) reported total cholesterol, LDL, HDL
erogeneity (I2 ¼ 30%, P ¼ 0.15) (Fig. 6C). and triglyceride levels. Data pooling showed that administration of
HbA1C and HOMA-IR were reported in 7 (n ¼ 505) and 9 probiotics resulted in a significant decrease in total cholesterol
(n ¼ 765) studies, respectively. Probiotic treatment did not reduce compared with the control group (MD ¼ 0.16 mmol/l; 95%
HbA1C (MD ¼ 0.03%; 95%CI ¼ 0.14, 0.09%; P ¼ 0.65) and HOMA- CI: 0.26, 0.05 mmol/l; P ¼ 0.003), with moderate heterogeneity
IR (MD ¼ 0.08; 95%CI ¼ 0.34, 0.18; P ¼ 0.54) with a high (I2 ¼ 71%; P < 0.0001) (Fig. 7A). Overall meta-analysis also found
(I2 ¼ 84%, P < 0.00001) and moderate heterogeneity (I2 ¼ 47%, a significant reduction in LDL levels in probiotic group
P ¼ 0.04), respectively (Fig. 6 B, D). (MD ¼ 0.09 mmol/l; 95%CI: 0.16, 0.03 mmol/l; P ¼ 0.006), with

4923
 K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

I2 (%) moderate heterogeneity (I2 ¼ 68%; P < 0.0001) (Fig. 7B). However,
the pooled effect of probiotics on HDL was non-significant
55

78

71

90

55

69
43
e
0

0
(MD ¼ 0.01 mmol/l; 95%CI: 0.04, 0.05 mmol/l; P ¼ 0.75),
although the heterogeneity between the studies was high
<0.00001

<0.00001

<0.00001
0.0004

0.0004
(I2 ¼ 86%; P < 0.0001) (Fig. 7C). Similarly, data pooling showed a

0.008
0.16

0.17

0.54

0.02
e
non-significant effect of probiotics on reducing triglyceride levels
p

(MD ¼ 0.02 mmol/l; 95%CI: 0.16, 0.12 mmol/l; P ¼ 0.79), also

Mean difference (95% CI)

with high heterogeneity (I2 ¼ 91%; P < 0.0001) (Fig. 7 D).

0.78 (1.08,-0.49)

0.90 (1.22,-0.58)

0.79 (1.06,-0.53)

0.71 (1.10,-0.32)

1.35 (2.45,-0.25)
0.54 (0.94,-0.14)
0.71 (-1.10,-0.32)

0.64 (1.53,0.26)

0.65 (2.70,1.41)
0.51 (-1.24,0.21)

3.8. Effects of probiotics on blood pressure

Seven studies (n ¼ 641) reported systolic and diastolic BP. Data

Fat mass (kg)

pooling detected a non-significant effect of probiotics on systolic

e

BP (MD ¼ 0.23 mmHg; 95%CI: 0.57, 0.12 mmHg; P ¼ 0.20) and

No

13

13

diastolic BP (MD ¼ 0.35 mmHg; 95%CI: 0.76, 0.06 mmHg;

6
7

8
5

9
3

4
9

P ¼ 0.09), with no heterogeneity among studies for both param-

I2 (%)

eters (I2 ¼ 0%; P > 0.05) (Fig. 8 A, B).

NA
33

42
28

34

38

33

30
41
0

0
<0.00001

<0.00001

3.9. Publication bias

<0.0001

<0.0001
<0.0001

<0.0001
0.0004
0.0003

0.004
0.65

0.55
p

Visual inspection of the funnel plots suggested that publication

bias was associated with the effect of probiotic supplementation
Mean difference (95% CI)

on glucose and HDL. Egger's test also indicated publication bias on

1.13 (1.54,-0.73)

1.12 (1.74,-0.51)
1.13 (1.75,-0.52)

1.19 (1.58,-0.80)

0.99 (1.65,-0.32)
1.23 (1.80,-0.66)
0.83 (-1.22,-0.44)
1.51 (-2.20,-0.83)

1.21 (-1.72,-0.70)

glucose (P ¼ 0.01) and HDL (P ¼ 0.002) (Figs. S1 and S2).

Waist circumference (cm)

0.31 (-1.66,1.04)

0.74 (1.70,3.18)

4. Discussion

In the present meta-analysis all the evaluated parameters of

body adiposity presented a statistically significant decrease after
No

13

11

11
5
8

5
7

6
7

probiotic consumption. The mechanisms for the beneficial effects

of probiotics on body adiposity remain unclear. Some of the
I2 (%)

mechanisms currently under study are modification of the gut

55

74
22

29
19

52

59

68
46
0

microbiota, reduction of intestinal permeability, and modulation

<0.0001

of the immune system [59,60]. The proposed mechanisms for the

0.0001

0.0001

0.0001
0.001

0.001
0.14

0.02

0.67

0.82

0.25

role of gut microbiota in the etiology of obesity include decreased

p

expression of the fasting induced adipose factor (FIAF) (an in-

Mean difference (95% CI)

hibitor of lipoprotein lipase), increasing the deposition of tri-

Results of subgroup analyses for body weight, body mass index, waist circumference and fat mass.

glycerides in adipose tissue [8]. Another potential mechanism is

0.24 (0.35,-0.12)

0.30 (0.42,-0.17)

CI: confidence interval, BMI: body mass index, NA: not applicable, CFU: colony-forming units.
0.28 (-0.45,-0.11)
0.15 (-0.27,-0.02)

