Curr Allergy Asthma Rep (2015) 15:65

DOI 10.1007/s11882-015-0567-4

ALLERGENS (RK BUSH AND JA WOODFOLK, SECTION EDITORS)

The Role of the Skin Microbiome in Atopic Dermatitis

Michael R. Williams 1 & Richard L. Gallo 1

# Springer Science+Business Media New York 2015

Abstract Atopic dermatitis (AD) is a common skin disease Introduction

that affects a large proportion of the population worldwide.
The incidence of AD has increased over the last several de- Atopic dermatitis (AD) is a chronic allergic skin disease the
cades along with AD’s burden on the physical and psycholog- includes frequent flares, and manifests with characteristic
ical health of the patient and family. However, current ad- findings of dry, red, and pruritic skin in a typical distribution
vances in understanding the mechanisms behind the patho- [1]. AD is one of the most common skin disorders and affects
physiology of AD are leading to a hopeful outlook for the 5–20 % of infants worldwide with lesser prevalence in adult-
future. Staphylococcus aureus (S. aureus) colonization on hood [2]. Although AD is rarely lethal, several studies have
AD skin has been directly correlated to disease severity but shown that AD frequently leads to a severely compromised
the functions of other members of the skin bacterial commu- way of life for patients and their families and thus is a major
nity may be equally important. Applying knowledge gained health care burden [3, 4]. Furthermore, AD often associates
from understanding the role of the skin microbiome in main- with other allergic diseases including asthma and allergic rhi-
taining normal skin immune function, and addressing the det- nitis [5], thus further compounding the importance of this
rimental consequences of microbial dysbiosis in driving in- disease. Finally, the number of infants and adults affected by
flammation, is a promising direction for development of new AD is higher in industrialized nations and has also grown over
treatments. This review discusses current preclinical and clin- the past several decades. Many suspect that a link to excessive
ical research focused on determining how the skin hygiene in these industrialized regions leads to a lack of ben-
microbiome may influence the development of AD. eficial host immune education provided by microbes on or
within the body [6, 7]. Understanding the mechanisms behind
AD and ways to treat it are therefore extremely important and
Keywords Skin microbiome . Dysbiosis . Atopic dermatitis . highly relevant topics in the fields of allergy and dermatology.
Staphylococcus aureus . Staphylococcus epidermidis . Both genetic and environmental factors play a substantial
Virulence factors role in the onset of AD. Genome-wide scans have revealed
that there are several shared chromosome loci among AD
patients where gene expression has been altered. These stud-
ies, however, clearly demonstrate that AD is a complex dis-
This article is part of the Topical Collection on Allergens ease with many potential genetic factors at play [1]. Specific
genetic mutations that have been linked to AD Include genes
* Richard L. Gallo involved in formation of the epidermal skin barrier such as
[email protected] filaggrin (FLG), genes involved in tight junctions (TJs), and
Michael R. Williams the serine protease inhibitor Kazal-type 5 (SPINK5) [8–12].
[email protected] Mutations in T helper cell 2 (Th2) cytokines IL-4 and IL-13
have also been correlated in AD pathogenesis [13, 14]. In
1
Department of Dermatology, University of California San Diego, most cases, data support that environmental factors including
9500 Gillman Dr., #0869, La Jolla, CA 92093, USA food and aeroallergens, as well as physical stressors including
65 Page 2 of 10 Curr Allergy Asthma Rep (2015) 15:65

hydration and scratching, can play a substantial role in disease but varies even more depending on skin topography [20]. The
severity as well [15–17]. use of next-generation DNA sequencing methods have allowed
A complete and in-depth analysis of the hypothesized us to better understand both the composition and potential roles
mechanisms that drive AD has been discussed previously [1, that these microorganisms, in particular bacteria, play on our
18, 19]. The purpose of this review is to focus on the rapidly skin. Importantly, as the technology has improved, so has our
advancing information that has shown a clear role for the skin understanding of what specific bacteria are associated with
microbiome in controlling the clinical manifestations of this disease.
disease (Fig. 1). Determining how microorganisms that inhab- 16S ribosomal RNA (16S rRNA) partial DNA sequencing
it the skin regulate AD can help us to better understand both was initially used to determine the microbial composition on
the mechanisms behind AD and provide new ways to apply the skin at the genus level and has been followed by the devel-
therapeutic strategies to combat the disease. opment of full-length 16S rRNA DNA sequencing techniques
to allow for more specific identification of the organism at the
species level [20, 21]. These initial sequencing methods
The Skin Microbiome and Changes in Atopic showed that our normal skin microbial flora consist of four
Dermatitis common phyla of bacteria—Firmicutes, Proteobacteria,
Bacteroidetes, and Actinobacteria (Table 1). Species of bacteria
Methods of Determining the Skin Microbiome detected by 16S rRNA DNA sequencing show that hundreds of
Composition bacteria frequently colonize the skin, while culture techniques
have found that the most commonly detected organisms in-
The skin is colonized by numerous species of bacteria, fungi, clude both Propionibacterium acnes and Staphylococcus
and viruses that together are known as the skin microbiome. epidermidis (S. epidermidis) among others [24–27]. DNA se-
The composition of this community varies between individuals quencing has also provided a useful way to track temporal

Fig. 1 Dysbiosis of the skin microbiome in AD. Genetic defects in both An acute Th2 response is thought to dampen certain antimicrobial peptide
physical (e.g., FLG and SPINK5) and immune (e.g., IL-4 and IL-13) skin (AMP) responses as well. These events all play a role in dysbiosis of the
barrier genes lead to increased skin barrier disruption. A decreased skin skin microbiome during AD leading to increased colonization by
barrier response allows for increased susceptibility of the skin to aller- S. aureus along with decreased overall microbial diversity. S. aureus
gens. Second, the skin becomes dry and itchy leading to more physical colonization is speculated to increase AD severity through secreting a
stress to the already damaged skin barrier. Overall, the decreased skin series of virulence factors that damage the skin barrier and increase in-
barrier leads to an increase in skin pH, altered keratinocyte adhesion flammation. Other mechanisms pertaining to the role of dysbiosis of the
properties, and both increased serine protease activity and inflammation. skin microbiome in altering AD pathogenesis have yet to be determined
Curr Allergy Asthma Rep (2015) 15:65 Page 3 of 10 65

