自由論題［研究論文］A Systematic Review and Meta-analysisof the Effects of Probiotics on Children
with Atopic Dermatitis

小児のアトピー性皮膚炎におけるプロバイオティ
クスの維持・改善効果についてのメタアナリシス
Yuri Yamamoto
Doctoral Program, Graduate School of Media and Governance, Keio University
山本 優理
慶應義塾大学大学院政策・メディア研究科後期博士課程

Daisuke Sugiyama
Assistant Professor, Department of Preventive Medicine and Public Health, School of Medicine,
Keio University
杉山 大典
慶應義塾大学医学部衛生学公衆衛生学教室専任講師

Abstract:

Atopic dermatitis (AD) is a chronic allergy characterized by excessive itching,which has one of the highest morbidities of any dermatological allergy. Recently,
the relationship between probiotics and AD has been discussed among physicians.
In order to determine the effects of probiotics on AD children, we conducted ameta-analysis based on the changes in SCORAD index. Although the main result
suggested that the probiotics group had similar result as the control group, the result
from sub-group analysis, divided by age and country region, suggested that AD
symptoms in the children (< 6 months) group became worse with the intervention ofprobiotics. From these results, we conclude that it is difficult to determine whether
probiotics are an effective intervention for children with AD.
アトピー性皮膚炎 (Atopic dermatitis; AD) はプロバイオティクスの効果が期待される慢性的アレルギー疾患である。本研究では小児 AD におけるプロバ
イオティクスの効果を明らかにするため、AD にプロバイオティクスで介入した
RCT の SCORAD の変化量をもとにメタアナリシスを行った。結果、対照群とは差がない可能性を示したが、年齢と国を考慮したサブグループ解析では生後6 ヶ月以内の群は AD を悪化させた。以上より、プロバイオティクスは小児 ADの維持・改善効果があるとは一概に言えないと結論づけた。

Keywords: infant, Atopic dermatitis, probiotics, Meta-analysis
小児、アトピー性皮膚炎、プロバイオティクス、メタアナリシス

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A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

1 Introduction
Atopic dermatitis (AD) is one of the most pervasive chronic allergic
diseases with itching and redness (Kay et al., 1994). One of the featuresof this disease is that its prevalence in children is higher than that of
adults. It is known that up to 10-20% of children and 1-3% of adults have
AD in Europe (Leung and Bieber, 2003). Although many causes havebeen speculated for AD, including genetic factors, environmental factors,
nutrition, and intestinal microbiota, the mechanism of this disease is still
unclear. As a genetic factor, it has been reported that the genetic mutationof filaggrin may cause the underlying symptoms of AD, while reducing thebarrier function of the skin (Hoffjan and Stemmler, 2015). Filaggrin is an
essential protein for skin barrier function, in particular, the formation ofa horny layer. When the skin barrier become weak due to have a mutation
on a gene coding filaggrin, the environment is also important factor for
inducing stimulation.
Dysbiosis, a microbial imbalance on our body, is said to be one of
the causes of AD. Intestinal microbiota are bacteria that live inside animal
intestinal tracts, and support the host’s digestive function, and provide
nutrition by producing secondary metabolites, as well as maintaining thehomeostasis of the host’s intestinal tract (Holmes et al., 2012). Additionally,
it became clear that there are relationships between intestinal microbiota andsome diseases, including AD (Björkstén et al., 1999; 2001; Kalliomäki et al.,2001). Microbiota is used as probiotics for improving our health. The mostnotable definition of probiotics is, “a live microbial feed supplement which
beneficially affects the host animal by improving its intestinal microbialbalance,” defined by Fuller (Fuller, 1989). Another notable definition states,“live micro-organisms which, when administered in adequate amounts,
confer a health beneﬁt on the host” as defined by FAO/WHO (FAO/WHO,
2001). Two words that are also related to probiotics, and are widely known areprebiotics and synbiotics (Schrezenmeir and de Vrese, 2001). One definition
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of prebiotics states, “a non-digestible food ingredient that beneficially affects
the host by selectively stimulating the growth and/or activity of one or alimited number of bacteria in the colon” (Gibson and Roberfroid, 1995).
Synbiotics is known as the mixture of probiotics and prebiotics.
Many different techniques are used to obtain knowledge from research;however, the quality of the research is dependent upon the study design. In
the epidemiology field, two types of observational study are mainly used,case-control study and cohort study. Case-control study involves comparing
the control and experimental group retrospectively. On the other hand, cohort
study involves following the specific group prospectively. In addition to these
designs, there is other kind of study known as intervention study. This study
has two methods, nonrandomized and randomized control trials (RCT). A
randomized control trial produces more quality data considering its lack ofsubject bias.
Furthermore, systematic review is one of the highest quality researchmethods used to collect and examine research data. Systematic review
is different from the review at the point that evaluation is conductedsystematically. This systematic review is an essential process of evidencebased medicine, and the method for integrating this data and evaluating
the result is called meta-analysis. (Sacks et al., 1987). Meta-analysis makes
is possible to reduce the problem of subject size and the obstacle of bias
among clinical trials. Summarizing the results of clinical trials related to
AD children and probiotics is important toward understanding the effectof probiotics and their mechanisms; in particular, the medical science,bacteriology, and molecular biology. Recently, Kim reported a meta-analysis
for the relationship between AD and the effect of probiotics (Kim et al.,2014). This report conducted a comprehensive study, from infant to adult,
and considered the AD severity and patient age. As a result, it was reported
that probiotics were effective for moderate to severe AD in patients of allages. However, as the interaction with the host intestinal environment was142