0.22 (-0.35,-0.09)

0.25 (-0.37,-0.12)

0.28 (-0.42,-0.14)
0.17 (-0.40,0.06)

0.07 (-0.39,0.25)

0.05 (-0.48,0.38)

0.14 (-0.39,0.10)
Body mass index (kg/m2)

the suppression of adenosine monophosphate-activated protein

kinase (AMPK), reducting fatty acid oxidation and increasing tri-
glycerides synthesis [61].
The significant decrease in body adiposity observed in this
meta-analysis is in agreement with previous meta-analyses con-
ducted in overweight and obese subjects [25e27,29,62]. In some
No

17

10

12

15

10
7

7
9

of these meta-analyses, all the evaluated parameters of body

I2 (%)

adiposity presented a significant decrease [27,62]. For example,

NA
70

76
53

30
81

74

71

73
71
0

Wang et al. [27] observed a significant decrease in body weight,

BMI, WC, fat mass and fat percentage. The mean decrease in body
<0.0001

<0.0001
0.0001

0.0009

weight observed in this meta-analysis was 0.63 kg, similar to the

0.004

0.001
0.03

0.03

0.28

0.89

0.07

reduction observed by John et al. [62] (0.64 Kg), Wang et al. [27]
p

(0.55 kg), and Borgeraas et al. [25] (0.60 kg), suggesting that
Mean difference (95% CI)

although statistically significant, this reduction is modest and the

0.70 (1.04,-0.35)

0.54 (1.03,-0.05)
0.92 (1.38,-0.45)

0.64 (0.99,-0.29)
0.71 (1.37,-0.05)

0.74 (1.18,-0.29)

0.72 (1.07,-0.37)

0.78 (1.24,-0.32)

use of probiotics might be a complementary approach in the

0.27 (0.76,0.22)

0.10 (1.55,1.35)

0.55 (1.13,0.04)

treatment of excessive adiposity.

(energy restriction)

It is worth mentioning that we observed a significant decrease

Body weight (kg)

in total, subcutaneous and visceral abdominal fat area with the use
of probiotics. Since central fat has a greater negative impact on the
metabolic risk associated with obesity, the reduction of this fat
No

17

10

10

11

16

11

compartment may represent an additional beneficial effect of

7

6
Dietary intervention
Vehicle of probiotic

probiotics, even considering the small reduction of body weight.

Number of species
Capsule/Powder

Duration (weeks)

To our knowledge, this is the first meta-analysis assessing the

Overall analysis

Dose (CFU/day)

effect of probiotic supplementation, on overweight or obese

Subgroup

subjects, on abdominal fat area. Most of the studies included in

1010
Single

<1010
Multi
Dairy
Table 2

Yes
8

No
<8

this meta-analysis measured these parameters by computed to-

mography [22,43,44,56].
4924
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 5. Forest plots of the effects of probiotics on C-reactive protein (A), tumor necrosis factor a (B), interleukin-6 (C), adiponectin (D) and leptin (E).

This meta-analysis is also the first to evaluate the effects of barrier, which may instigate low-grade inflammation, as compo-
probiotics on weight loss accompanied with concurrent energy nents and/or metabolites of the microbiota can translocate into the
restriction. Although weight loss was not significant when pro- circulation. A proinflammatory response can be elicited by several
biotic supplementation was accompanied with energy restriction, PAMPs, such as LPS when detected by specialized immune cells,
the decrease in BMI was observed only when energy restriction was equipped with pathogen-recognition receptors as toll-like re-
used, while the reduction in WC and fat mass was significant with ceptors (TLRs). The activation of these receptors triggers the pro-
and without energy restriction. These findings suggest that pro- duction of proinflammatory mediators as cytokines [63,64].
biotics may have beneficial effects on body adiposity independent Moreover, dysbiosis may reduce butyrate levels in the gut which
of concurrent energy restriction. Another important finding of this could favor inflammation. Butyrate exerts local anti-inflammatory
meta-analysis is that the dose and the duration of probiotic sup- effects in the intestinal mucosa and its reduction could result in a
plementation are important for a significant effect on body dysfunctional gut mucosal barrier, resulting in the leakage of bac-
adiposity, as a decrease in body adiposity was only observed in terial toxins such as LPS, triggering systemic inflammation [65,66].
studies using at least 1010 CFU/day and lasting at least 8 weeks. Previous meta-analyses have also observed a significant decrease in
In the present meta-analysis probiotics were associated with a CRP following probiotic administration [67,68], but to our knowl-
significant decrease in serum levels of TNF-a and of CRP, after the edge this is the first meta-analysis to evaluate exclusively over-
exclusion of the study [36] considered as an outlier, suggesting a weight/obesity subjects and to observe a significant reduction in
beneficial effect for inflammatory markers. Low-grade inflamma- TNF-a.
tion is a hallmark of obesity and its related metabolic disorders [6]. Insulin levels evaluated in this meta-analysis were significantly
In healthy subjects gut microbiota is characterized by a diverse reduced by probiotics, suggesting a possible beneficial role in in-
composition and an intact intestinal barrier. Whereas obesity is sulin sensitivity. Although the effect of probiotics on other pa-
associated with dysbiosis and impaired and defective intestinal rameters of glucose metabolism, such as HbA1C and HOMA, were