Table 1 Changes to skin microbial diversity in normal versus AD skin has a unique skin microbiome based in part upon life experi-
Normal skin atopic Lesional skin ences and in part upon factors genetically predetermined by
the host.
Actinobacteria (phylum) The skin microbiome has been investigated extensively for
- Corynecbacterium (genus) Decreased relative abundance its role in communicating with the immune response.
- Propionibacterium (genus) S. epidermidis, a highly abundant commensal bacteria, has
- Rothia (genus) been shown to modify innate inflammatory responses through
- Actinomyces (genus) a Toll-like receptor (TLR) cross talk mechanism. In this study,
Bacteroidetes (phylum) it was revealed that S. epidermidis could suppress TLR3-
- Prevotella (genus) No change mediated keratinocyte inflammation due to skin injury by
Proteobacteria (phylum) stimulating TLR2 with lipoteichoic acid (LTA) [31].
- Alphaproteobacteria (class) Decreased relative abundance S. epidermidis can also increase T cell recruitment to the skin
- Betaproteobacteria (class) in germ-free mouse models and influence T cell maturation
- Gammaproteobacteria (class) [32•]. Similarly, the host skin immune response can act on the
Firmicutes (phylum) microbiome. Keratinocytes in the epidermis detect microbial
- Streptococcus (genus) Decreased relative abundance flora on the skin surface via pattern recognition receptors
- Staphylococcus (genus) Streptococcus/Granulicatella
(PRRs). Such recognition by TLR2 leads to production of host
- Granulicatella (genus) Increased absolute and relative
abundance Staphylococcus
antimicrobial peptides (AMPs) including the beta-defensins 2
and 3 (DEFΒ-2/DEFΒ-3) that defend the skin from microbial
(Data from [22, 23•]) evasion. TLR2 activation in the skin by the microbial flora can
also influence mast cell recruitment and increase tight barrier
shifts in the skin microbial flora during normal versus disease junctions leading to a stronger skin barrier [33–35].
states, and this will be discussed later in the review. Beyond Interestingly, commensal bacteria still survive on the skin sur-
16S rRNA DNA sequencing, recent efforts have begun to ap- face despite TLR activation and AMP production by
ply metagenomics [28••]. Metagenomics is a method that has keratinocytes. These findings have led to the speculation that
been used for studying the composition of microbial commu- there must be a permissive relationship with common skin
nities in both the gut and oral cavities. It uses DNA sequencing microbial flora. This prevents both a constitutively active im-
of full-length microbial genomes allowing for identification of mune response as well as allowing for commensal bacteria to
microbes at the strain level. This degree of specificity provides help protect our skin from pathogens.
a tool for determining which bacterial strains are present on the Recently, it was discovered that bacteria are normally pres-
skin. Knowing the specific strains, and not just the species of ent within the different layers of the skin and not just on the
bacteria, permits one to explore the molecular mechanisms by skin surface [36••]. This demonstrated that bacteria could pen-
which individual bacteria influence skin immune function. etrate the outer skin barrier and interact normally with many
different cell types that exist in the deeper dermis. Based upon
this finding, the capacity for the skin microbiome to influence
Normal Skin Microbial Flora immune homeostasis in normal and disease states becomes
more apparent. In the future, it will be important to determine
The colonization of bacteria on specific regions on the skin how microbes that have penetrated the skin barrier and that
depends upon the local skin environment including moisture reside in either the epidermis, dermis, or subcutaneous layers
levels, pH, and keratinocyte cell surface adhesion proteins. communicate with the host and vice versa.
For instance, Staphylococcus and Corynebacterium species Commensal skin microbes seeking to retain their niche on
thrive in specific environments on the skin such as the sole specific skin sites have also developed defense mechanisms
of the foot and the popliteal fossa (back of the knee). Dry against other bacteria that may seek to colonize the skin sur-
environments such as the volar forearm (inside forearm) and face. For example, some strains of S. epidermidis produce
hypothenar palm (palm of hand) are more prone to harbor a bacteriocins that are toxic to other bacterial species such as
mixed population of bacteria including both β-Proteobacteria Staphylococcus aureus [37]. S. epidermidis can also target
and Flavobacteriales [20]. Environmental factors such as diet, S. aureus through production of both the serine protease Esp
age, and gender also play a role in the makeup of the skin and phenol-soluble modulins (PSMs) that prevent S. aureus
microbial flora [29]. Infants are essentially born microbe free biofilm formation and growth, respectively [38, 39]. Another
until exposure to the external environment allows for imme- common commensal bacteria on the skin, P. acnes, inhibits
diate colonization of their skin [30]. Throughout their lifespan, S. aureus growth as well [40]. Thus, commensal skin mi-
the microbial diversity can change. This environmental influ- crobes can communicate with our skin in order to promote a
ence on our skin microbial flora means that each individual stronger skin barrier and immune response, and have methods
65 Page 4 of 10 Curr Allergy Asthma Rep (2015) 15:65