A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

not considered, we focused on the children and home country in orderto put the diversity of host intestinal microbiota into consideration. The
children’s profiles have less diversity than the adults’ profiles (Kostic etal., 2013). The purpose of this systematic review and meta-analysis was todetermine the effects of probiotics on AD children.

2 Methods
PubMed and Cochrane Library were searched in June of 2015 withthe following keywords: “Dermatitis, Atopic”[Mesh] OR atopic dermatitis
AND “Probiotics”[Mesh], OR “Lactobacillus”[Mesh], OR “Bifidobacteriales
Infections”[Mesh], OR “Lactococcus”[Mesh], OR “Saccharomyces”[Mesh],
OR “Streptococcus thermophilus”[Mesh], OR “Bacillus Subtilis”[Mesh],
OR “Enterococcus faecalis”[Mesh], OR “Clostridium”[Mesh]． The typeof article was filtered to include only Randomized control trials. After asystematic search, we conducted a manual search. Included were (1) articlesof the RCT type, (2) patients of age (< 10 years) with AD, (3) cases withintervention conducted by using probiotics, (4) articles written in English.
Excluded were (1) cases in which intervention was conducted by using
prebiotics or synbiotics, (2) cases in which the main target was an allergy
such as food allergy. WHO’s definition of probiotics was used for this study,
and if indigestible sugar or fibers were included as part of the intervention,
we regarded it as prebiotics. Before conducting a meta-analysis, we checked
the article qualities using CONSORT (Moher et al., 2010) to compare thequality of the RCTs. The 9 studies that met these requirements included
crossover trials. When the quality of an article is checked, CONSORT
does not accept crossover trials, however, we used CONSORT because thechecklist for crossover trials was not yet published.
The primary outcome was the change of SCORAD index (Stalder etal., 1993) from baseline to post-treatment. SCORAD index is the majorindex for evaluating AD symptoms. A small index size indicates that
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the symptom is mild, and a large index size indicates that the symptom
is severe. In order to combine the results from these RCTs, the standard
deviation (S.D.) of each study was calculated and incorporated. The
requirement of this research was written the average and S.D. or standard
error (S.E.) of SCORAD from baseline to after treatment in both groupcontrol and intervention. Data syntheses were based upon, either the fixedor the random effect model, according to the extent of heterogeneity(p-value of Cochrane Q-test < 0.05). All of the statistical analyses were
performed by R 3.1.2 (R Foundation for Statistical Computing, Vienna,
Austria. http://www.r-project.org/index.html). A two sided p-value < 0.05
was set as the significant level.

