Iran J Public Health, Vol. 49, No.7, Jul 2020, pp.

1222-1231 Review Article

The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as

a Biomarker of Intestinal Permeability: A Systematic Review and
Meta-Analysis
Amirhossein RAMEZANI AHMADI 1, Mehdi SADEGHIAN 1, *Meysam ALIPOUR 2,
Samira AHMADI TAHERI 3, Sepideh RAHMANI 3, Amir ABBASNEZHAD 4
1. Department of Nutrition, School of Allied Medical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2. Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3. Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
4. Nutritional Health Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
*Corresponding Author: Email: Meysam.aalipour@yahoo.com

(Received 08 Jan 2020; accepted 17 Apr 2020)

Abstract
Background: This systematic review and meta-analysis was conducted to obtain a conclusive result on the in-
fluence of probiotics/synbiotic on serum levels of zonulin. Data related to serum levels of zonulin were extract-
ed to determine the effects of probiotic/synbiotic on intestinal permeability.
Methods: The literature search was conducted across the Cochrane Central Register of Controlled Trials, Pub-
Med, Scopus and ISI Web of Science, Search up to Nov 2018. Clinical trials evaluating the effect of probi-
otic/synbiotic on serum zonulin levels of all human subjects were included.
Results: Nine studies (including 496 intervention and 443 control subjects) met the inclusion criteria for the
meta-analysis. According to the meta-analysis, probiotic/synbiotic has a significant effect on serum zonulin re-
duction (WMD=-10.55 [95% CI: -17.76, -3.34]; P=0.004). However, the high level of heterogeneity was ob-
served among the studies (I2=97.8, P<0.001). The subgroup analysis suggested study quality, blinding, study
duration, Participants age, subject's health status and supplement type as sources of heterogeneity.
Conclusion: Probiotic/synbiotic have favorable effects on serum levels of zonulin as a measure of intestinal
permeability. However, the results should be interpreted with caution due to the high heterogeneity and further
evidence is required before definitive recommendations can be made.

Keywords: Probiotic; Synbiotic; Gut barrier; Intestinal permeability; Zonulin

Introduction
The gastrointestinal epithelium, covered by a sin- Zonula occludens toxin (Zot) which temporarily
gle layer of epithelial cells, forms a protective bar- increases the paracellular permeability without
rier between apical and basolateral compart- damage to the epithelium (2). Zonulin, a 47-kDa
ments. The function of the epithelial barrier protein, is an endogenous analog of Zot that can
mostly relies on intercellular junctions, known as similarly improve paracellular transport to Zot
tight junctions which consist of cytoplasmic (3). Zonulin represents a physiological defensive
plaque proteins including zonula occludens (1). mechanism against microorganism colonization
One of the modulators of these tight junctions is of the small intestine (4). Altered intestinal per-

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 Ramezani Ahmadi et al.: The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as …

meability in several pathological conditions in- prebiotics including inulin, starch, and
cluding autoimmune diseases, diseases of the fructooligosaccharides) are promising groups of
nervous systems, and neoplastic conditions has nutraceuticals that affect intestinal permeability
been associated with overexpression of zonulin through alterations in expression of tight junction
in the intestinal mucosa (5). Moreover, antigen proteins (11). Several studies have been conduct-
presentation in human macrophages appears to ed to investigate the impacts of probiotics on se-
be regulated by zonulin. This would change the rum or fecal levels of zonulin; however, the re-
cytokine profile and subsequently potentiate the sults were inconsistent and inconclusive (11, 12).
switch from immune tolerance to autoimmunity Therefore, we conducted this systematic review
(6). and meta-analysis to review systematically the
Strategies aimed at modifying the intestinal barri- influence of probiotics or synbiotic on serum
er function through downregulating zonulin levels of zonulin.
pathway suggest a potential therapeutic target for
the treatment of these chronic diseases. Zonulin Materials and Methods
inhibitor Larazotide acetate featured an
upcoming result in celiac disease; however, safety This research conducted by following the guide-
and efficacy of Larazotide need to be determined lines and the PRISMA statement for reporting
by large clinical trials (7). Besides conventional systematic reviews and meta-analysis. Table 1
treatments, several nutritional compounds includ- outlined the PICOS (population, intervention,
ing Colostrum bovinum (8), Apple-Derived Pec- comparator, outcome, and setting) criteria used
tin (9), vitamins A and D (10) have been found to to perform the systematic review. Due to the
modulate the epithelial barrier by reducing serum study type, ethical approval was not necessary
levels of zonulin. Probiotic (live microorganisms) according to local legislation.
and synbiotic (containing probiotic strains and