of their own to prevent invasion by pathogenic bacteria. Taken of NS patients has not yet been studied to reveal the total
together, it is apparent that the normal skin microbiome has microbial composition [44, 45].
multiple essential actions to maintain immune homeostasis, Hyper IgE syndrome (HIES), a primary immunodeficiency
and some commensal bacteria might even be considered as disease, represents another allergic skin disease where STAT3,
another immunocyte functioning in coordination with host- a crucial signaling kinase, is mutated. HIES patients experi-
derived immune cells. ence eczema as well as increased blood IgE levels. 16S rRNA
sequencing has revealed that the skin microbiome of HIES
Dysbiosis of the Skin Microbiome in AD patients has increased colonization of S. aureus along with,
to a lesser extent, Corynebacterium [46•]. Thus, several aller-
The skin microbial flora can enter a state of dysbiosis, defined gic skin diseases, which display dry and flaky skin and a
as a change in relative composition of the different microbes compromised skin barrier, display dysbiosis of the skin
compared to normal, during a disease state. This is most well microbiome and in particular increased S. aureus colonization.
described in AD. It was first observed in the 1970s that there
was increased S. aureus colonization on AD lesions [22].
Since then, multiple studies have observed this phenomenon, Microbial Mechanisms for Increased AD Severity
although the sheer complexity of how microbial composition
changes in AD was not established until the use of 16S rRNA Physical Changes to the Skin Barrier and the Role
DNA sequencing [23•]. Sequencing revealed that AD patients of Antimicrobial Peptides in Skin Microbiome Dysbiosis
have an overall increase of colonization by Staphylococcae
species along with an overall decrease in the number of dif- AD skin harbors a very different environment for bacterial
ferent types of bacteria (microbial diversity) on involved skin. growth than that of normal skin, and this may be the funda-
It particular S. aureus colonization of the skin is increased, as mental explanation for the dysbiosis observed in AD. A dys-
previously shown, while S. epidermidis is increased to a lesser functional physical skin barrier leads to an increase in pH on
extent. These increases result in dysbiosis since the expansion the skin surface that favors S. aureus growth [47, 48].
of these populations is not accompanied by a proportional Differentiated keratinocytes in the epidermis that are directly
increase in the other bacteria found on normal skin. exposed to microbes have altered cell surface marker expres-
The prevalence of S. aureus colonization on AD lesional sion as well. In particular, it has been found that both fibro-
skin varies, with some reporting the capacity to culture nectin and fibrinogen expressions are increased in
S. aureus from AD to be approximately 80–100 % while it keratinocytes from AD patients and these markers directly
is detectable with much lower frequency (5–20 %) in healthy bind to S. aureus in vitro [49, 50].
individuals [41]. Increased colonization of S. aureus on AD Immunological forces at play in the skin also influence
skin is strongly linked to increased severity of the disease [41, changes to the skin microbial composition during AD.
42]. The role of S. aureus colonization in increasing AD se- Endogenous AMPs are important for preventing pathogenic mi-
verity will be discussed below, and this association highlights crobes from infecting the skin. Two main classes of AMPs in the
why it is important to understand the mechanism of S. aureus skin are cathelicidin and DEFΒs [51, 52]. Both of these have the
virulence on AD skin in order to come up with more appro- ability to kill S. aureus in vitro. However, in AD skin,
priate therapeutic solutions. However, the association is not cathelicidin as well as DEFΒ-2 and DEFΒ-3 expression is de-
clearly one of cause and effect as elimination of S. aureus is creased in comparison to similarly inflamed psoriatic skin [53].
not a solution for this disease. Second, keratinocyte models show that the AD-associated Th2
cytokines IL-4, IL-5, and IL-13 can decrease expression of host
Dysbiosis of the Skin Microbiome in Other Allergic Skin AMPs in vitro [54]. Besides Th2-specific cytokines, IL-10 has
Diseases also been linked to decreasing AMP production [55]. Overall,
the lack of host AMPs represents another reason for decreased
Besides AD, other rare skin diseases associated with allergy microbial diversity and enhanced S. aureus growth on AD skin.
also have been reported to experience shifts in the skin
microbiome. Netherton syndrome (NS) is a rare skin disease S. aureus Virulence Factors in AD Severity
caused by a loss-of-function mutation in SPINK5, a key serine
protease inhibitor in the epidermis [43]. Decreased SPINK5 It is proposed that the association of dysbiosis with AD disease
expression leads to a hyperactive serine protease response and severity is more complex than simply AD leading to changes in
increased inflammation and desquamation, or stratum bacterial growth due to the factors described above. It is apparent
corneum shedding. This disease has been associated with both that, in some cases, the bacterial community can further drive
increased IgE levels in the blood as well as increased coloni- the disease. A well-known example of this is the hypothesis that
zation by S. aureus although in depth 16S rRNA sequencing S. aureus can increase the severity of AD by secreting a variety
Curr Allergy Asthma Rep (2015) 15:65 Page 5 of 10 65

of virulence factors (Table 2). The most well studied of these are induce TNF-α production in keratinocytes in a non-toxic man-
the superantigens (SAgs). SAgs function mechanistically by ner [64]. Finally, S. aureus-secreted PSMs are also known to
binding to the non-peptide groove of major histocompatibility increase inflammation in keratinocytes [69]. Although much is
complex class II (MHC-II) on antigen-presenting cells (APCs), known of the virulence factors discussed above, more are still
including skin keratinocytes, as well as to the T cell receptor being discovered. Understanding all of these virulence factors
(TCR) β-chains. This leads to non-specific activation of approx- and how they affect the skin barrier during AD is crucial to our
imately 5–20 % of all naïve T cells and systemic inflammation ability to combat S. aureus-mediated AD severity.
through production of pro-inflammatory cytokines including
TNF-α and IL-1β [70–73]. SAgs produced by S. aureus include Role of Proteases in Microbial Dysbiosis and AD Severity
the staphylococcal enterotoxins (SEs) and toxic shock syndrome
toxin 1 (TSST-1) [56–58]. Several studies have shown direct Maintaining the balance of activity between proteases and
correlations between SAg-producing S. aureus strains on AD their inhibitors is essential to upholding a functional skin bar-
patients and AD severity. It was observed in one study that 57 % rier. During AD, patients display an increase in serine protease
of AD patient S. aureus skin isolates produced SAgs as opposed activity. Specifically, the serine protease family known as the
to 33 % of control patient isolates. The SAg-positive S. aureus– kallikreins (KLKs) is observed to have increased activity [74,
colonized AD patients also displayed increased AD severity 75]. Hyperactive KLK responses have been studied in NS
based upon Scoring Atopic Dermatitis (SCORAD) with 58± patients and appear to be responsible for increased desquama-
17 as opposed to 41±7 in control patients [57]. A second study tion of the skin, altered cathelicidin and filaggrin processing,
revealed that elevated levels of SEA- and SEB-specific IgE and increased PAR-2 activity and inflammation [76–79].
antibodies in the blood correlated with increased AD severity Thus, the increased KLK activity in AD skin helps create a
[59]. compromised skin barrier and possibly aids in increasing
Another factor that is proposed to increase AD severity is S. aureus colonization of the skin.
that of hemolysin-α or α-toxin. α-Toxin monomers form a Exogenous serine proteases released from S. aureus have
heterodimer complex on the cell membrane that creates a po- also been studied for their role in damaging the skin barrier.
rous channel leading to cell lysis. This has been shown in The V8 serine protease increases desquamation of the epider-
in vitro studies where α-toxin is severely toxic to keratinocytes mis in vitro as well as being able to alter skin barrier integrity
[60, 61]. It has been proposed that Th2 cytokines can also in murine models [66, 67]. The serine-like proteases, exfolia-
increase α-toxin-induced keratinocyte toxicity [62]. Murine tive toxins A and B (ETA/B), have mostly been described for
models with subcutaneous injections of α-toxin display in- their role in inducing staphyloccocal scalded skin syndrome
creased inflammation at the site of injection [63]. Although (SSSS) [68]. In SSSS, ETA/B cleave desmoglein-1, a
high concentrations of α-toxin are toxic to host cells, low con- corneodesmosomal adhesion protein that plays a crucial role
centration can also stimulate keratinocyte cytokine production in regulating desquamation. Excess shedding of the stratum
leading to increased inflammation as well [64]. corneum, or the uppermost epidermal layer, leads to a
Other S. aureus virulence factors also can possibly influence disrupted skin barrier and increased bacterial invasion.
AD severity. δ-Toxin can target skin mast cells leading to de- Although S. aureus serine proteases have not been directly
granulation and increased inflammation [65]. Protein A can linked to AD, their virulence can easily suggest another mech-
anism for enhanced AD severity.
Table 2 Mechanisms of S. aureus-mediated AD severity