3 Results
Sixty-four trials were identified in total from PubMed and CochraneLibrary, and nine RCTs were included in the meta-analysis (Figure 1,
Supplementary List 1: http://tinyurl.com/znrpexg). We excluded 2 studies
that were not written in English, 4 studies that were not original papers
and 27 studies that differed from our purpose. Finally, 24 studies wereseparated into 3 groups, infant and mother, child, and adult. Thirteen
studies categorized into the child group included 2 studies focused on
infants. It is known that the profile of intestinal microbiota differs between
neonates and infants, so we excluded these 2 studies from the child group.
Additionally, the outcome of 2 studies did not employ the SCORAD index.
Although we performed a hand search for references from these 9 articles,
no articles satisfied the requirement (Supplementary List 2: http://tinyurl.
com/hmgmjm5).
The summary of these 9 studies is shown in table 1. The maximum
and minimum intervention terms were 6 months and 6 weeks, respectively.
There were two types of interventions, powder and capsule. Whenprescribed the powder, the amount and type of liquid were limited. Thirteen

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A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

Figure 1 Flow diagram of the process of selecting relevant trials
In total, 64 articles were satisfactory using these keywords.

species of intestinal microbiota were used as probiotics. Probiotics werecomposed of one specific species of bacteria in 5 studies and 2 species ofbacteria in 4 other studies. Bacteria from the Lactobacillus genus wereused as probiotics in all 9 studies. The most frequently used bacteria inthese studies were the Lactobacillus rhamnosus strain GG (LGG). The
minimum amount of bacteria was 1×109 Count-Forming Units (CFU), twice
a day, and the maximum amount of bacteria was 2×1010 CFU / g once aday. In these studies, allergy existence was also considered as baseline data,
along with personal data. As usual, a steroid was used as a main treatment.
Although the amount of steroid was limited, steroid uses in these studies
were permitted. Within these 9 studies, 4 studies showed improvement of
the symptom outcome, and the other 5 studies showed no improvement. In
addition, the 4 studies showing the effects of probiotics were focused onchildren with age > 6 months.

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Outcome A: molecular outcome, B: microbial outcome, C: Symptom outcome. Molecular outcome represented as amount of IgA. Microbial outcome
included amount of microbial population. Symptom outcome included SCORAD index.
○ : written, ● : ineffective, ◆ : effective

Table 1 Evidence table of review

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A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

After screening, we conducted an evaluation on the quality of RCTs
(Table 2). Only 5 studies within the 9 studies estimated the 95% CI within the
SCORAD index. Weston’s study reported statistic results and baseline data
separately; therefore, these two reports were used for evaluation. As a result,no studies significantly lacked the necessary data. For this reason, sub-group
analysis was not conducted in this study.
Although 9 studies were included for evaluation, only 5 studies wereused for meta-analysis (Table 3, Figure 2A) due to the limitation of statistical
data. Four studies were not significant enough to mention the results of
their SCORAD index. Figure 2 shows the results of meta-analysis basedon the changes of SCORAD index. Although heterogeneity was large inTable 2 CONSORT checklists for evaluating studies’ quality

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Result

Y: Written, I: Written partially, n.r.: Not reported, -: Not reported (not necessary)
1-9: Corresponded to the article’s number from table 1

Table 3 Studies included in meta-analysisAge(months)

Probiotics

Country

Fölster-Holst et al(2006)

1-55

Lactobacillus rhamnosus strain GG

Germany

Gore et al(2012)

3-6

Larsen et al(2011)

7-24

6Sistek et al(2006)

1-10(years)Lactobacillus rhamnosus
Bifidobacteria lactis

New
Zealand7

Han et al(2012)

1-13(years)Lactobacillus plantarum CJLP133

Korea

#

Author (Year)