Table 1: PICOS (population, intervention, comparator, outcome, and setting) criteria used to perform the systematic
review

PICOS Criteria
Population All human subjects
Intervention Probiotic/synbiotic supplementation
Comparator Control group (placebo or without intervention)
Outcome Serum level of zonulin
Setting Randomized Clinical Trials

Search strategy tion: probiotic*, symbiotic, synbiotic, prebiotic,

Two researchers (MA and AR) independently "lactic acid bacteria", Streptococc*, "S. thermo-
searched databases including the Cochrane Cen- philes", Bifidobacter*, Lactobacill*, Lactococc*,
tral Register of Controlled Trials, PubMed, Sco- Saccharomyces, Bacillus, "B. mesentericus",
pus, ISI Web of Science, and google scholar for Enterococc*, "E. faecium", "B. clausii", Clostrid-
clinical trials that investigated the effect of probi- ium, "C. butyricum", "Escherichia coli Nissle",
otic/synbiotic on serum levels of zonulin. The "E. coli Nissle", VSL#3, bifidu*, pediococc*,
search included all studies published as original LGG, Rhamnosos, Reuteri, Acidophilus, Lactis,
full-text articles covering a period up to Nov Plantarrum, Bulgaricus, Johnsonii, Ecologic, Fae-
2018. The literature search was conducted using calis, zonulin, "intestinal permeability", "GI per-
the following keywords and medical subject meability", "gastrointestinal permeability". No
heading (MeSH) terms in any possible combina- restriction was applied to publication year, and all

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 Iran J Public Health, Vol. 49, No.7, Jul 2020, pp. 1222-1231

studies published in English were included. The fixed method meta-analysis. In case of significant
reference lists of included studies were investigat- heterogeneity between studies, a random-effects
ed to identify any additional relevant studies. The meta-analysis was carried out (14). Heterogeneity
title and abstract of the search output were was evaluated using the I2 index and Cochrane’s
screened by two reviewers separately and poten- Q test. Heterogeneity was considered low if I2 <
tially relevant studies were identified. 30%, moderate if I2 = 30%-75%, and high if I2
>75% (15). Subgroup analyses were performed
Study Selection according to study quality (low or high), blinding
After that the relevance of a study was con- (yes or no), age (under 45 yr or more than 45 yr),
firmed, publication’s full texts were reviewed and supplement type (probiotic or synbiotic), study
those that fulfilled the eligibility criteria were in- duration (less than 3 months or more than 3
cluded. The following eligibility criteria were ap- months), and participant's health status (healthy
plied: 1) published in English or Persian; 2) using or not healthy) to identify the potential sources
probiotic/synbiotic as the supplement; 3) report- of heterogeneity. In addition, sensitivity analysis
ing serum zonulin as the outcome of the study. and meta-regression were performed to investi-
Following studies were excluded: 1) articles with- gate further on heterogeneity sources. Begg’s
out full-text availability, non-English, ecological rank correlation, Egger’s linear regression, and
study, qualitative study, opinion pieces, confer- funnel plots were used to examine for the pres-
ence abstracts, review articles and editorials; 2) ence of publication bias. All analyses were carried
reporting unrelated data. out using Stata, ver. 14 SE (Stata Crop, College
Station, TX, USA). P-values <0.05 were consid-
Data Extraction ered statistically significant.
The data were extracted independently by 2 re-
viewers (MA and AR), and in the event of Results
disagreement, a decision being made after MS
cross-examined doubtful data. Studies character- Characteristics of the studies
istics including first author's name, publication As shown in Fig. 1, the early electronic search
year, country, study design, quality score, sample resulted in 538 studies, after duplicate removal.
size, supplement and placebo composition, study Following the title and abstract screen, 492 stud-
duration, participant's gender, age, and health ies were excluded due to reporting unrelated data,
status were extracted. Moreover, to evaluate the being review articles, and not be written in Eng-
effect of probiotic/synbiotic on zonulin concen- lish.
tration, the mean ± SD of the serum zonulin be- Overall, 46 studies were evaluated for eligibility,
fore and after supplementation was extracted and 37 studies were excluded for the following
from eligible studies. reasons: did not report serum levels of zonulin as
study outcome, did not provide enough data, or
Assessment of risk of bias was published as study protocol. Nine studies
The quality of the studies was evaluated by 2 sep- met the inclusion criteria for the meta-analysis
arate reviewers according to the Jadad score (13). (16-24). Table 2 summarizes the characteristics of
The Jadad score considers randomization, blind- all studies included in the systematic review. All
ing, description of withdrawals and dropouts. trials had a parallel study design. Studies were
Each study was scored between 0-5; higher num- conducted in China (23, 24), Finland (17, 22),
bers represent better quality. Netherlands (20, 21), Turkey (18) and the USA
(16). Moreover, one of the studies was
Statistical analysis multicentric with different countries (19). Most
The effect size, estimated as the weighted mean of the studies recruited both male and female
difference (WMD), was used to perform the