Virulence factors Mechanism for increased AD severity Ref(s)

Effect of Other Bacterial Strains on AD Pathogenesis
SAgs (SEA/B, TSST-1) Non-specific APC-mediated T cell [56–59]
activation, keratinocyte cytokine Besides increased S. aureus colonization of the skin in AD, 16S
production rRNA DNA sequencing has revealed increased S. epidermidis
α-Toxin Keratinocyte lysis and TNF-α [60–64]
production colonization. However, the function of increased S. epidermidis
δ-Toxin Mast cell degranulation and [65] colonization on AD skin remains unclear. The presence of
inflammation S. epidermidis on germ-free mouse skin can lead to an increase
V8 and ETA/B DSG-1 cleavage leading to both [66–68]
increased desquamation and in T cell effector function in an IL-1-dependent manner. This
skin inflammation seems to have a protective role against infections [32•].
Protein A Keratinocyte TNF-α production [64] S. epidermidis has also been shown in both murine and
PSM Keratinocyte inflammation [69] keratinocyte models to have a protective role through the ampli-
SAg superantigen, SEA and SEB enterotoxins A and B, TSST-1 toxin
fication of endogenous AMPs [80, 81]. Finally, there is evidence
shock syndrome toxin 1, ETA and ETB exfoliative toxins A and B, that S. epidermidis can prevent S. aureus biofilm formation in
PSM phenol-soluble modulins the nasal cavities as well as produce its own AMPs to prevent
65 Page 6 of 10 Curr Allergy Asthma Rep (2015) 15:65

other pathogens from colonizing the skin [37, 82]. Therefore, with antibiotics could affect the beneficial microbes such as
increased S. epidermidis colonization in AD skin may represent S. epidermidis on the skin as well.
a way for the skin to naturally prevent increased S. aureus col- Bleach baths in combination with antibiotics can also de-
onization in AD. However, the increased abundance of crease the severity of AD [90, 91]. In 2013, a study in
S. epidermidis in AD may not correlate with the protective and Malaysia revealed that dilute bleach baths performed twice a
beneficial effects discussed above since these effects are strain- week for 2 months decreased both AD severity and S. aureus
dependent, and it is not clear if these beneficial strains are active colonization [92]. Although bleach baths have potential to
in AD. The use of metagenomics and species-specific bacterial successfully treat AD through clearance of S. aureus, more
sequencing should provide useful insight into the role of studies need to be conducted to confirm the current results
S. epidermidis on AD skin. with or without antibiotic activity. In particular, it is unlikely
Recently, it has been reported that Corynebacterium bovis that the highly dilute bleach bath solution is directly antimi-
colonization is increased in an ADAM17 knockout model of crobial for the skin surface. Beneficial actions of the bleach
AD in mice [83]. Increased Corynebacterium bovis coloniza- bath solution may relate to other hydrating or immunological
tion led to a robust Th2 response in the skin, a key character- effects [93]. In the few studies where S. aureus has decreased
istic of acute AD. 16S rRNA DNA sequencing has only re- with bleach bath treatments, it is important to understand if
vealed increased Corynebacterium in HIES though, and not in this effect occurred as a consequence of improved function of
AD skin. Thus, this might serve as a way that dysbiosis of the the skin rather than the action of the bath directly on the bac-
skin microbiome can increase HIES severity by altering the teria. It is also important to understand how bleach baths affect
immune response versus that seen in AD. the total skin microbiome. Overall, it is clear that the current
treatment of S. aureus in AD patients represents at best a
limited solution for some patients suffering from frank
super-infection and other more targeted therapies are needed
Therapeutic Strategies to Combat S. aureus on AD to correct the dysbiosis seen on AD skin.
Skin

Since S. aureus colonization has been linked to increased AD Conclusions

severity, multiple therapeutic strategies have attempted to tar-
get specifically S. aureus colonization. The most common We have known for over 30 years that the community of
used treatments for S. aureus on AD skin include both bacteria changes on the skin during AD, and recent DNA
topical/oral antibiotics and mild bleach baths. Studies con- sequencing approaches have further described in greater detail
ducted so far, however, have produced conflicting results. the magnitude of dysbiosis seen in this disease. S. aureus col-
Many topical/oral antibiotic treatments can kill S. aureus in onization has been studied in greatest depth and appears to be
the short term on AD patients including muripocin, a significant factor that exacerbates the disorder. However,
flucloxacillin, retapamulin, and cephalexin [84–86]. other species such as S. epidermidis also show increased col-
However, few of these patients see decreased AD severity. onization and may modulate AD pathogenesis. Today, it ap-
S. aureus colonization also typically relapses in AD patients pears that understanding how the full community of different
after 4 to 8 weeks of antibiotic treatment [87]. A study in 2002 bacteria interact and communicate with each other is neces-
showed that a combination therapy of multiple antibiotics in- sary to best treat this disease.
cluding muripocin, chlohexidine, and cephalexin improved Since S. aureus colonization increases the most during AD
clinical AD scores in 9 out of 10 patients with S. aureus col- flares and is correlated with AD severity, much work has fo-
onization [88], but this is not the typical clinical experience. cused on the mechanisms of S. aureus virulence on the skin. As
Corticosteriods, antiinflammatory reagents used as a staple for discussed earlier, S. aureus produces a series of virulence factors
treatment of AD, have also been used in combination with that can directly disrupt the skin barrier and potentially act as the
antibiotics to improve AD severity [41]. This suggests that reason for S. aureus-mediated increased AD severity. It is im-
perhaps removal of S. aureus alone is not sufficient for AD portant, however, to consider mechanisms that still have yet to
treatment but antiinflammatory reagents are also necessary. be studied. One possible future direction is to study how
Furthermore, there also are other important issues that deter S. aureus colonization can lead to changes in gene expression
using antibiotics as a treatment method for AD. The recent rise by the host. If S. aureus virulence factors were to target the
of methicillin-resistant S. aureus (MRSA) strains and their expression of skin barrier proteins (e.g., filaggrin, keratins, and
ability to colonize AD skin is a clear demonstration of one skin-specific proteases and inhibitors) that are vital for maintain-
major issue [89]. Antibiotic therapy for AD patients is also ing an intact skin barrier against pathogens, then AD severity
relatively non-specific, targeting mostly all Gram-positive would likely be increased. Another interesting event to study is
bacteria. Thus, treating S. aureus colonization on AD skin that of increased bacterial penetration into the skin. It is now
Curr Allergy Asthma Rep (2015) 15:65 Page 7 of 10 65