1
2
3
4
5

Lactobacillus
Bifidobacterium

England

NCFM
Bifidobacterium animalis subsp. lactis
Bi-07

148

Denmark

A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

a randomized effect model, meta-analysis of entire studies did not show asignificant decrease in the SCORAD index within the probiotics group ascompared to that within the control group (estimator: -0.27, 95% CI: -3.69
to 3.15, p = 0.88; Table 4, Figure 2A). This 95% CI was extended across 0;
therefore, the effect of probiotics was not observed in this meta-analysis.
Additionally, Han’s study was the only study showing the effects of probiotics
for AD, and there were no commonalities between other studies in terms ofprobiotics type, intervention term, or patients.
Next, we conducted sub-group analysis by age group. These 9
studies were separated by the patients age, which was 6 months (Figure2B). The heterogeneity of studies that focused on children < 6 months
was small (p = 0.96). As the result of sub-group analysis, the estimatorof SCORAD was 2.01 (95% CI: 0.89 to 3.13, p < 0.001; Table 4, Figure2B) and the effects of probiotics in increasing the index are shown. The
heterogeneity of studies that focused on children > 6 months was large (p< 0.001). As the result of sub-group analysis, the estimator of SCORAD
was -2.04 (95% CI: - 6.06 to 1.99, p = 0.32; Table 4, Figure 2 C) and theeffects of probiotics in decreasing the index are shown (Figure 2C). 95%
CI was extended across 0; therefore, the effects of probiotics were notshown in this sub-group analysis.
As the other sub-group analysis, we focused on the patient’s countryof origin. In this analysis, we found that the studies conducted in Europe
showed a similar result among each trial (Figure 2D). The heterogeneity ofthe sub-group analysis was not significant (p = 0.14). As the result of subgroup analysis, the estimator of SCORAD was 1.53 (95% CI: 0.60 to 2.47,
p < 0.001; Table 4, Figure 2D) and the effects of probiotics in significantly
increasing the index were shown. As the result of these sub-group analyses,
the common factor toward showing large heterogeneity came from including
Han and Sistek’s studies.

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Figure 2 Includes the forest plots and statistics of shifts of SCORAD
A-D: Left side means negative and right side means positive. The horizontal axis showsthe estimator of changes of SCORAD index mean and the box size depends on the size of
population. Dotted line indicates the estimator of statistical model. A: All, B: < 6months, C: > 6months, D: Europe.

Table 4 Estimator of changes of SCORAD index mean
ObjectA

7

R

B < 6 months

3

F

C > 6 months

4

R

D

5

F

1

All

1
Included
F/R
trial numbers

EuropeEstimator(P-value)-0.27(P = 0.88)
2.01(P < 0.001)-2.04(P = 0.32)
1.5341(P = 0.001)

F: Fixed effect, R: Random effect150

95% CI (Estimator)