4925
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 6. Forest plots of the effects of probiotics on glucose (A), glycated hemoglobin (B), insulin (C) and HOMA-IR (D). Culpepper 2019 a, Bifidobacterium subtilis group vs. placebo
group; Culpepper 2019 b, Lactobacillus plantarum group vs. placebo group; Culpepper 2019 c, Bifidobacterium lactis group vs. placebo group; Krumbeck 2018 a, Bifidobacterium
adolescentis group vs. placebo group; Krumbeck 2018 b, Bifidobacterium lactis group vs. placebo group.

not significant. The mean levels of glucose and HbA1C in the RCT release of glucagon-like peptide (GLP)-1, which in turn increases
included in this meta-analysis were not in the diabetic range. Some postprandial insulin release and decreases glucagon secretion
previous meta-analyses including diabetic subjects suggest a [8,74,75].
beneficial effect of probiotics on glycemic control and/or insulin Total cholesterol and LDL were significantly reduced by pro-
resistance [69e72]. The potential mechanisms remain incom- biotics supplementation. These results are in agreement with other
pletely understood. However, the decrease in the inflammation meta-analyses [76e79]. Yet not fully understood, cholesterol
may reduce insulin resistance [73]. Gut microbiota and their lowering mechanisms may be partially explained by deconjugation
products can also modulate glucose metabolism. For example, of bile salts in the intestinal lumen, via bile salt hydrolase activity
butyrate can act as ligand for G-protein coupled receptors (GPCR41 produced by some probiotics. This deconjugation leads to a lower
and GPCR43) of gut enteroendocrine L cells and promote the reabsorption of bile salts, promoting an increase in the required

4926
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 7. Forest plots of the effects of probiotics on total cholesterol (A), low density lipoprotein cholesterol (B), high density lipoprotein cholesterol (C) and triglycerides (D).
Agerholm-Larsen 2000 a, Streptococcus thermophilus and Lactobacillus acidophilus group vs. placebo group; Agerholm-Larsen 2000 b, Streptococcus thermophilus and Lactobacillus
rhamnosus group vs. placebo group; Agerholm-Larsen 2000 c, Streptococcus thermophilus and Enterococcus faecium group vs. placebo group; Culpepper 2019 a, Bifidobacterium
subtilis group vs. placebo group; Culpepper 2019 b, Lactobacillus plantarum group vs. placebo group; Culpepper 2019 c, Bifidobacterium lactis group vs. placebo group; Krumbeck
2018 a, Bifidobacterium adolescentis group vs. placebo group; Krumbeck 2018 b, Bifidobacterium lactis group vs. placebo group.

4927
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Fig. 8. Forest plots of the effects of probiotics on systolic blood pressure (A) and diastolic blood pressure (B). Agerholm-Larsen 2000 a, Streptococcus thermophilus and Lactobacillus
acidophilus group vs. placebo group; Agerholm-Larsen 2000 b, Streptococcus thermophilus and Lactobacillus rhamnosus group vs. placebo group; Agerholm-Larsen 2000 c, Strep-
tococcus thermophilus and Enterococcus faecium group vs. placebo group; Krumbeck 2018 a, Bifidobacterium adolescentis group vs. placebo group; Krumbeck 2018 b, Bifidobacterium
lactis group vs. placebo group.

amount of endogenous cholesterol for the synthesis of bile salts bias and all outcome variables of the primary aim of the study
[80,81]. Some probiotics contain enzymes able to catalyze the presented low or moderate level of heterogeneity with no evi-
transformation of cholesterol into cholest-4-en-3-one, an inter- dence of publication bias. There were a few noted limitations.
mediate in the conversion to coprosterol or coprostanol, which are First, a high level of heterogeneity and evidence of publication
directly excreted in the feces. Probiotics may also alter bowel pH, bias were observed for some secondary outcomes. Second, the
micelles formation and the transport pathways of cholesterol and/ sample size of some RCTs was small. Third, strain types were
or lipoproteins [82]. Considering that abnormal serum levels of inconsistent among analyzed studies. Fourth, lower representa-
cholesterol are major risk factors for CVDs [83], our findings sup- tion of male subjects as well as younger (18e35 years) and elderly
port that the supplementation with probiotics may help reduce this (>65 years) persons in the included studies and the lack of long-
risk in overweight and obese individuals. term data (>24 weeks).
In contrast to previous meta-analyses [84e86], we found no In conclusion, this systematic review and meta-analysis sug-
significant reduction in BP. This difference may be related to the gests that probiotic supplementation has a modest beneficial effect
exclusion of studies conducted on hypertensive patients, because on body weight and body adiposity in individuals with overweight
the effect of probiotics seems to be greater at higher BP levels and obesity, indicating a potential complementary therapeutic
[84,85]. Experimental models have shown that gut microbiota approach. Probiotics were effective independent of the association
plays a role in the regulation of BP. The underlying mechanisms with energy restriction, while were more effective when consumed
include the SCFA pathway, as they can bind to GPCRs expressed in at higher doses and for a duration of at least 8 weeks. Additionally,
the renal juxtaglomerular apparatus and in smooth muscle cells of our results suggest that in individuals with overweight and obesity,
small resistance vessels [87,88]. It has also been demonstrated that probiotics have beneficial effects on some markers of cardiovas-
lower microbiota diversity and dysbiosis are associated with hy- cular risk related with excessive adiposity such as inflammation
pertension, and evidence suggests that the changes in microbiota and altered lipid and glucose metabolism.
precede the increase in BP [89,90]. Recently, Brunt et al. reported
that there is a clear role of TMAO in promoting age-related Statement of authorship
endothelial dysfunction via oxidative stress, which increases risk
of hypertension and CVDs [91]. In this context, RCTs that investi- Pontes, KSS: Conceptualization, designed the search strategy,
gated the effects of probiotics on endothelial function [92,93] and made the study selection, data extraction and quality assessment,
pulse wave velocity [56], observed improvement in these writing-original draft, interpretation and analysis of the data ob-
parameters. tained from the network meta-analysis.
There were strengths of the present meta-analysis. First, was Guedes, MR: Conceptualization, designed the search strategy,
the exclusive inclusion of studies using control group for com- made the study selection, data extraction and quality assessment,
parison. Second, this is the first meta-analysis reporting the ef- writing-original draft, interpretation and analysis of the data ob-
fects of probiotics on abdominal fat area in subjects with tained from the network meta-analysis.
overweight or obesity. Third, the eligibility criteria of the RCTs Cunha, MR: Conceptualization, designed the search strategy,
included in the meta-analysis were very similar, including over- made the study selection, data extraction and quality assessment,
weight/obese individuals and excluding comorbidities. Fourth, in writing-original draft.
subgroup analysis, we observed the effectiveness of probiotics Mattos, SS: Conceptualization, designed the search strategy,
independent of energy restriction. Fifth, all studies were classified made the study selection, data extraction and quality assessment,
as good by Cochrane assessment tool for randomized trials risk of writing-original draft.
4928
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

