REVIEW

CURRENT
OPINION Evidence of preventive effect of probiotics and
prebiotics for infantile eczema
Philippe A. Eigenmann

Purpose of review
Infantile eczema, and in particular atopic dermatitis are, in many children, the first manifestation of their
predisposition to an atopic disease. Among existing prevention strategies, supplementation with probiotics
and prebiotics belong to the most promising beneficial interventions. Highlighting the most recent literature,
we review here the most recent studies on probiotics and prebiotics and hypothesize on the most efficient
intervention strategies.
Recent findings
Various probiotics and prebiotics, either alone or in combinations, have been administered, in general,
during the late phase of pregnancy and up to 6 months of age. In general, a combination of probiotics
and prebiotics given from pregnancy until early infancy has a higher potential for protecting the infant from
developing early manifestations of eczema than short administration of one specific microorganism.
Summary
The effect of probiotics and prebiotic supplementations on early manifestations of atopy such as infantile
eczema are conflicting. Nevertheless, prevention strategies should aim for an enhanced efficacy by
addressing not only interventions on the microbiota, but by combining them to other interventions, for
example, to those aiming at actively inducing antigen-specific tolerance.
Keywords
allergy, atopic dermatitis, infantile eczema, microbiota, probiotics

INTRODUCTION clearly show that the microbiota has a global

The mammalian gut is colonized by a large number
of various nonpathogenic bacteria. The host
immune system has adapted, through evolution
tolerance, to these microorganisms, also called
microbiota, and in addition a subtle homeostasis
has been established. This is for the common benefit
of the bacteria and the host alike.
The microbiota is actively involved in several
useful activities in the gut, such as food digestion,
but the microbiota also clearly influences the local
as well the global immune response of the host.
Exploring this effect with a particular focus on
allergic inflammation, early works have identified
that germ-free mice have a skewed immune
response favoring IgE antibody production and a
decreased interferon production [1]. Interestingly,
early colonization with Bifidobacterium infantis
permitted induction of oral tolerance to a common
food antigen. More recent work has shown that
early secondary microbial colonization of germ-free
mice favor activation and expansion of colonic
T-regulatory cells [2]. These and other studies
allergy-protective effect.
These experimental findings could be translated
to clinical studies, for example, in early studies
comparing Estonian to Swedish children in whom
allergy-free individuals had a gut microflora predom-
inant in lactobacilli, whereas allergy-prone individ-
uals had higher numbers of coliforms Gram-negative
bacteria as well as Staphylococcus aureus, possibly in
relation to the individual’s diet [3].
Taken together, these studies and others have
led to similar results strongly suggesting that a gut
microbiota rich in probiotics (i.e. lactobacillae and
others) might be protective for allergy and that such
University Hospitals of Geneva and Medical School of The University of
Geneva, Department of Child and Adolescent, Geneva, Switzerland
Correspondence to Philippe A. Eigenmann, Hôpitaux Universitaires de
Genève, Département de Pédiatrie. 6 rue Willy-Donzé, CH-1211 Genève
14, Geneva, Switzerland. Tel: +41 22 382 45 31; fax: +41 22 382 47 79;
e-mail: Philippe.Eigenmann@hcuge.ch
Curr Opin Allergy Clin Immunol 2013, 13:426–431
DOI:10.1097/ACI.0b013e3283630bad