Heterogeneity
P-value- 3.69 / 3.15

< 0.001

0.89 / 3.13

0.96

- 6.06 / 1.99

< 0.001

0.60 / 2.47

0.14

A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

4 Discussion
In this study, we conducted meta-analyses including 5 trials thatconsidered the age and country region. Five trials conducted in Europe weregathered as one sub-group. The result of the sub-group analysis showed thatthe symptoms became worse when the European AD children took probiotics.
The heterogeneity of these data was large and 95% CI was extended across0, even when using a randomized effect model. This result suggests that itis difficult to conclude if the probiotics had an effect on AD children, as
this result is consistent with Kim’s previous research (Kim et al., 2014).
Björkstén reported that the amount of Enterococcus and Bifidobacterium wassignificantly small between one-month-old and one-year-old AD children’s
intestinal tract (Björkstén et al., 2001), as it is said that probiotics rearrange
the profiles of intestinal microbiota and suppress symptoms. Although themethod of treatment was discussed, the effect was not shown clearly in thecase of AD. There remains causal ambiguity, as many reports and books do
not refer to the effect of probiotics for AD, and the effects were dependent oneach clinical trial (van der Aa et al., 2010). The reasons for variation in theeffects of bacteria on patients were thought to include patient age, gender,
race, life style, original profiles of intestinal microbiota, amount of probiotics,
kinds of species, and the clinical trial design. The features of intestinal
microbiota were dependent on kinds and strains, which served to produce thedisparity in data regarding the effect of these microbiota.
LGG, used in many reports, was bacillus and produced lactate. It wasreported to give benefits for hosts and resistance to stomach acid and bile
acid. Unfortunately, the trials that used LGG had the following 3 results;
probiotics had effects, no effects were observed, and unclear, therefore,
LGG’s effects as probiotics are still unclear. In addition, some trials did notrefer to the strain of bacteria, and because the species were different among
these trials, it is difficult to discuss the effect of the probiotics.
We conducted sub-analysis according to the patient’s age and country,
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which were thought to be a cause of heterogeneity. In the case of sub-group
analysis including trials with patient age < 6 months, the changes in SCORAD
index increased. This suggested that the probiotics did not have the effect ofsuppressing the AD symptoms, as AD became worse. In the case of sub-group
analysis including trials with object age > 6 months, the heterogeneity was
small and the changes in SCORAD index did not increase. This suggested
that probiotics had the effect of suppressing the AD symptoms, as AD did not
become worse. The clinical use of probiotics is defined as intake of bacteria
known to benefits us, and the effects of probiotics were thought to depend on
the host intestinal environment and immune system. It is known that the hostmicrobial profiles change relative to the host age, and it was reported thataerobic bacteria increased first, followed by anaerobic bacteria that increased
through oxygen consumption, as reported by the study focused on the host’s
growth (Turroni et al., 2012). Smith reported that microbial patterns were
almost the same and not dependent on the host animal (Smith, 1965).
Additionally, the result of sub-group analysis considering the patient’s
country showed that the heterogeneity was small. The changes in SCORAD
index increased. When we compared the heterogeneity of meta-analysis
including whole trials and sub-analysis by considering the country, the sizeof heterogeneity decreased. This sub-group segmentation, which consideredpatient country regions, was different from Kim’s research, and suggested thatthe country regions are a possible factor in changing the size of heterogeneity.
When we considered the results of the sub-group analysis, it seems that
one of the causes for effects of bacteria on patients was the host intestinal
environment. There were already some reports focused on the relationshipamong the microbial profiles, diet, and country, and the intestinal microbial
profiles were divided into three types and the differences were dependent on
the diet (Arumugam et al., 2011). It may also be noted that Japanese intestinal
microbiota have a potential to digest seaweed such as laver (Hehemann et al.,2010). The country region and race are important factors in understanding the152A Systematic Review and Meta-analysis of the Effects of Probiotics on Children with Atopic Dermatitis

details of systems related to intestinal microbiota.
There were some similarities within the large heterogeneity. For example,
when data was integrated and the heterogeneity was large, studies by Han and
Sistek were included for analysis. From this result, it was suggested that these
two trials most directly affected the size of heterogeneity. We did not integratethese two trials because there were many discrepancies in the data, because
the reliability was low, as the countries in which the trials were performed
were Korea and New Zealand. Lactobacillus plantarum CJLP133, used in
Han’s study, was isolated from Kimchi and suggested to control the immune
system (Lee et al., 2011). In addition, this strain was also reported to have theeffect of suppressing AD in an AD mouse by oral intervention (Won et al.,2011). This strain also demonstrated the effect of curing dermatitis-like AD
by inducing house dust and mites on an NC/Nga mouse (Won et al., 2012).
In summary, clinical trials that focused on the effects of probiotics on
infant AD were screened systematically. Among these studies, the differencesof patient age and country region produced the strongest effects on AD. On
the other hand, it is difficult to discuss the effect of probiotics considering
the differences in probiotics, as well as the differing dynamics of microbial
profiles, which proved to be a major limitation of this study. As the numberof trials using the same strain of probiotics increases around the world, it will
become easier to analyze and discuss the effect of probiotics. In addition,
the effect of host microbial profiles was considered in this study; therefore,
it is important to focus on these profiles, as well as changes to the hostenvironment.

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〔受付日 2016. 7. 28〕〔採録日 2016.11.16〕

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