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 Ramezani Ahmadi et al.: The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as …

gender, while two studies were conducted only in intervention ranged from 14 to 180 days. Four
males (16) or females (17). The duration of the studies recruited healthy subjects (16, 17, 19, 21).

Fig. 1: Flow chart of the process of the study selection

Other studies were conducted on colorectal car- has a significant effect on reducing serum zonulin
cinoma (23), Colorectal liver metastases (24), compared to the placebo groups (WMD=-10.55
overweight or obese (22), non-alcoholic fatty liv- [95% CI: -17.76, -3.34]; P=0.004; Fig. 2). Howev-
er disease (18), and migraine patients (20). Ac- er, the high level of heterogeneity was observed
cording to Jadad scores, 7 studies were classified among the studies (I2=97.8, P<0.001).
as high-quality papers (score≥3) (16, 17, 19, 20, The subgroup analysis showed that heterogeneity
22-24) and 2 studies were classified as low-quality was significant in high-quality studies (n=11,
(18, 21). I2=97.9, P<0.001), with blinding (n=9, I2=98.4,
P<0.001), less than 3 months of study duration
Findings from the meta-analysis (n=5, I2=99.1, P<0.001), subjects with age more
Overall, 9 studies provided 13 effect sizes, includ- than 45 yr (n=8, I2=98.2, P<0.001), studies that
ing 496 intervention and 443 control subjects, enrolled not healthy subjects (n=7, I2=98.9,
regarding the effect of probiotic/synbiotic sup- P<0.001), and trials that supplemented by probi-
plementation on the serum levels of zonulin. Ac- otic (n=9, I2=98.3, P<0.001) (Table 3).
cording to the meta-analysis, probiotic/synbiotic

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 Iran J Public Health, Vol. 49, No.7, Jul 2020, pp. 1222-1231

Table 2: Characteristics of included studies

First Country Sample Mean RCT Duration Supplement Comparison Health Jaded
author, size age design (days) content group status score
publication (M/F) (yr) (blinding)
year
Liu, 2013 China 78/72 62.2 Parallel 16 Lactobacillus Maltodextrin Colorectal 4
(23) (Yes) plantarum, carcinoma
Lactobacillus
acidophilus-11,
Bifidobacterium
longum-88