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 Preventive effect of probiotics and prebiotics for infantile eczema Eigenmann
KEY POINTS
 The gut flora provides a unique interaction with the host
immune system, and might protect from developing
early allergic symptoms.
 Results of studies on early supplementations with
probiotics and prebiotic to prevent children with a
genetic risk for developing atopic dermatitis
are conflicting.
 The protective effect is strongly dependent on the
microorganism(s) provides by the supplementation.
Lactobacillus rhamnosus has been the most extensively
studied and has been shown to beneficially modulate
the immune system.
 Nevertheless, most efficient allergy prevention measures
will need combining probiotics and prebiotic
supplementations with other interventions. Optimal
interventions strategies still need to be defined.
a microbiota pattern should be favored by active
bacterial colonization, or by promoting a probiotics
friendly environment by enriching the diet with
prebiotics.
Capitalizing on this, preventive strategies of
allergic disease, including atopic dermatitis, have
been targeted by promoting an allergy-protective
gut microflora. To achieve this, two specific strat-
egies, separately or in conjunction, have been
addressed in various studies. In the first, the intes-
tinal microflora was supplemented with live bacteria
potentially providing a health benefit to the host,
that is, by adding so-called probiotics. In the second
strategy, food components that benefit the host by
selectively stimulating either the growth and/or
the activity of nonpathogenic, allergy protective,
bacteria in the gut were administered. These non-
digestible food components are called prebiotics
and are mainly composed of oligosaccharides added
to the infant’s diet.
The aim of this review will be to provide a state-
of-the-art assessment of the most important studies
exploring the protective role of probiotics and/or
prebiotics to prevent atopic dermatitis, in particular
by commenting on more recent studies.
ANALYZING THE MOST RELEVANT EARLY
CLINICAL STUDIES
Early works are best summarized by reviewing meta-
analysis on studies exploring the effect of probiotics
and prebiotics. The first systematic review of
studies up to 2009 compared the administration
of probiotics versus placebo in a nonselected
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population of infants [4]. Four studies, totaling over
1200 patients, were included in the meta-analysis.
Although the three smaller studies [5–7] concluded
no or only a slight but not significant effect of
probiotics, the largest study [8], including over
900 infants whose mothers had received a mixture
of four probiotic bacterial strains along with
prebiotic galacto-oligosaccharides (GOS) versus
placebo, with subsequent administration to the
infants for 6 months, indicated a protective effect
of probiotics with a risk ratio of 0.7 [95% confidence
interval (CI): 0.51 0.96]. When analyzed together,
probiotics intervention in these studies led to a
decreased risk ratio of 0.8 but without statistical
significance (95% CI: 0.62 1.02). Nevertheless,
allergy prevention is, in general, aimed at high-risk
groups. By targeting this population, a separate
analysis including the three of these four studies
(excluding [6]) concluded a similar absence of a
protective effect of probiotics (risk ratio 0.81, 95%
CI; 0.63–1.04). It was concluded from these major
studies published up to 2009 that supplementations
with probiotics might be envisaged nevertheless
with, at the most, a moderate protective effect for
infantile eczema. In addition, as emphasized by
others [9], the heterogeneity of outcome measured
as well as study designs limits the conclusions to be
drawn by systematic reviews.
A similar meta-analysis was conducted in order
to analyze studies exploring the effect of specific
prebiotics versus placebo [10]. Here, only two
studies qualified with the correct criteria for the
analysis. In the first study, by Moro et al. [11], 200
infants were administered a fructo-oligosaccharides/
galacto-oligosaccharides (GOS/FOS) formula versus
placebo since weaning and evaluated for eczema at
6 months of age. They found a protective effect of
the prebiotic supplemented formula versus the
placebo formula with 9.8% (95% CI 5.4–17.1%) of
infants developing atopic eczema in the treated
versus 23.1% (95% CI 16.0–32.1%) in the placebo
group. The second group of investigators by Ziegler
et al. [12] used a formula supplemented with two
different concentrations of polydextrose and GOS.
Neither one of these supplemented formulas pre-
vented infantile eczema, nor did the common
analysis of these two populations show any protec-
tive effect of prebiotic formulas versus nonsupple-
mented formulas for infantile eczema (risk ratio: 0.6,
95% CI: 0.15–2.42).
The authors of these two meta-analysis (probi-
otics or probiotics versus placebo) did not see
enough evidence to recommend, at this stage, pro-
biotics and prebiotic supplemented formulas for
prevention of atopic dermatitis and recommended
further trials.
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 Pharmacotherapy and evidence based medicine
RECENT RELEVANT IMMUNOLOGIC AND
BACTERIOLOGIC INVESTIGATION ON
PROBIOTICS AND THE MICROBIOTA
A general and justified criticism made to probio-
tics and prebiotics studies is that a variety of organ-
