doi: 10.1111/1346-8138.

13072 Journal of Dermatology 2015; 42: 1137–1142

REVIEW ARTICLE
Microbiome and pediatric atopic dermatitis
Claire E. POWERS,1 Diana B. MCSHANE,2 Peter H. GILLIGAN,3 Craig N. BURKHART,2
Dean S. MORRELL2
1
Duke University School of Medicine, Durham, 2Department of Dermatology, University of North Carolina Chapel Hill, 3Clinical
Microbiology-Immunology Laboratories, University of North Carolina Hospitals, Chapel Hill, North Carolina, USA

ABSTRACT
Atopic dermatitis is a chronic inflammatory skin condition with drastic impacts on pediatric health. The
pathogenesis of this common disease is not well understood, and the complex role of the skin microbiome in the
pathogenesis and progression of atopic dermatitis is being elucidated. Skin commensal organisms promote nor-
mal immune system functions and prevent the colonization of pathogens. Alterations in the skin microbiome may
lead to increased Staphylococcus aureus colonization and atopic dermatitis progression. Despite the evidence for
their important role, probiotics have not been deemed efficacious for the treatment of atopic dermatitis, although
studies suggest that probiotics may be effective at preventing the development of atopic dermatitis when given
to young infants. This review will cover the most recent published work on the microbiome and pediatric atopic
dermatitis.

Key words: antimicrobial cationic peptides, atopic dermatitis, microbiota, probiotics, Staphylococcus aureus.

INTRODUCTION progression of atopic dermatitis and present recent evidence

Atopic dermatitis is a chronic inflammatory skin condition that
primarily arises in childhood.1 Worldwide, approximately 2 mil-
lion children suffer from atopic dermatitis with a lifetime preva-
lence as high as 20% and rising in affluent countries, which
are disproportionally affected.2 The psychosocial and financial
burdens of atopic dermatitis on children and their families are
great, with time-consuming treatments, diet and household
changes, and a significant financial impact of almost $US 1 bil-
lion a year in the USA.3,4 Eighty-four percent of children with
atopic dermatitis report difficulty falling asleep and greater than
one-third are embarrassed or angry about their appearance.3
Atopic dermatitis is a common clinical presentation with multi-
ple interrelated etiologies including inflammatory, barrier func-
tion and microbial factors (Fig. 1). Alteration of our skin
microbiome due to antibiotics and antimicrobial soaps causes
a reduction in microbial antigen exposure. This reduced expo-
sure is theorized as a risk factor for the development of atopic
diseases such as atopic dermatitis.5 Indeed, the recent eluci-
dation of the role of the filaggrin (filament aggregating protein)
gene in the pathogenesis of atopic dermatitis in a significant
number of people supports associations between barrier func-
tion and alteration of the skin microbiome in the development
of atopic dermatitis. Approximately 42% of atopic dermatitis
patients have a filaggrin mutation and abundant Staphylococ-
cus aureus in comparison with normal skin commensals.6,7
This review will cover the current evidence on the complex
effects of the skin microbiome on the pathogenesis and
on probiotic use for treatment of atopic dermatitis.
ROLE OF THE MICROBIOME IN NORMAL SKIN
At birth, newborns possess a fairly uniform microbiome. Its
composition is determined initially by mode of delivery, with
newborns born vaginally harboring the mother’s vaginal flora,
dominated by Lactobacillus, and those born by cesarean sec-
tion inheriting communities similar to those on their mothers’
skin.8 Evolution of the microbiome into distinct anatomical
niches occurs after infancy until finally, in early childhood, an
individual’s microbial community achieves relative long-term
stability.9 The skin microbiota is organized by anatomical struc-
tures, with sweat glands, hair follicles and sebaceous glands
providing unique microbial niches.10 The antecubital and popli-
teal fossae, commonly involved atopic dermatitis sites, contain
some of the most diverse microbial populations.5,9 Overarching
phyla that dominate the skin microbiome include Actinobacte-
ria (genus Propionibacterium and Corynebacterium), Firmicutes
(genus Staphylococcus), Proteobacteria and Bacteroidetes.5,9
(Fig. 2) Staphylococcus epidermidis, usually a benign commen-
sal, is ubiquitous on the skin and usually colonizes the head,
axilla and nares.11 Numerous microbial species across the skin
perform vast and diverse functions. Namely, our microbiota
enhance the skin’s innate immune response to unwelcome
microbes via the production of antimicrobial peptides12 such
as cathelicidins and b-defensins.13 Skin commensals further
modulate immune system development via promotion of type 1