Barreto-Silva, MI: made the statistical analyses; interpretation [9] Barrington WT, Lusis AJ. Association between the gut microbiome and
atherosclerosis. Nat Rev Cardiol 2017;14(12):699e700.
and analysis of the data obtained from the network meta-analysis,
[10] Tang WHW, B€ ackhed F, Landmesser U, Hazen SL. Intestinal microbiota in
writing-review & editing. cardiovascular health and disease: JACC state-of-the-art review. J Am Coll
Neves, MF: Conceptualization, writing-review & editing. Cardiol 2019;73(16):2089e105.
Marques, BCAA: Conceptualization, designed the search strat- [11] Torres-Fuentes C, Schellekens H, Dinan T, Cryan JF. The microbiota-gut-brain
axis in obesity. Lancet Gastroenterol Hepatol 2017;2(10):747e56.
egy, performed the search strategy, made the study selection, data [12] Liu H, Chen X, Hu X, Niu H, Tian R, Wang H, et al. Alterations in the gut
extraction and quality assessment, made the statistical analyses, microbiome and metabolism with coronary artery disease severity. Micro-
writing-original draft, interpretation and analysis of the data ob- biome 2019;7(1):68.
[13] Trøseid M, Andersen GØ, Broch K, Hov JR. The gut microbiome in coronary
tained from the network meta-analysis. artery disease and heart failure: current knowledge and future directions.
Kelin, MRST: Conceptualization, designed the search strategy, EBioMedicine 2020;52:102649.
performed the search strategy, made the study selection, data [14] Brown JM, Hazen SL. Microbial modulation of cardiovascular disease. Nat Rev
Microbiol 2018;16(3):171e81.
extraction and quality assessment, made the statistical analyses, [15] van den Munckhof ICL, Kurilshikov A, Ter Horst R, Riksen NP, Joosten LAB,
writing-original draft, interpretation and analysis of the data ob- Zhernakova A, et al. Role of gut microbiota in chronic low-grade inflammation
tained from the network meta-analysis, writing-review & editing. as potential driver for atherosclerotic cardiovascular disease: a systematic
review of human studies. Obes Rev 2018;19(12):1719e34.
[16] Kazemian N, Mahmoudi M, Halperin F, Wu JC, Pakpour S. Gut microbiota and
Financial support cardiovascular disease: opportunities and challenges. Microbiome 2020;8(1):
36.
~o de Aper- [17] Schiattarella GG, Sannino A, Toscano E, Giugliano G, Gargiulo G, Franzone A,
This study was financed in part by the Coordenaça
et al. Gut microbe-generated metabolite trimethylamine-N-oxide as cardio-
feiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance vascular risk biomarker: a systematic review and dose-response meta-anal-
Code 001. ysis. Eur Heart J 2017;38(39):2948e56.
[18] Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert
consensus document: the international scientific association for probiotics
Conflict of interest and prebiotics consensus statement on the scope and appropriate use of the
term probiotic. Nat Rev Gastroenterol Hepatol 2014;11(8):506e14.
None declared. [19] Agerholm-Larsen L, Raben A, Haulrik N, Hansen AS, Manders M, Astrup A.
Effect of 8 week intake of probiotic milk products on risk factors for cardio-
vascular diseases. Eur J Clin Nutr 2000;54(4):288e97.
Acknowledgments [20] Fathi Y, Ghodrati N, Zibaeenezhad MJ, Faghih S. Kefir drink causes a significant
yet similar improvement in serum lipid profile, compared with low-fat milk,
in a dairy-rich diet in overweight or obese premenopausal women: a ran-
We would like to thank Kelly Picard BSc RD from University of domized controlled trial. J Clin Lipidol 2017;11(1):136e46.
Alberta for her contributions to this work which consisted of [21] Hibberd AA, Yde CC, Ziegler ML, Honore  AH, Saarinen MT, Lahtinen S, et al.
providing insightful comments, raising important questions and Probiotic or synbiotic alters the gut microbiota and metabolism in a rando-
mised controlled trial of weight management in overweight adults. Benef
reviewing grammar on this work. Microbes 2019;10(2):121e35.
[22] Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, Akai Y, et al. Regulation
Appendix A. Supplementary data of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults
with obese tendencies in a randomized controlled trial. Eur J Clin Nutr
2010;64(6):636e43.
Supplementary data to this article can be found online at [23] Minami J, Kondo S, Yanagisawa N, Odamaki T, Xiao JZ, Abe F, et al. Oral
https://doi.org/10.1016/j.clnu.2021.06.023. administration of Bifidobacterium breve B-3 modifies metabolic functions in
adults with obese tendencies in a randomised controlled trial. J Nutr Sci
2015;4:e17. https://doi.org/10.1017/jns.2015.5.