known that the skin microbiome extends into the epidermis, 2. Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB, Manuel JC.
The burden of atopic dermatitis: impact on the patient, family, and
dermis, and subcutaneous layers. Thus, an altered skin barrier
society. Pediatr Dermatol. 2005;22:8.
in AD can result in increased S. aureus penetration into deeper 3. Beikert FC, Langenbruch AK, Radtke MA, Kornek T, Purwins S,
layers of skin. Perhaps this could lead to increased disease se- Augustin M. Willingness to pay and quality of life in patients with
verity as well by mechanisms yet to be investigated. Recently, it atopic dermatitis. Arch Dermatol Res. 2014;306:279–86.
4. Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its
has been published that skin adipocytes respond as immune cells
impact on the family and financial cost. Arch Dis Child. 1997;76:4.
to S. aureus infection [94]. Perhaps S. aureus colonization and 5. Kapoor R, Menon C, Hoffstad O, Bilker W, Leclerc P, Margolis DJ.
penetration can target adipocytes to mount an immune response The prevalence of atopic triad in children with physician-confirmed
and increase AD severity. Thus, there remain various hypotheses atopic dermatitis. J Am Acad Dermatol. 2008;58:68–73.
6. Ring J, Kramer U, Schafer T, Behrendt H. Why are allergies in-
to be studied in terms of how S. aureus or other microbes may
creasing? Curr Opin Immunol. 2001;13:8.
modulate AD severity. 7. Williams H, Stewart A, von Mutius E, Cookson W, Anderson HR,
Current methods of treatment for AD do not address how International Study of, A., Allergies in Childhood Phase, O., and
resident microbes on the skin such as S. epidermidis are altered. Three Study, G. Is eczema really on the increase worldwide? J
Allergy Clin Immunol. 2008;121:947–54. e915.
Some novel small-scale studies have attempted to remove
8. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M.
S. aureus colonization to improve the clinical symptoms of Association of SPINK5 gene polymorphisms with atopic dermatitis
AD. Such approaches have even included adding antimicrobial in the Japanese population. Br J Dermatol. 2003;148:665.
factors to clothing [95, 96]. These methods, however, face sim- 9. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H,
ilar problems as previous studies in that they lack an approach to Lee SP, et al. Common loss-of-function variants of the epidermal
barrier protein filaggrin are a major predisposing factor for atopic
selectively protect the normal microbiome. Some of the most dermatitis. Nat Genet. 2006;38:441–6.
promising therapeutic strategies to combat S. aureus-mediated 10. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-
AD severity may be linked to methods already being used in the Lacava A, et al. Loss-of-function variations within the filaggrin
gut. Fecal microbiota therapy (FMT) is a method for replacing a gene predispose for atopic dermatitis with allergic sensitizations. J
Allergy Clin Immunol. 2006;118:214–9.
diseased gut microbiome in a state of dysbiosis with bacteria 11. Zhao LP, Di Z, Zhang L, Wang L, Ma L, Lv Y, et al. Association of
from normal patients. FMT has been shown to successfully SPINK5 gene polymorphisms with atopic dermatitis in Northeast
revert gut microbial dysbiosis in patients with recurrent China. J Eur Acad Dermatol Venereol. 2012;26:572–7.
Clostridium difficile infection (CDI) as well as provided prom- 12. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN,
Cheadle C, et al. Tight junction defects in patients with atopic der-
ising results for other gastrointestinal diseases [97]. Similarly, matitis. J Allergy Clin Immunol. 2011;127(773–786):e771–7.
the use of microbial skin transplant therapy could be useful in 13. Kawashima T, Noguchi E, Arinami T, Yamakawa-Kobayashi K,
treating AD. It is worth exploring if the skin microbiome of a Nakagawa H, Otsuka F, et al. Linkage and association of an inter-
healthy donor can be transplanted onto a patient’s skin with AD leukin 4 gene polymorphism with atopic dermatitis in Japanese
families. J Med Genet. 1998;35:502–4.
and evaluate if this can repair the skin microbiome. Overall, the 14. Tsunemi Y, Saeki H, Nakamura K, Sekiya T, Hirai K, Kakinuma T,
most promising future therapeutic strategies will seek to prevent et al. Interleukin-13 gene polymorphism G4257A is associated with
microbial dysbiosis. atopic dermatitis in Japanese patients. J Dermatol Sci. 2002;30:
100–7.
15. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson
Compliance with Ethics Guidelines HA. Prevelance of IgE-mediated food allergy among children with
atopic dermatitis. Pediatrics. 1998;101:6.
16. Fuiano N, Fusilli S, Incorvaia C. House dust mite-related allergic
diseases: role of skin prick test, atopy patch test, and RAST in the
Conflict of Interest The authors declare no conflicts of interest. diagnosis of different manifestations of allergy. Eur J Pediatr.
2010;169:819–24.
Human and Animal Rights and Informed Consent This article does 17. Hong J, Buddenkotte J, Berger TG, Steinhoff M. Management of
not contain any studies with human or animal subjects performed by any itch in atopic dermatitis. Semin Cutan Med Surg. 2011;30:71–86.
of the authors. 18. Leung DYM, Bieber T. Atopic dermatitis. Lancet. 2003;361:151–
60.
19. Oyoshi MK, He R, Kumar L, Yoon J, Geha RS. Chapter 3 cellular
and molecular mechanisms in atopic. Dermatitis. 2009;102:135–
References 226.
20. Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC,
et al. Topographical and temporal diversity of the human skin
Papers of particular interest, published recently, have been microbiome. Science. 2009;324:1190–2.
highlighted as: 21. Grice EA, Segre JA. The skin microbiome. Nature reviews.
Microbiology. 2011;9:244–53.
• Of importance 22. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in
•• Of very importance the lesions of atopic dermatitis. Br J Dermatol. 1974;90:525–30.
23.• Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA,
1. Beiber T. Mechanisms of disease atopic dermatitis. NEJM. et al. Temporal shifts in the skin microbiome associated with disease
2008;358:12. flares and treatment in children with atopic dermatitis. Genome Res.
65 Page 8 of 10 Curr Allergy Asthma Rep (2015) 15:65