Liu, 2015 China 70/64 60.1 Parallel 16 LP, LA-11, BL- Maltodextrin Colorectal 4
(24) (Yes) 88 liver metas-
tases
Stenman, Finland 31/103 50.0 Parallel 180 Group1: LU Microcrystalline Overweight 5
2016 (22) (Yes) Group 2: B420 cellulose and Obese
Group3:
LU+B420
Wilms, Netherlands 11/9 20.7 Parallel 14 Synbiotic Maltodextrin Healthy 2
2016 (21) (Yes)

Çakır, 2017 Turkey 18/10 12.2 Parallel 120 Synbiotic No placebo NAFLD 1
(18) (No)

de Roos, Netherlands 56/4 39.9 Parallel 84 Probiotic mix- Maize starch, Migraine 4
2017 (20) (Yes) ture Maltodextrin

Kantah, Multicenter N/A 50 Parallel 150 Group 1: Syn- Marine PUFA Healthy 3
2017 (19) (No) biotic extract
Group 2: Pro-
biotic
Group 3: Syn-
biotic + Probi-
otic
Mokkala, Finland -/101 30.4 Parallel 147 Bifidobacterium Microcrystalline Pregnant 5
2018 (17) (Yes) animalis ssp. cellulose
Latics 420 and
Lactobacillus
rhamnosus
HN001
Townsend, USA 25/- 20.1 Parallel 84 Bacillus subtilis Maltodextrin Baseball 4
2018 (16) (Yes) DE111 Players
RCT, randomized controlled trial; M, male; F, female; NR, not reported; NAFLD, non-alcoholic fatty liver disease;

Sensitivity analysis suggested that this association type, participants’ age, and health status were not
disappeared following the study of Liu et, al. (24) found to be associated with this relationship (Ta-
was omitted (WMD=-5.55 [95% CI: -11.76, ble 3).
0.65]). According to meta-regression, there was Visual inspection of the funnel plot (Fig. 3)
significant evidence for an association between demonstrated no publication bias of trials that
study duration and the effect of probi- investigated the effect of probiotic/synbiotic
otic/synbiotic on serum levels of zonulin (Coef- supplementation on the serum levels of zonulin
ficient=33.23, 95% CI=0.30, 66.16, P=0.048). (Egger's test P=0.154; Begg's test P=0.502).
However, study quality, blinding, supplement

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 Ramezani Ahmadi et al.: The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as …

Table 3: Overall estimates of meta-analysis on the effect of probiotic/synbiotic on the serum zonulin

Outcomes Subgroups No. of References WMD P- I2 P-value for Meta-regression

effect (95% value (%) heterogeneity
size CI) Coefficient P-
(95% CI) value
Zonulin (ng/ml) 13 (16-24) -10.55 (- 0.004 97.8 <0.001
17.76, -
3.34)
Study quality High 11 (16, 17, 19, -11.87 (- 0.053 97.9 <0.001 19.26 (-59.18, 0.570
20, 22-24) 23.88, 97.72)
0.13)
Low 2 (18, 21) 0.04 (- 0.900 0.0 0.493
0.64, 0.73)
Blinding Yes 9 (16, 17, 20- -14.14 (- 0.012 98.4 <0.001 -7.24 (-59.97, 0.748
24) 25.15, - 45.49)
3.14)
No 4 (18, 19) 0.11 (- 0.760 0.0 0.782
0.59, 0.81)
Intervention <3 mo 5 (16, 20, 21, -24.37 (- 0.023 99.1 <0.001 33.23 (0.30, 0.048
duration 23, 24) 45.36, - 66.1)
3.37)
≥3 mo 8 (17-19, 22) -0.09 (- 0.785 37.4 0.131
0.76, 0.57)
Age < 45 yr 5 (16-18, 20, 0.08 (- 0.805 0.0 0.838 -27.08 (- 0.151
21) 0.57, 0.73) 67.41, 13.24)
≥ 45 yr 8 (19, 22-24) -16.15 (- 0.089 98.2 <0.001
34.75,
2.44)
Supplement Probiotic 9 (16, 17, 20, -14.56 (- 0.026 98.3 <0.001 18.26 (-56.42, 0.572
Type 22-24) 27.35, - 92.94)
1.78)
Synbiotic 4 (18, 19, 21) 0.05 (- 0.883 0.0 0.701
0.63, 0.74)
Health status Healthy 6 (16, 17, 19, 0.07 (- 0.933 0.0 0.782 -9.58 (-45.89, 0.542
21) 1.62, 1.77) 26.71)
Not 7 (18, 20, 22- -18.51 (- 0.009 98.9 <0.001
healthy 24) 32.34, -
4.69)