Correspondence: Dean S. Morrell, M.D., Department of Dermatology, University of North Carolina Chapel Hill, 410 Market Street, Suite 400,
Chapel Hill, NC 27516, USA. Email: morrell@med.unc.edu
Received 10 May 2015; accepted 10 July 2015.

© 2015 Japanese Dermatological Association 1137

C.E. Powers et al.

S. aureus
Glabella
colonization

Cer, free Alar crease

Acquired stressors fatty acids, Toxin- + superantigen-
pH, RH, PS AMP producing S. aureus
sphingosine
External auditory
canal Retroauricular
Folliculitus/ crease
Sustained barrier defect Th1 Th2
AD lesion Nare
impetigo
Occiput
T-B-cell
Cer synthesis Manubrium
activation
Inhereited Keratinocytes Back
defects protease
FLG Pruritus Axillary vault
dysregulation
LEKTI neuropeptides Buock
Specific lge
Antecubital
Scratching/excoriations fossa Gluteal
crease
Volar
Figure 1. Secondary infections can further aggravate barrier forearm Popliteal fossa
abnormality in atopic dermatitis. AD, atopic dermatitis; AMP, Hypothenar
adenosine monophosphate; Cer, ceramide; FLG, filaggrin; palm Plantar heel
LEKTI, lymphoepithelial Kazal-type related trypsin inhibitor; PS, Interdigital
psychological stress; RH, relative humidity; Th1, T-helper 1; web space
Th2, T-helper 2. Reprinted with permission from Macmillan Inguinal crease
Publishers.49
Umbilicus

T-helper (Th)-cell function through interleukin (IL)-1 signaling Toe web space
pathways14 while potentially inhibiting the development of type
2 Th-cell functions responsible for allergic conditions including Acnobacteria Bacteroidetes Proteobacteria
atopic dermatitis, asthma and allergic rhinitis.15 Corynebacteriaceae Cyanobacteria Divisions contribung <1%
Propionibacteriaceae
Firmicutes Unclassified
Micrococciaceae
Other Acnobacteria Other Firmicutes
ROLE OF THE MICROBIOME IN ATOPIC Staphylococcaceae Sebaceous
Moist
DERMATITIS Dry