2012;22:850–9. First study to use 16S rRNA sequencing to an- 41. Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, et al. Skin colo-
alyze the skin microbiome of normal versus atopic dermatitis nization by Staphylococcus aureus in patients with eczema and
patients. atopic dermatitis and relevant combined topical therapy: a double-
24. Fitz-Gibbon S, Tomida S, Chiu BH, Nguyen L, Du C, Liu M, et al. blind multicentre randomized controlled trial. Br J Dermatol.
Propionibacterium acnes strain populations in the human skin 2006;155:680–7.
microbiome associated with acne. J Invest Dermatol. 2013;133: 42. Pascolini C, Sinagra J, Pecetta S, Bordignon V, De Santis A, Cilli L,
2152–60. et al. Molecular and immunological characterization of
25. Tomida S, Nguyen L, Chiu BH, Liu J, Sodergren E, Weinstock GM, Staphylococcus aureus in pediatric atopic dermatitis: implications
et al. Pan-genome and comparative genome analyses of for prophylaxis and clinical management. Clin Dev Immunol.
propionibacterium acnes reveal its genomic diversity in the healthy 2011;2011:718708.
and diseased human skin microbiome. mBio. 2013;4:e00003–13. 43. Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine
26. Wang Y, Kuo S, Shu M, Yu J, Huang S, Dai A, et al. AD, et al. Mutations in SPINK5, encoding a serine protease inhib-
Staphylococcus epidermidis in the human skin microbiome medi- itor, cause Netherton syndrome. Nat Genet. 2000;25:2.
ates fermentation to inhibit the growth of Propionibacterium acnes: 44. Hannula-Jouppi K, Laasanen SL, Heikkila H, Tuomiranta M,
implications of probiotics in acne vulgaris. Appl Microbiol Tuomi ML, Hilvo S, et al. IgE allergen component-based profiling
Biotechnol. 2014;98:411–24. and atopic manifestations in patients with Netherton syndrome. J
27. Kloos WE, Musselwhite MS. Distribution and persistence of Allergy Clin Immunol. 2014;134:985–8.
Staphylococcus and Micrococcus species and other aerobic bacteria 45. Renner ED, Hartl D, Rylaarsdam S, Young ML, Monaco-Shawver
on human skin. Appl Microbiol. 1975;30:381–5. L, Kleiner G, et al. Comel-Netherton syndrome defined as primary
28.•• Oh J, Byrd AL, Deming C, Conlan S, Program NCS, Kong HH, immunodeficiency. J Allergy Clin Immunol. 2009;124:536–43.
et al. Biogeography and individuality shape function in the human 46.• Oh J, Freeman AF, Program NCS, Park M, Sokolic R, Candotti F,
skin metagenome. Nature. 2014;514:59–64. Major study involv- et al. The altered landscape of the human skin microbiome in pa-
ing the use of metagenomics to define the skin microbiome. tients with primary immunodeficiencies. Genome Res. 2013;23:
29. Belkaid Y, Segre JA. Dialogue between skin microbiota and immu- 2103–14. Second major study analyzing how the skin
nity. Science. 2014;346:7. microbiome composition is effected during disease states by
30. Capone KA, Dowd SE, Stamatas GN, Nikolovski J. Diversity of 16S rRNA sequencing.
the human skin microbiome early in life. J Invest Dermatol. 47. Knor T, Meholjic-Fetahovic A, Mehmedagic A. Stratum corneum
2011;131:2026–32. hydration and skin surface pH in patients with atopic dermatitis.
31. Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, Acta Dermatovenerol Croat ADC. 2011;19:242–7.
et al. Commensal bacteria regulate Toll-like receptor 3-dependent 48. Rippke F, Schreiner V, Doering T, Maibach HI. Stratum corneum
inflammation after skin injury. Nat Med. 2009;15:1377–82. pH in atopic dermatitis: impact on skin barrier function and coloni-
32.• Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, zation with Staphylococcus Aureus. Am J Clin Dermatol. 2004;5:
Kastenmuller W, et al. Compartmentalized control of skin immu- 217–23.
nity by resident commensals. Science. 2012;337:1115–9. 49. Bhanu S, Francois PP, NuBe O, Foti M, Hartford OM, Vaudaux P,
Demonstrated direct communication between skin commensal et al. Fibronectin-binding protein acts as Staphylococcus aureus
bacteria and host immune response in murine models. invasin via fibronectin bridging to integrin α5β1. Cell Microbiol.
33. Lai Y, Cogen AL, Radek KA, Park HJ, Macleod DT, Leichtle A, 1999;1:17.
et al. Activation of TLR2 by a small molecule produced by 50. Cho SH, Strickland I, Boguniewicz M, Leung DY. Fibronectin and
Staphylococcus epidermidis increases antimicrobial defense against fibrinogen contribute to the enhanced binding of Staphylococcus
bacterial skin infections. J Invest Dermatol. 2010;130:2211–21. aureus to atopic skin. J Allergy Clin Immunol. 2001;108:269–74.
34. Wang Z, MacLeod DT, Di Nardo A. Commensal bacteria 51. Dean SN, Bishop BM, van Hoek ML. Natural and synthetic
lipoteichoic acid increases skin mast cell antimicrobial activity cathelicidin peptides with anti-microbial and anti-biofilm activity
against vaccinia viruses. J Immunol. 2012;189:1551–8. against Staphylococcus aureus. BMC Microbiol. 2011;11:114.
35. Yuki T, Yoshida H, Akazawa Y, Komiya A, Sugiyama Y, Inoue S. 52. Harder J, Bartels J, Christophers E, Schroder JM. Isolation and
Activation of TLR2 enhances tight junction barrier in epidermal characterization of human beta -defensin-3, a novel human induc-
keratinocytes. J Immunol. 2011;187:3230–7. ible peptide antibiotic. J Biol Chem. 2001;276:5707–13.
36.•• Nakatsuji T, Chiang HI, Jiang SB, Nagarajan H, Zengler K, Gallo 53. Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T,
RL. The microbiome extends to subepidermal compartments of et al. Endogenous antimicrobial peptides and skin infections in
normal skin. Nat Commun. 2013;4:1431. Revolutionary study atopic dermatitis. N Engl J Med. 2002;347:10.
indentifying that microbial communities can penetrate and re- 54. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF,
side in deeper layers of the skin. et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis,
37. Otto M. Staphylococcus colonization of the skin and antimicrobial skin prevents induction of innate immune response genes. J
peptides. Expert Rev Dermatol. 2010;5:183–95. Immunol. 2003;171:3262–9.
38. Sugimoto S, Iwamoto T, Takada K, Okuda K, Tajima A, Iwase T, 55. Howell MD, Novak N, Bieber T, Pastore S, Girolomoni G,
et al. Staphylococcus epidermidis Esp degrades specific proteins Boguniewicz M, et al. Interleukin-10 downregulates anti-
associated with Staphylococcus aureus biofilm formation and microbial peptide expression in atopic dermatitis. J Invest
host-pathogen interaction. J Bacteriol. 2013;195:1645–55. Dermatol. 2005;125:738–45.
39. Cogen AL, Yamasaki K, Sanchez KM, Dorschner RA, Lai Y, 56. McFadden JP, Noble WC, Camp RD. Superantigenic exotoxin-
MacLeod DT, et al. Selective antimicrobial action is provided by secreting potential of staphylococci isolated from atopic eczema-
phenol-soluble modulins derived from Staphylococcus tous skin. Br J Dermatol. 1993;128:631–2.
epidermidis, a normal resident of the skin. J Invest Dermatol. 57. Zollner TM, Wichelhaus TA, Hartung A, Von Mallinckrodt C,
2010;130:192–200. Wagner TO, Brade V, et al. Colonization with superantigen-
40. Shu M, Wang Y, Yu J, Kuo S, Coda A, Jiang Y, et al. Fermentation producing Staphylococcus aureus is associated with increased se-
of Propionibacterium acnes, a commensal bacterium in the human verity of atopic dermatitis. Clin Exp Allergy. 2000;30:7.
skin microbiome, as skin probiotics against methicillin-resistant 58. Johnson WM, Tyler SD, Ewan EP, Ashton FE, Pollard DR, Rozee
Staphylococcus aureus. PLoS One. 2013;8, e55380. KR. Detection of genes for enterotoxins, exfoliative toxins, and
Curr Allergy Asthma Rep (2015) 15:65 Page 9 of 10 65