isms or combinations of organisms are explored
rendering comparison and thus recommendation
for prevention more difficult. Nevertheless, a
few microorganisms have been selected early for
extensive characterizations and studies. Among
these, Lactobacillus rhamnosus has been extensively
studied in animals, mostly in mice, for its effect on
the immune system. In a recent noteworthy
study exploring the gut immune response to
L. rhamnosus administration, investigators supple-
mented recently weaned pigs daily with L. rhamno-
sus HN001 in order to prevent sensitization to
Ascaris allergens [13]. Following probiotics pretreat-
ment, the pigs were sensitized through the skin and
the respiratory tract. Ascaris-sensitized pigs fed
HN001 had fewer severe skin reactions as well as
fewer respiratory symptoms. These clinical changes
came along with an increased IL-10 in conjunction
to an increase of interferon-g production by cells
activated by Ascaris antigen. This study nicely con-
firmed previous observations in mice that certain
probiotics strains might be protective for allergy,
moreover showing that protection is not restricted
to one mammalian species.
Recently, a study has investigated the effect of
administering L. rhamnosus GG to the pregnant
women in order to increase the gut microbiota
diversity. Pregnant women with a history of allergy
received, from the 36th week of gestation until
delivery, a supplement of L. rhamnosus GG or
maltodextrin placebo once daily. Fecal samples
were collected in 7-day-old neonates and microbial
diversity was assessed by terminal restriction frag-
ment-length polymorphism [14]. In this popu-
lation, administration of L. rhamnosus GG to the
mothers during late pregnancy had no effect on the
gut microbiota diversity when compared with
placebo administration. In another recent investi-
&&
gation, Abrahamsson et al. [15 ] assessed the
microbial diversity and characterized the dominant
bacterial population in the stool during the
first year of life in relation to atopic eczema. These
investigators found that infants with atopic
eczema had a lower diversity of total microbiota
at 1 month of age, in particular, in the bacterial
phylum of Bacteroidetes and of Bacteroides. At
12 months of age, Proteobacteria were more abun-
dant in infants without allergic manifestations.
They concluded that by using a new method
applying high-throughput 16S-based molecular
microbiology they observed a lower intestinal
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microbial diversity during the first months of life,
which was associated with subsequent develop-
ment of atopic eczema. These observations were
suggesting that allergy modulation was influenced
by the early microbial content of the gut, in particu-
lar by bacteria belonging to the phyla Bacteroidetes
and Proteobacteria. Interestingly, the potential
role for allergy modulation of bifidobacteria and
clostridia, as observed in earlier studies could not be
confirmed here.
MOST RECENT CLINICAL TRIALS ON
ATOPIC DERMATITIS PREVENTION BY
USING PROBIOTICS AND PREBIOTICS
Further clinical trials after the above cited system-
atic reviews [4,10] explored the modulation of the
microbiota in infants on early allergic diseases.
Wickens et al. [16] reported a study performed in
two centers in New Zealand, in which pregnant
mothers were supplemented from the 35th week
of gestation until 6 months after giving birth when
breastfeeding, as well as their infants from birth up
to 2 years of age, with L. rhamnosus HN001 and
B. lactis HN019 versus placebo. They then explored
the infant’s cumulative prevalence of eczema from
birth up to the age of 2 years. At the age of 2 years,
children having received L. rhamnosus had a signifi-
cantly reduced risk of developing eczema (14.8%),
when compared with children having received
placebo (26.8%). This effect was not confirmed for
B. lactis. There was no difference in sensitization for
any allergen, in particular food allergens at 2 years.
In addition, they found an increased presence of
L. rhamnosus in the feces at 3 months of age. They
concluded a favorable preventive effect of L. rham-
nosus but not B. lactis on the cumulative prevalence
of eczema up to 2 years.
In a trial performed in Australia, L. rhamnosus
GG was administered to 250 pregnant women with a
high risk of allergic disease for their offspring, from
36 weeks of gestation until delivery [17]. Unlike in
most other studies, probiotics supplementations
were not pursued in the lactating mothers or in
infants. Prevalence of atopic eczema in infants
was similar in both groups (probiotic supple-
mented: 18%; placebo: 19%), and consistently
remained without a statistically significant differ-
ence when various criteria for eczema diagnosis were
used. In addition, sensitization rates to common
foods (hen’s egg, peanut, and cow’s milk) were
similar in both groups. In addition, various cyto-
kines (IL-10, IL-13, TNF-a, and interferon-g)
measured after stimulation of umbilical cord blood
activated T-cells did not show any specific pattern
in either group.
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 Preventive effect of probiotics and prebiotics for infantile eczema Eigenmann
Following a similar aim to the previous studies, a
group of investigators from Finland supplemented
pregnant mothers with allergic and atopic sensitiz-
ation, with either a mix of L. rhamnosus and B.