A child’s early skin microbiome may positively influence immune

system development away from allergic over-sensitization.16
Evidence supporting this concept offers one explanation for the
pathophysiology of atopic dermatitis in a child with decreased
skin microbiome richness or diversity. A wealth of epidemiologi-
cal data on the prevalence of atopic dermatitis in microbe-
depleted or microbe-exposed groups also bolsters this relation-
ship. Day-care attendance has been linked to increased
microbial antigen exposure and reductions in risk of developing
atopic dermatitis in some studies17,18 while other studies have
not observed this relationship.19,20 Early exposure to bacterial
endotoxin in the household environment also appears to be
protective against developing atopic dermatitis in some stud-
ies,21,22 yet findings of unclear long-term benefits23 and an
increased risk of atopic reactions in high-risk infants24 have
raised concerns about bacterial endotoxin. An intriguing ran-
domized placebo controlled trial treated 2500 pregnant women
in Uganda with albendazole during the third trimester in order to
observe the effect of this anti-helminthic treatment on develop-
ment of the infant’s microbiome and eventual risk for atopic
dermatitis. They found a double-increased risk of atopic der-
matitis in the infants whose mothers received albendazole com-
pared with placebo.25 Another randomized controlled trial
treated over 2000 children directly with albendazole and saw no
increase in the incidence of atopic disease.26 Finally, cesarean
section, which exposes infants to a limited microbial population
as compared with vaginal delivery, was found to increase the
Figure 2. Topographical distribution of bacteria on skin sites.
The skin microbiome is highly dependent on the microenviron-
ment of the sampled site. The family-level classification of bac-
teria colonizing an individual subject is shown, with the phyla
in bold. The sites selected were those that show a predilection
for skin bacterial infections and grouped as sebaceous or oily
(blue circles), moist (typically skin creases) (green circles) and
dry, flat surfaces (red circles). The sebaceous sites are: gla-
bella (between the eyebrows); alar crease (side of the nostril);
external auditory canal (inside the ear); retroauricular crease
(behind the ear); occiput (back of the scalp); manubrium (upper
chest); and back. Moist sites are: nare (inside the nostril); axil-
lary vault (armpit); antecubital fossa (inner elbow); interdigital
web space (between the middle and ring fingers); inguinal
crease (side of the groin); gluteal crease (topmost part of the
fold between the buttocks); popliteal fossa (behind the knee);
plantar heel (bottom of the heel of the foot); toe web space;
and umbilicus (navel). Dry sites are: volar forearm (inside of the
mid-forearm); hypothenar palm (palm of the hand proximal to
the little finger); and buttock. Reprinted with permission from
Macmillan Publishers.50
risk of atopic dermatitis diagnosis among 2500 infants in
Germany,27 but a meta-analysis of data from 1966 to 2007 con-
cluded there was no excess risk.28 It appears that larger patient
populations may be needed to demonstrate the true effect.
Observations that skin microbial communities change during
atopic dermatitis flare and recovery periods has sparked inter-

1138 © 2015 Japanese Dermatological Association

 Microbiome and pediatric atopic dermatitis

est in the ability of skin commensal organisms to promote skin
recovery. Traditional atopic dermatitis treatment with anti-
inflammatory and antimicrobial medications, even if intermit-
tent, has been linked to greater microbial diversity, specifically
increases in the populations of Streptococcus, Corynebac-
terium and Propionibacterium (Fig. 3).29 In one study, treatment
with emollient creams for 84 days caused clinical improvement
in 72% of children, whose skin microbial diversity resembled
non-diseased skin at study conclusion.30 The children in the
emollient group also had decreased skin abundance of Staphy-
lococcus species at the end of the study.
Beyond the skin microbiota, gastrointestinal microbiota may
enhance the development of tolerance to allergens. Analysis of
terminal restriction fragment length polymorphism of fecal
microbiota diversity found that diversity was lower during the
first 18 months of life in infants with atopic dermatitis com-
pared with healthy controls.31 The large ALLERGY-FLORA pro-
ject studied 318 infants from Europe using only analyzed
culturable intestinal bacteria, a less ideal measure of diversity,
and failed to identify such a relationship.32
It has been well established that tissue from atopic dermati-
tis lesions produces fewer antimicrobial peptides such as
cathelicidins and human b-defensins13 that defend against
unwanted microbes. This deficiency suggests alterations in the
commensal skin microbiome, which as mentioned above, are
known producers of these antimicrobial peptides.10 It also
explains the increased susceptibility to infection by viral, bacte-
rial and fungal pathogens observed in atopic dermatitis. This
risk of infection is much lower in psoriasis, a skin disease also
considered to be caused by a defective skin barrier but with
increased antimicrobial peptides.33 Given these differences,
variances in the skin microbiome may have a role in individu-
als’ inflammatory responses and clinical presentations.
ROLE OF MICROBIAL PATHOGENS IN ATOPIC
DERMATITIS
Atopic dermatitis has long been associated with colonization
and frequent infections by the pathogen S. aureus.34 Ninety
percent of chronic dermatitis lesions contain S. aureus. This is
in contrast to 5% S. aureus colonization in skin of non-atopic
individuals.35 Beyond causing frequent pyogenic infections, the
role of S. aureus in the pathogenesis of atopic dermatitis is
being elucidated. S. aureus superantigens may stimulate
peripheral T lymphocytes that react to form dermatitis
lesions.36 Superantigens also downregulate the production of
antimicrobial peptides by halting Th17 T-cell produced IL-17
and IL-22 which drive antimicrobial peptide production in nor-
mal skin.37 Furthermore, patients with atopic dermatitis fre-
quently have elevated IgE levels and often make IgE specific
for these superantigens whose levels are positively correlated
with disease severity.38 The fact that topical corticosteroid
treatment alone decreases the colonization of S. aureus on
atopic skin supports the idea that inflammation may play an