Fig. 2: Forest plot of trials examining the effect of probiotic/symbiotic on serum zonulin

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 Iran J Public Health, Vol. 49, No.7, Jul 2020, pp. 1222-1231

Fig. 3: Funnel plots detailing publication bias in the studies selected for analysis. Visual inspection of funnel plots
indicating that there is no publication bias among studies

Discussion studies, blinded trials, studies with longer dura-

tion, and those recruited healthy subjects younger
Findings of the current meta-analysis suggest that than 45 yr old. The supplemented probiotics may
compared to placebo, supplementation with pro- surpass certain lactic acid bacteria that activate
biotic/synbiotic significantly reduces serum levels Toll-like receptor 2 (TLR2) signaling pathway
of zonulin; however, there was high heterogenei- (12). TLR2 is localized in cell membranes of the
ty among selected studies. When the analysis was intestinal epithelium. It induces epithelial re-
separately performed for probiotic and synbiotic, sistance in the activated form (29, 30). Moreover,
a significant reduction was observed in those that protective role of probiotics on intestinal perme-
received probiotic only. Moreover, subgroup ability may be explained in part by inhibiting p38
analysis based on study quality, blinding, duration MAPK, a Ser/Thr kinase related to the upregula-
of intervention, age, and health status could ex- tion of several inflammatory indices (23). In vitro
plain the source of heterogeneity among studies. studies assumed that the combination of probiot-
Zonulin is considered as a physiological modula- ics with prebiotics might change intestinal per-
tor of intestinal permeability and a surrogate meability simultaneously (31, 32). Therefore, we
marker of the dysfunctional gut barrier (3, 5, 25). confined the analysis to supplemental synbiotic
Certain gut microbes, in particular pathogens, and observed that the results were no longer sig-
might induce the release of zonulin from the gut nificant. Because of varying study populations
suggesting a mechanistic link between alterations and probiotic products, more powerful clinical
in the gut microbiota and gut barrier function (4). trials with longer follow-up are needed to con-
Despite the small sample size, our finding is of firm this finding.
importance due to the increased levels of circulat- Sensitivity analysis indicated that results might
ing zonulin in a wide range of chronic diseases have been disproportionally influenced by a study
(26-28). Although we observed heterogeneity (24). After excluding this trial, the meta-analysis
among studies, the results were not significant no longer produced significant results that might
when the analysis was confined to high-quality be responsible for the obtained results. This

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 Ramezani Ahmadi et al.: The Effects of Probiotic/Synbiotic on Serum Level of Zonulin as …

might be due to a considerable weight of mean size. High heterogeneity was noted and further
difference derived from lower reported values for evidence is required before definitive recommen-
mean serum zonulin and small standard devia- dations can be made.
tion. Moreover, the study was conducted on pa-
tients with colorectal liver metastasis (CLM) that Ethical considerations
have higher postoperative levels of serum zonulin
rather than colorectal cancer patients without Ethical issues (Including plagiarism, informed
liver metastasis (23). Therefore, there may be a consent, misconduct, data fabrication and/or fal-
liver barrier playing a role in the change of post- sification, double publication and/or submission,
operative zonulin levels in CLM. When we exam- redundancy, etc.) have been completely observed
ined the association between study duration and by the authors.
the effect of probiotic/synbiotic on serum levels
of zonulin, we found that studies with longer du- Conflicts of interest
ration of intervention had lower serum levels of
zonulin. The authors declare no conflict of interest.
Some strengths should be highlighted in this me-
ta-analysis. We used a rigorous search strategy
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