longum, or Lactococcus paracasei and B. longum, or
&&
placebo [18 ]. The supplementation to the mothers
started 2 months before delivery and lasted up to
2 months of breastfeeding. Over 200 infants com-
pleted the follow-up for assessment of eczema
during the first 24 months of life. The investigators
found a reduced risk of developing eczema in the
group of infants whose mothers had received the
mix of L. rhamnosus and B. longum [odds ratio (OR)
0.17, CI: 0.08–0.35] as well as in the second group
whose mothers had received the mix of L. paracasei
and B. longum (OR 0.16, CI: 0.08–0.35). In addition,
the ORs for chronically persistent eczema were
decreased in both groups. Nevertheless, probiotics
had no effect on atopic sensitization in these
infants. In addition to early childhood outcome
for allergies and sensitization, a group of investi-
gators from Taiwan also assessed the effect on the
mothers, in a study in which pregnant women
suffering from atopic diseases were supplemented
with Lactobacillus GG, beginning in the second
trimester of pregnancy. The follow-up of the
children, until 36 months of life, in this randomized,
placebo-controlled trial, did not show any effect in
the treated group. However, mothers who received
Lactobacillus GG had significantly improved their
allergies, in conjunction with an observed T helper1
(Th1)-type cytokine modification in the serum
(increase of IL-12p70 levels) [19].
Although most studies are characterizing the
protective effect on eczema in infants or in early
childhood, it is of interest to assess the long-term
protective effect of probiotics and prebiotics.
Wickens et al. [20] investigated the supplementation
of L. rhamnosus HN001 from the 35th week of
gestation up to 6 months of breastfeeding, followed
by infant supplementation until 2 years of age. They
found by 4 years of age, in over 400 infants, a
significantly reduced cumulative prevalence of
eczema with a reduced hazard ratio (0.57; CI:
0.39–0.83), and interestingly also of rhinoconjunc-
tivitis (0.38; CI: 0.18–0.83) in HN001 supplemented
infants. They concluded that this probiotic, given in
the first 2 years of life, provides a protective effect for
early manifestations of atopy (i.e. atopic eczema),
but also for later manifestations of the atopic
march, here rhino-conjunctivitis. Nevertheless,
these results are not supported by other trials
reported here, suggesting that these cannot be
extended to other populations.
The gut-resident microbiota provides an intrigu-
ing and fascinating imprinting of the immune
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system of an individual. Clearly, the benefit of an
allergy-protecting pattern of the microbiota is age
related, with a window of opportunity in the early
months of life. At this specific age, a flora rich
in probiotics has a high potential benefit for the
prevention of allergic diseases. This benefit is
particularly high because of the nonpathogenic
characteristics of the probiotics, and the absence of
side-effects when providing microbial supplements.
Early studies have raised a theoretical interest in
modulating allergic disease with supplementations
of probiotics and prebiotics. If initial studies had
provided sometimes conflicting results, more recent
works have been more positive in suggesting an
allergy-protective immune modulation with probi-
otics and prebiotic supplementations. Nevertheless,
it is difficult to make a general recommendation at
this stage, mostly related to the various strains
studied not allowing generalization of the results.
A few specific strains, and in particular L. rhamnosus,
have been studied by several investigators with
promising results. However, a combination of
various probiotics, or probiotics and probiotics
might even enhance the protective effect of bac-
terial prevention strategies. The ideal combination
and concentration of microorganisms, if existing,
remains to be found.
In addition, the various designs of time and
modalities for probiotics and prebiotics adminis-
tration make interpretation of study results and
recommendations more difficult. In general, it
might be concluded that microbial supplementa-
tions should begin during the last months or weeks
of pregnancy, and ideally be pursued up to 6 months
of life. Exclusive maternal supplementation does
not include the benefit of an optimal immune inter-
vention in the infant during the window of oppor-
tunity provided by the immune system during the
first months of life. Thus, infants should be supple-
mented through lactation, or thereafter.
The methodology of the latest studies is clearly
of high quality and will allow, in combination with
studies to come, pinpointing of the most effective
strategies combining probiotics and/or prebiotics
for prevention of atopic eczema in particular, or
&&
allergic diseases, in general (Table 1) [16,17,18 ,
19,20]. However, interventions for allergy pre-
vention are complex and should address several
strategies, for example, by also including early
exposure of potential allergens in order to promote
antigen-specific tolerance. Clearly, probiotics and
prebiotics supplementations are part, but only
one part of optimal allergy prevention in allergy
prone infants. Finally, nutritional supplementa-
tions should always include a safety assessment
before administration, as allergic children might
www.co-allergy.com 429
 Pharmacotherapy and evidence based medicine