(a) 1.0 Actinobacteria

Corynebacteriaceae
0.8 Propionibacteriaceae
Mean proportion

Bacteroidetes
0.6 Other
Proteobacteria
Alphaproteobacteria
0.4
Betaproteobacteria
Comamonadaceae
0.2 Gammaproteobacteria
Firmicutes
0.0 Clostridia
Flare, Flare, Bacilli
Controls Baseline no intermittent Postflare Streptococcaceae
treatment treatment Staphylococcaceae
(b) 1.0

0.8
Mean proportion

Non-Staphylococcus
Staphylococcus, other
0.6
S. hominis
S. epidermidis
0.4 S. capitis
S. aureus
0.2

0.0

Figure 3. Bacterial taxonomic classifications in the atopic dermatitis skin microbiome. (a) Mean relative abundance of the 14 major
phyla order in the antecubital and popliteal creases for controls and atopic dermatitis disease states: baseline, flare (no treatment
and intermittent) and post-flare. (b) Mean relative abundances for antecubital and popliteal creases of species-level classifications
of staphylococcal species. Order of subjects follows A. Reprinted with permission from Cold Spring Harbor Laboratory Press.29

© 2015 Japanese Dermatological Association 1139

C.E. Powers et al.

important role in establishing S. aureus colonization of dermati-
tis lesions.39 Staphylococcal protein A has also been demon-
strated to have direct chemical irritant properties.40
Other microbes implicated in the exacerbation of atopic
dermatitis include S. epidermidis and the yeast species
Malassezia. S. epidermidis may be more abundant in patients
with atopic dermatitis41 and the proportion of S. epidermidis
on the skin is higher during atopic dermatitis flares than post-
flare.29 Patients with atopic dermatitis have higher levels of IgE
antibodies against Malassezia as compared with healthy con-
trols. Furthermore, the severity of atopic dermatitis symptoms
can improve in some patients after a 1–2-month daily treat-
ment with oral ketoconazole or itraconazole.42 While these and
other microbes play a pathogenic role in the atopic dermatitis
progression, none seem to play as critical a role in pathogene-
sis and progression as S. aureus.
IMPLICATIONS FOR MANAGEMENT
As information regarding the potential effects of skin micro-
biome alteration on the pathogenesis of atopic dermatitis has
emerged, a plethora of trials looking at use of oral probiotics to
both prevent and treat atopic dermatitis have appeared.43
Table 1 summarizes six most recent randomized clinical trials
performed in children selected based upon a PubMed search
“atopic dermatitis probiotic” with the “Therapy/RCT” filter
applied. A 2008 Cochrane review that analyzed 10 randomized
trials comprising 781 children found that probiotics are not an
effective treatment for atopic dermatitis and that probiotics do
carry a small risk of adverse events including infection and
bowel ischemia.44 A second meta-analysis reviewed 10 trials
encompassing 1898 children demonstrated that probiotics may
be more efficacious at preventing atopic dermatitis than treat-
ing it.45 This meta-analysis found a significant risk reduction in
future incidence of atopic dermatitis as high as 61% associ-
ated with the use of maternal prenatal and/or infant postnatal
probiotics. One of the recent larger trials looking at prevention
of atopic dermatitis provided a Lactobacillus probiotic to 425
mothers from 35 weeks of gestation onward, and then to their
infants during the first 2 years of life. They found decreased
prevalence of dermatitis in these children at 4 years of age in
the probiotic group versus placebo but non-significant reduc-
tions in Scoring Atopic Dermatitis severity score (SCORAD).46
As laid out in Table 1 and demonstrated by the 2008 Cochrane
review, multiple trials have failed to see any efficacy in treating
atopic dermatitis with oral probiotics. Recently, two posters
presented at the American College of Allergy, Asthma and
Immunology 2014 meeting offered results of a topical probiotic
extract (the exact composition of the probiotic extract has not
yet been released by the company that produces it) that