References [24] Zarrati M, RajiLahiji M, Salehi E, Yazdani B, Razmpoosh E,
ShokouhiShoormasti R, et al. Effects of probiotic yogurt on serum omentin-
[1] Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, 1, adropin, and Nesfatin-1 concentrations in overweight and obese partic-
et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: ipants under low-calorie diet. Probiotics Antimicrob Proteins 2019;11(4):
update from the GBD 2019 study. J Am Coll Cardiol 2020;76(25):2982e3021. 1202e9.
[2] Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, [25] Borgeraas H, Johnson LK, Skattebu J, Hertel JK, Hjelmesaeth J. Effects of pro-
et al. American heart association council on epidemiology and prevention biotics on body weight, body mass index, fat mass and fat percentage in
statistics committee and stroke statistics subcommittee. Heart disease and subjects with overweight or obesity: a systematic review and meta-analysis of
stroke statistics-2020 update: a report from the American heart association. randomized controlled trials. Obes Rev 2018;19(2):219e32.
Circulation 2020;141(9):e139e596. [26] Suzumura EA, Bersch-Ferreira AC, Torreglosa CR, da Silva JT, Coqueiro AY,
[3] Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, Kuntz MGF, et al. Effects of oral supplementation with probiotics or synbiotics
et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular in overweight and obese adults: a systematic review and meta-analyses of
disease: a report of the American college of cardiology/American heart asso- randomized trials. Nutr Rev 2019;77(6):430e50.
ciation task force on clinical practice guidelines. Circulation 2019;140(11): [27] Wang ZB, Xin SS, Ding LN, Ding WY, Hou YK, Liu CQ, et al. The potential role of
e596e646. probiotics in controlling overweight/obesity and associated metabolic pa-
[4] Chait A, den Hartigh LJ. Adipose tissue distribution, inflammation and its rameters in adults: a systematic review and meta-analysis. Evid Based Com-
metabolic consequences, including diabetes and cardiovascular disease. Front plement Alternat Med 2019 Apr;(15):3862971.
Cardiovasc Med 2020;7:22. https://doi.org/10.3389/fcvm.2020.00022. [28] Cao S, Ryan PM, Salehisahlabadi A, Abdulazeem HM, Karam G, Cernevi   te_ R,
ciu
[5] Bray GA, Kim KK, Wilding JPH, World Obesity Federation. Obesity: a chronic et al. Effect of probiotic and synbiotic formulations on anthropometrics and
relapsing progressive disease process. A position statement of the World adiponectin in overweight and obese participants: a systematic review and
Obesity Federation. Obes Rev 2017;18(7):715e23. meta-analysis of randomized controlled trials. J King Saud Univ Sci
[6] Fuster JJ, Ouchi N, Gokce N, Walsh K. Obesity-induced changes in adipose 2020;32(2):1738e48.
tissue microenvironment and their impact on cardiovascular disease. Circ Res [29] Yan S, Tian Z, Li M, Li B, Cui W. Effects of probiotic supplementation on the
2016;118(11):1786e807. regulation of blood lipid levels in overweight or obese subjects: a meta-
[7] Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, et al. 2016 analysis. Food Funct 2019;10(3):1747e59.
European guidelines on cardiovascular disease prevention in clinical practice: [30] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting
the sixth joint task force of the European society of cardiology and other items for systematic reviews and meta-analyses: the PRISMA statement. Ann
societies on cardiovascular disease prevention in clinical practice (constituted Intern Med 2009;151(4):264e9.
by representatives of 10 societies and by invited experts)Developed with the [31] Higgins JPT, Savovic J, Page MJ, Elbers RG, Sterne JAC. Chapter 8: assessing risk
special contribution of the European association for cardiovascular prevention of bias in a randomized trial (updated September 2020). Cochrane. In:
& rehabilitation (EACPR). Eur Heart J 2016;37(29):2315e81. https://doi.org/ Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors.
10.1093/eurheartj/ehw106. Cochrane handbook for systematic reviews of interventions version 6.1; 2020.
[8] Muscogiuri G, Cantone E, Cassarano S, Tuccinardi D, Barrea L, Savastano S, Available from: www.training.cochrane.org/handbook.
et al. On behalf of the Obesity Programs of nutrition, Education, Research and [32] Higgins JPT, Li T, Deeks JJ. Chapter 6: choosing effect measures and computing
Assessment (OPERA) group. Gut microbiota: a new path to treat obesity. Int J estimates of effect (updated September 2020). Cochrane. In: Higgins JPT,
Obes Suppl 2019;9(1):10e9. Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane

4929
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

handbook for systematic reviews of interventions version 6.1; 2020. Available lipopolysaccharide (LPS) level and cardiometabolic profile in obese post-
from: www.training.cochrane.org/handbook. menopausal women: a 12-week randomized clinical trial. Nutrients
[33] Higgins JPT. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414): 2018;10(6):773.
557e60. [56] Szulin ska M, Łoniewski I, Skrypnik K, Sobieska M, Korybalska K, Suliburska J,
[34] Review manager. Version 5.3. Cochrane Collab: The Nordic Cochrane Centre; et al. Multispecies probiotic supplementation favorably affects vascular
2014. Copenhagen. function and reduces arterial stiffness in obese postmenopausal women-A 12-
[35] Banach K, Glibowski P, Jedut P. The effect of probiotic yogurt containing week placebo-controlled and randomized clinical study. Nutrients
Lactobacillus acidophilus LA-5 and Bifidobacterium lactis BB-12 on selected 2018;10(11):1672.
anthropometric parameters in obese individuals on an energy-restricted diet: [57] Takahashi S, Anzawa D, Takami K, Ishizuka A, Mawatari T, Kamikado K, et al.
a randomized, controlled trial. Appl Sci 2020;10:5830. https://doi.org/ Effect of Bifidobacterium animalis ssp. lactis GCL2505 on visceral fat accu-
10.3390/app10175830. mulation in healthy Japanese adults: a randomized controlled trial. Biosci
[36] Brahe LK, Le Chatelier E, Prifti E, Pons N, Kennedy S, Blædel T, et al. Dietary Microbiota Food Health 2016;35(4):163e71.
modulation of the gut microbiota–a randomised controlled trial in obese [58] Zarrati M, Shidfar F, Nourijelyani K, Mofid V, Hossein zadeh-Attar MJ, Bidad K,
postmenopausal women. Br J Nutr 2015;114(3):406e17. et al. Lactobacillus acidophilus La5, Bifidobacterium BB12, and Lactobacillus
[37] Culpepper T, Rowe CC, Rusch CT, Burns AM, Federico AP, Girard SA, et al. Three casei DN001 modulate gene expression of subset specific transcription factors
probiotic strains exert different effects on plasma bile acid profiles in healthy and cytokines in peripheral blood mononuclear cells of obese and overweight
obese adults: randomised, double-blind placebo-controlled crossover study. people. Biofactors 2013;39(6):633e43.
Benef Microbes 2019;10(5):497e509. [59] Mazloom K, Siddiqi I, Covasa M. Probiotics: how effective are they in the fight
[38] Fathi Y, Faghih S, Zibaeenezhad MJ, Tabatabaei SH. Kefir drink leads to a against obesity? Nutrients 2019;11(2):258. https://doi.org/10.3390/
similar weight loss, compared with milk, in a dairy-rich non-energy-restricted nu11020258.
diet in overweight or obese premenopausal women: a randomized controlled [60] Abenavoli L, Scarpellini E, Colica C, Boccuto L, Salehi B, Sharifi-Rad J, et al. Gut
trial. Eur J Nutr 2016;55(1):295e304. microbiota and obesity: a role for probiotics. Nutrients 2019;11(11):2690.
[39] Hajipoor S, Hekmatdoost A, Rezaie M, Nachvak SM, Alipour M, Eskandari S, https://doi.org/10.3390/nu11112690.
et al. The effect of yogurt co-fortified with probiotic and vitamin D on lipid [61] Wicin  ski M, Ge˛ balski J, Gołe˛ biewski J, Malinowski B. Probiotics for the treat-
profile, anthropometric indices and serum 25-hydroxi vitamin D in obese ment of overweight and obesity in humans-A review of clinical trials. Mi-
adult: a Double-Blind Randomized- Controlled Trial. Food Sci Nutr 2021;9: croorganisms 2020;8(8):1148. https://doi.org/10.3390/
303e12. microorganisms8081148.
[40] Higashikawa F, Noda M, Awaya T, Danshiitsoodol N, Matoba Y, Kumagai T, [62] John GK, Wang L, Nanavati J, Twose C, Singh R, Mullin G. Dietary alteration of
et al. Antiobesity effect of Pediococcuspentosaceus LP28 on overweight sub- the gut microbiome and its impact on weight and fat mass: a systematic re-
jects: a randomized, double-blind, placebo-controlled clinical trial. Eur J Clin view and meta-analysis. Genes 2018;9(3):167. https://doi.org/10.3390/
Nutr 2016;70(5):582e7. genes9030167.
[41] Ivey KL, Hodgson JM, Kerr DA, Lewis JR, Thompson PL, Prince RL. The effects of [63] Cerdo  T, García-Santos JA, Bermúdez MG, Campoy C. The role of probiotics and
probiotic bacteria on glycaemic control in overweight men and women: a prebiotics in the prevention and treatment of obesity. Nutrients 2019;11(3):
randomised controlled trial. Eur J Clin Nutr 2014;68(4):447e52. 635. https://doi.org/10.3390/nu11030635.
[42] Ivey KL, Hodgson JM, Kerr DA, Thompson PL, Stojceski B, Prince RL. The effect [64] Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling
of yoghurt and its probiotics on blood pressure and serum lipid profile; a metabolic inflammation. Nat Rev Immunol 2020;20(1):40e54.
randomised controlled trial. NutrMetab Cardiovasc Dis 2015;25(1):46e51. [65] Trøseid M, Andersen GØ, Broch K, Hov JR. The gut microbiome in coronary
[43] Kim M, Kim M, Kang M, Yoo HJ, Kim MS, Ahn YT, et al. Effects of weight loss artery disease and heart failure: current knowledge and future directions.
using supplementation with Lactobacillus strains on body fat and medium- EBioMedicine 2020;52:102649. https://doi.org/10.1016/
chain acylcarnitines in overweight individuals. Food Funct 2017;8(1):250e61. j.ebiom.2020.102649.
[44] Kim J, Yun JM, Kim MK, Kwon O, Cho B. Lactobacillus gasseri BNR17 supple- [66] Al Bander Z, Nitert MD, Mousa A, Naderpoor N. The gut microbiota and
mentation reduces the visceral fat accumulation and waist circumference in inflammation: an overview. Int J Environ Res Publ Health 2020;17(20):7618.
obese adults: a randomized, double-blind, placebo-controlled trial. J Med https://doi.org/10.3390/ijerph17207618.