toxic shock syndrome toxin 1 in Staphylococcus aureus by the 77. Sakabe J, Yamamoto M, Hirakawa S, Motoyama A, Ohta I, Tatsuno
polymerase chain reaction. J Clin Microbiol. 1991;29:426–30. K, et al. Kallikrein-related peptidase 5 functions in proteolytic pro-
59. Bunikowski R, Mielke M, Skarabis H, Herz U, Bergmann RL, cessing of profilaggrin in cultured human keratinocytes. J Biol
Wahn U, et al. Prevelance and role of serum IgE antibodies to the Chem. 2013;288:17179–89.
Staphylococcus aureus-derived superantigens SEA and SEB in 78. Stefansson K, Brattsand M, Roosterman D, Kempkes C, Bocheva
children with atopic dermatitis. J Allergy Clin Immunol. G, Steinhoff M, et al. Activation of proteinase-activated receptor-2
1999;103:6. by human kallikrein-related peptidases. J Invest Dermatol.
60. Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K, 2008;128:18–25.
Janicke RU. alpha-Toxin is a mediator of Staphylococcus aureus- 79. Yamasaki K, Schauber J, Coda A, Lin H, Dorschner RA, Schechter
induced cell death and activates caspases via the intrinsic death NM, et al. Kallikrein-mediated proteolysis regulates the antimicro-
pathway independently of death receptor signaling. J Cell Biol. bial effects of cathelicidins in skin. FASEB J Off Publ Fed Am Soc
2001;155:637–48. Exp Biol. 2006;20:2068–80.
61. Walev I, Martin E, Jonas D, Mohamadzadeh M, Muller-Klieser W, 80. Cogen AL, Yamasaki K, Sanchez KM, Dorschner RA, Lai Y,
Kunz L, et al. Staphylococcal alpha-toxin kills human keratinocytes Macleod DT, et al. Selective antimicrobial action is prodived by
by permeabilizing the plasma membrane for monovalent ions. phenol-soluble modulins derived from staphylococcus epidermidis,
Infect Immun. 1993;61:8. a normal resident of the skin. J Investig Dermatol. 2010;130:9.
62. Brauweiler AM, Goleva E, Leung DY. Th2 cytokines increase 81. Wanke I, Steffen H, Christ C, Krismer B, Gotz F, Peschel A, et al.
Staphylococcus aureus alpha toxin-induced keratinocyte death Skin commensals amplify the innate immune response to pathogens
through the signal transducer and activator of transcription 6 by activation of distinct signaling pathways. J Invest Dermatol.
(STAT6). J Invest Dermatol. 2014;134:2114–21. 2011;131:382–90.
63. Hong SW, Choi EB, Min TK, Kim JH, Kim MH, Jeon SG, et al. An 82. Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K, et al.
important role of alpha-hemolysin in extracellular vesicles on the Staphylococcus epidermidis Esp inhibits Staphylococcus aureus
development of atopic dermatitis induced by Staphylococcus aure- biofilm formation and nasal colonization. Nature. 2010;465:346–9.
us. PLoS One. 2014;9, e100499. 83. Kobayashi T, Glatz M, Horiuchi K, Kawasaki H, Akiyama H,
64. Ezepchuk YV, Leung DY, Middleton MH, Bina P, Reiser R, Norris Kaplan DH, et al. Dysbiosis and Staphyloccus aureus colonization
DA. Staphylococcal toxins and protein A differentially induce cy- drives inflammation in atopic dermatitis. Immunity. 2015;42:756–
totoxicity and release of tumor necrosis factor-alpha from human 66.
keratinocytes. J Invest Dermatol. 1996;107:603–9. 84. Ewing CI, Ashcroft C, Gibbs AC, Jones GA, Connor PJ, David TJ.
65. Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Munoz-Planillo Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol.
R, Hasegawa M, et al. Staphylococcus delta-toxin induces allergic 1998;138:1022–9.
skin disease by activating mast cells. Nature. 2013;503:397–401. 85. Lever R, Hadley K, Downey D, Mackie R. Staphylococcal coloni-
66. Hanakawa Y, Selwood T, Woo D, Lin C, Schechter NM, Stanley zation in atopic dermatitis and the effect of topical mupirocin ther-
JR. Calcium-dependent conformation of desmoglein 1 is required apy. Br J Dermatol. 1988;119:189–98.
for its cleavage by exfoliative toxin. J Invest Dermatol. 2003;121: 86. Parish LC, Jorizzo JL, Breton JJ, Hirman JW, Scangarella NE,
383–9. Shawar RM, et al. Topical retapamulin ointment (1%, wt/wt) twice
67. Hirasawa Y, Takai T, Nakamura T, Mitsuishi K, Gunawan H, Suto daily for 5 days versus oral cephalexin twice daily for 10 days in the