Table 1. Recent randomized clinical trials on the efficacy of probiotics in the treatment of pediatric atopic dermatitis yield mixed
results

First author Study population Probiotic Results Country

Yang 51
n = 100, ages 2–9
Wickens46 n = 425, maternal
supplementation 35
weeks gestation to
6 weeks, infant
supplementation
for first 2 years
Han52 n = 118, ages 12 months
to 13 years
Gore53 n = 208, ages 3–6 months
Wu54 n = 60, ages 2–14 years,
moderate to severe
van der Aa55 n = 90, ages <7 months
Lactobacillus and
Bifidobacterium
Lactobacillus rhamnosus or
Bifidobacterium animalis
Lactobacillus
plantarum CJLP133
Bifidobacterium lactis or
Lactobacillus paracasei
Lactobacillus salivarius
Bifidobacterium breve
Cytokine levels not significantly Korea
different at week 6 (IL-4, P = 0.50;
P = 0.58; TNF-a, P = 0.82). Improved
clinical severity in both intervention
and placebo groups at 6 weeks.
Decreased cumulative prevalence New Zealand
of dermatitis by 4 years, hazard
ratio 0.57 (95% CI 0.39–0.83) with
L. rhamnosus. Non-significant
reductions in SCORAD scores >10
(HR = 0.74 [95% CI = 0.52–1.05]).
SCORAD at week 14 was lower in the Korea
probiotic group than placebo
(P = 0.044). Eosinophil count, IFN-c
and IL-4 significantly decreased from
baseline in intervention group.
No significant difference between UK
SCORAD in placebo and each
probiotic group.
At 8 and 10 weeks, treatment (synbiotic) Taiwan
group SCORAD scores (27.4  12.7)
were significantly lower than controls
(prebiotic) (36.3  14.9). (P = 0.022)
No significant differences between the Netherlands
symbiotic and the placebo groups in
cytokine production and circulating
regulator T-cell percentage.

CI, confidence interval; HR, hazard ratio; IFN, interferon; IL, interleukin; SCORAD, Scoring Atopic Dermatitis severity score; TNF, tumor necrosis
factor.

1140 © 2015 Japanese Dermatological Association


worked equivalently to topical dexamethasone in treating ato-
pic dermatitis.47 This promising but speculative topical extract
may function to disrupt S. aureus biofilms, a concept that has
also recently been demonstrated in vitro by showing that
topically applied Lactobacillus rhamnosus GG (108 colony-
forming units/mL) increases epidermal keratinocyte survival
during exposure to S. aureus from 25% to 57% (P = 0.01).48
CONCLUSION
Atopic dermatitis is a chronic inflammatory skin condition in
the pediatric population characterized by recurrent pruritic
flares of disease activity. Destruction of the skin’s normal
barrier function is likely involved in the pathogenesis of atopic
dermatitis49 and commensal organisms promote normal skin
barrier function through the production of antimicrobial pep-
tides that defend against skin pathogens. A lack of normal
microbial skin diversity combined with an overabundance of
staphylococcal species in patients with atopic dermatitis fur-
ther leads to disruption of skin-barrier homeostasis. The ability
to analyze the makeup of the human microbiome is expanding
rapidly with the use of sensitive high-throughput DNA sequenc-
ing5 rather than data from cultured isolates. Understanding the
breadth of the skin microbiome and its protective role offers
novel insights into the relationship between the microbiome
and atopic dermatitis disease progression. The ability to har-
ness the human microbiome in order to treat common inflam-
matory conditions such as atopic dermatitis has not yet been
fully realized. Randomized clinical trials of probiotics to treat
atopic dermatitis have not demonstrated efficacy, especially
when compared with traditional treatment modalities. However,
more evidence exists for using probiotics to prevent atopic
dermatitis development. Most probiotics for atopic dermatitis
have only contained one or two microbes, which is in contrast
to the normal skin that maintains a plethora of commensal
organisms. Therefore, even if deemed effective, the exact com-
position, along with the route of administration and safety of an
eventual probiotic treatment, must be determined.
CONFLICT OF INTEREST: None declared.
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