Food 2018;21(5):454e61. [67] Mazidi M, Rezaie P, Ferns GA, Vatanparast H. Impact of probiotic adminis-
[45] Krumbeck JA, Rasmussen HE, Hutkins RW, Clarke J, Shawron K, tration on serum C-reactive protein concentrations: systematic review and
Keshavarzian A, et al. Probiotic Bifidobacterium strains and gal- meta-analysis of randomized control trials. Nutrients 2017;9(1):20. https://
actooligosaccharides improve intestinal barrier function in obese adults but doi.org/10.3390/nu9010020.
show no synergism when used together as synbiotics. Microbiome 2018;6(1): [68] Mousavi SN, Saboori S, Asbaghi O. Effect of daily probiotic yogurt consump-
121. tion on inflammation: a systematic review and meta-analysis of randomized
[46] Lim S, Moon JH, Shin CM, Jeong D, Kim B. Effect of Lactobacillus sakei, a controlled clinical trials. Obesity Med 2020;18. https://doi.org/10.1016/
probiotic derived from Kimchi, on body fat in Koreans with obesity: a ran- j.obmed.2020.100221.
domized controlled study. Endocrinol Metab (Seoul) 2020;35(2):425e34. [69] Ruan Y, Sun J, He J, Chen F, Chen R, Chen H. Effect of probiotics on glycemic
[47] Madjd A, Taylor MA, Mousavi N, Delavari A, Malekzadeh R, Macdonald IA, control: a systematic review and meta-analysis of randomized, controlled
et al. Comparison of the effect of daily consumption of probiotic compared trials. PloS One 2015;10. https://doi.org/10.1371/journal.pone.0132121.
with low-fat conventional yogurt on weight loss in healthy obese women [70] Samah S, Ramasamy K, Lim SM, Neoh CF. Probiotics for the management of
following an energy-restricted diet: a randomized controlled trial. Am J Clin type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res
Nutr 2016;103(2). 323-239. Clin Pract 2016;118:172e82.
[48] Majewska K, Kre˛ gielska-Narozna_ M, Jakubowski H, Szulin  ska M, Bogdan  ski P. [71] Sun J, Buys NJ. Glucose- and glycaemic factor-lowering effects of probiotics on
The multispecies probiotic effectively reduces homocysteine concentration in diabetes: a meta-analysis of randomised placebo-controlled trials. Br J Nutr
obese women: a randomized double-blind placebo-controlled study. J Clin 2016;115(7):1167e77.
Med 2020;9(4):998. https://doi.org/10.3390/jcm9040998. [72] Yao K, Zeng L, He Q, Wang W, Lei J, Zou X. Effect of probiotics on glucose and
[49] Michael DR, Jack AA, Masetti G, Davies TS, Loxley KE, Kerry-Smith J, et al. lipid metabolism in type 2 diabetes mellitus: a meta-analysis of 12 random-
A randomised controlled study shows supplementation of overweight and ized controlled trials. Med Sci Mon 2017;23:3044e30453.
obese adults with lactobacilli and bifidobacteria reduces bodyweight and [73] Wu H, Ballantyne CM. Metabolic inflammation and insulin resistance in
improves well-being. Sci Rep 2020;10(1):4183. obesity. Circ Res 2020;126(11):1549e64.
[50] Minami J, Iwabuchi N, Tanaka M, Yamauchi K, Xiao JZ, Abe F, et al. Effects of [74] Delzenne NM, Knudsen C, Beaumont M, Rodriguez J, Neyrinck AM, Bindels LB.
Bifidobacterium breve B-3 on body fat reductions in pre-obese adults: a Contribution of the gut microbiota to the regulation of host metabolism and
randomized, double-blind, placebo-controlled trial. Biosci Microbiota Food energy balance: a focus on the gut-liver axis. Proc Nutr Soc 2019;78(3):
Health 2018;37(3):67e75. 319e28.
[51] Praznikar ZJ, Kenig S, Vardjan T, Bizjak MC, Petelin A. Effects of kefir or milk [75] Gurung M, Li Z, You H, Rodrigues R, Jump DB, Morgun A, et al. Role of gut
supplementation on zonulin in overweight subjects. J Dairy Sci 2020;103(5): microbiota in type 2 diabetes pathophysiology. EBioMedicine 2020;51:
3961e70. 102590. https://doi.org/10.1016/j.ebiom.2019.11.051.
[52] Rajkumar H, Mahmood N, Kumar M, Varikuti SR, Challa HR, Myakala SP. Effect [76] Sun J, Buys N. Effects of probiotics consumption on lowering lipids and CVD
of probiotic (VSL#3) and omega-3 on lipid profile, insulin sensitivity, in- risk factors: a systematic review and meta-analysis of randomized controlled
flammatory markers, and gut colonization in overweight adults: a random- trials. Ann Med 2015;47(6):430e40.
ized, controlled trial. Mediat Inflamm 2014;2014:348959. [77] Hendijani F, Akbari V. Probiotic supplementation for management of cardio-
[53] Skrypnik K, Bogdan  ski P, Sobieska M, Suliburska J. The effect of multistrain vascular risk factors in adults with type II diabetes: a systematic review and
probiotic supplementation in two doses on iron metabolism in obese post- meta-analysis. Clin Nutr 2018;37(2):532e41.
menopausal women: a randomized trial. Food Funct 2019;10(8):5228e38. [78] Yan S, Tian Z, Li M, Li B, Cui W. Effects of probiotic supplementation on the
[54] Stenman LK, Lehtinen MJ, Meland N, Christensen JE, Yeung N, Saarinen MT, regulation of blood lipid levels in overweight or obese subjects: a meta-
et al. Probiotic with or without fiber controls body fat mass, associated with analysis. Food Funct 2019;10(3):1747e59.
serum zonulin, in overweight and obese adults-randomized controlled trial. [79] Pourrajab B, Fatahi S, Dehnad A, Varkaneh HK, Shidfar F. The impact of pro-
Biomedicine 2016;13:190e200. biotic yogurt consumption on lipid profiles in subjects with mild to moderate
[55] Szulin ska M, Łoniewski I, van Hemert S, Sobieska M, Bogdan  ski P. Dose- hypercholesterolemia: a systematic review and meta-analysis of randomized
dependent effects of multispecies probiotic supplementation on the controlled trials. Nutr Metabol Cardiovasc Dis 2020;30(1):11e22.