also react to potential food allergens present in the

Large, well designed trial; investigator diagnosed

preparations of strains tested/no other clinical

allergic diseases assessed/one strain is tested

eczema/no long-term outcome measured, no

Immunologic studies done in addition to clinical

Large trial, long-term follow-up (4 years), other

preparation [21].

outcome/no long-term outcome measured,

Follow-up until 3 years of age, other allergic

diseases assessed/questionnaire-based
Follow-up until 2 years of age, various
no other allergic diseases assessed
other allergic diseases assessed
CONCLUSION

outcomes of allergy measured

Meta-analyses including early studies, as well as
Strength/weaknesses of study

more recent studies, show that the protective effect

assessment (in part)

of probiotics and prebiotic supplementations on
early manifestations of atopy such as infantile
eczema remains controversial. If an ideal probiotics
and prebiotic supplementation can be determined
through future studies, it will still likely be only
partially effective, and prevention strategies should
aim for an enhanced efficacy not only by addressing
Reduced risk of eczema in both

Reduces prevalence of eczema

No difference between treated

interventions on the microbiota, but by combining

Less eczema in L. rhamnosus

improvement of allergic

and rhino-conjunctivitis them with other interventions.

HN001-treated group

symptoms in mothers
No effect on children,
treated groups
and untreated

Acknowledgements
None.
Effect

Conflicts of interest
The author received consulting honoraria from Danone
Cumulative prevalence of eczema

developing of allergic diseases

Cumulative incidence of eczema

Cumulative incidence of eczema

Point and cumulative prevalence

and Nestlé.
Eczema at age and 4 years
up to the age of 2 years

No funding was received to support the preparation of

during the first year

of sensitization and

this article.
up to age 2 years
Primary outcome

up to 3 years

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Papers of particular interest, published within the annual period of review, have
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Table 1. Summary of the most recent trials on probiotics and eczema

& of special interest

&& of outstanding interest
and B. lactis HN019
L. rhamnosus HN001

L. rhamnosus HN001

Additional references related to this topic can also be found in the Current
L. paracasei and

World Literature section in this issue (p. 459).

L. rhamnosus and
L. rhamnosus GG

Lactobacillus GG
B. longum, or

B. longum

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