H, et al. Staphylococcus aureus extracellular protease causes epi- treatment of secondarily infected dermatitis: results of a randomized
dermal barrier dysfunction. J Invest Dermatol. 2010;130:614–7. controlled trial. J Am Acad Dermatol. 2006;55:1003–13.
68. Ladhani S. Understanding the mechanism of action of the exfolia- 87. Gilani SJ, Gonzalez M, Hussain I, Finlay AY, Patel GK.
tive toxins ofStaphylococcus aureus. FEMS Immunol Med Staphylococcus aureus re-colonization in atopic dermatitis: beyond
Microbiol. 2003;39:181–9. the skin. Clin Exp Dermatol. 2005;30:10–3.
69. Syed AK, Reed TJ, Clark KL, Boles BR, Kahlenberg JM. 88. Breuer K, Haussler S, Kapp A, Werfel T. Clinical and Laboratory
Staphylococcus aureus phenol soluble modulins stimulate the re- Investigations Staphylococcus aureus: colonizing features and in-
lease of pro-inflammatory cytokines from keratinocytes and are fluence of an antibacterial treatment in adults with atopic dermatitis.
required for induction of skin inflammation. Infect Immun. 2015. Br J Dermatol. 2002;147:7.
70. Proft T, Fraser JD. Bacterial superantigens. Clin Exp Immunol. 89. Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin
2003;133:8. RE, VBoyle-Vavra S, et al. Community-acquired methicilin-resis-
71. Hirose A, Ikejima T, Gill DM. Established macrophagelike cell tant staphylococcus aureus in children with no identified
lines synthesize interleukin-1 in response to toxic shock syndrome presdisposing risk. JAMA. 1998;279:6.
toxin. Infect Immun. 1985;50:6. 90. Barnes TM, Greive KA. Use of bleach baths for the treatment of
72. Kim KH, Han JH, CHung JH, Cho KH, Eun HC. Role of staphy- infected atopic eczema. Aust J Dermatol. 2013;54:251–8.
lococcal superantigen in atopic dermatitis: influence on 91. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS.
keratinocytes. J Korean Med Sci. 2006;21:9. Treatment of Staphylococcus aureus colonization in atopic derma-
73. Bhardwaj N, Friedman SM, Cole BC, Nisanian AJ. Dendritic cells titis decreases disease severity. Pediatrics. 2009;123:e808–14.
are potent antigen-presenting cells for microbial superantigens. J 92. Wong SM, Ng TG, Baba R. Efficacy and safety of sodium hypo-
Exp Med. 1992;175:7. chlorite (bleach) baths in patients with moderate to severe atopic
74. Komatsu N, Saijoh K, Kuk C, Liu AC, Khan S, Shirasaki F, et al. dermatitis in Malaysia. J Dermatol. 2013;40:874–80.
Human tissue kallikrein expression in the stratum corneum and 93. Leung TH, Zhang LF, Wang J, Ning S, Knox SJ, Kim SK. Topical
serum of atopic dermatitis patients. Exp Dermatol. 2007;16:513–9. hypochlorite ameliorates NF-kappaB-mediated skin diseases in
75. Voegeli R, Rawlings AV, Breternitz M, Doppler S, Schreier T, Fluhr mice. J Clin Invest. 2013;123:5361–70.
JW. Increased stratum corneum serine protease activity in acute 94. Zhang LJ, Guerrero-Juarez CF, Hata T, Bapat SP, Ramos R, Plikus
eczematous atopic skin. Br J Dermatol. 2009;161:70–7. MV, et al. Innate immunity. Dermal adipocytes protect against in-
76. Borgono CA, Michael IP, Komatsu N, Jayakumar A, Kapadia R, vasive Staphylococcus aureus skin infection. Science. 2015;347:
Clayman GL, et al. A potential role for multiple tissue kallikrein 67–71.
serine proteases in epidermal desquamation. J Biol Chem. 95. Koller DY, Halmerbauer G, Bock A, Engstler G. Action of a silk
2007;282:3640–52. fabric treated with AEGIS in children with atopic dermatitis: a 3-
65 Page 10 of 10 Curr Allergy Asthma Rep (2015) 15:65

month trial. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr antimicrobial to a special silk fabric in the treatment of atopic der-
Allergy Immunol. 2007;18:335–8. matitis. Dermatology. 2008;217:191–5.
96. Stinco G, Piccirillo F, Valent F. A randomized double-blind study to 97. Aroniadis OC, Brandt LJ. Intestinal microbiota and the efficacy of
investigate the clinical efficacy of adding a non-migrating fecal microbiota transplantation in gastrointestinal disease.
Gastroenterol Hepatol. 2014;10:230–7.