4930
K.S.S. Pontes, M.R. Guedes, M.R. Cunha et al. Clinical Nutrition 40 (2021) 4915e4931

[80] Huang Y, Wang X, Wang J, Wu F, Sui Y, Yang L, et al. Lactobacillus plantarum [87] Pluznick J, Protzko R, Gevorgyan H, Peterlin Z, Sipos A, Han J, et al. Olfactory
strains as potential probiotic cultures with cholesterol-lowering activity. receptor responding to gut microbiota-derived signals plays a role in renin
J Dairy Sci 2013;96(5):2746e53. secretion and blood pressure regulation. Proc Natl Acad Sci U S A
[81] Ishimwe N, Daliri E, Lee B, Fang F, Du G. The perspective on cholesterol- 2013;110(11):4410e5.
lowering mechanisms of probiotics. Mol Nutr Food Res 2015;59(1):94e105. [88] Marques F, Mackay C, Kaye D. Beyond gut feelings: how the gut microbiota
[82] Cicero AFG, Colletti A, Bajraktari G, Descamps O, Djuric DM, Ezhov M, et al. regulates blood pressure. Nat Rev Cardiol 2018;15(1):20e32.
Lipid lowering nutraceuticals in clinical practice: position paper from an In- [89] Yang T, Santisteban M, Rodriguez V, Li E, Ahmari N, Carvajal J, et al. Gut
ternational Lipid Expert Panel. Arch Med Sci 2017;13(5):965e1005. dysbiosis is linked to hypertension. Hypertension 2015;65(6):1331e40.
[83] Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. [90] Sun S, Lulla A, Sioda M, Winglee K, Wu M, Jacobs D, et al. Gut microbiota
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA composition and blood pressure. Hypertension 2019;73(5):998e1006.
guideline on the management of blood cholesterol: a report of the American [91] Brunt VE, Gioscia-Ryan RA, Casso AG, VanDongen NS, Ziemba BP,
college of cardiology/American heart association task force on clinical practice Sapinsley ZJ, et al. TMAO promotes age-related vascular oxidative stress and
guidelines. Circulation 2019;139(25):e1082e143. endothelial dysfunction in mice and healthy humans. Hypertension
[84] Khalesi S, Sun J, Buys N, Jayasinghe R. Effect of probiotics on blood pressure: a 2020;76:101e12.
systematic review and meta-analysis of randomized, controlled trials. Hy- [92] Malik M, Suboc TM, Tyagi S, Salzman N, Wang J, Ying R, et al. Lactobacillus
pertension 2014;64(4):897e903. plantarum 299v supplementation improves vascular endothelial function and
[85] Lewis-Mikhael A, Davoodvandi A, Jafarnejad S. Effect of Lactobacillus planta- reducesinflammatory biomarkers in men with stable coronary artery disease.
rum containing probiotics on blood pressure: a systematic review and meta- Circ Res 2018;123:1091e102.
analysis. Pharmacol Res 2020 Mar;153:104663. [93] Rezazadeh B, Gargari P, Jafarabadi M, Alipour B. Effects of probiotic yogurt on
[86] Chi C, Li C, Wu D, Buys N, Wang W, Fan H, et al. Effects of probiotics on pa- glycemic indexes and endothelial dysfunction markers in patients with
tients with hypertension: a systematic review and meta-analysis. Curr metabolic syndrome. Nutrition 2019;62:162e8.
Hypertens Rep 2020;22. https://doi.org/10.1007/s11906-020-01041-5.

4931