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Microbiome in Atopic Dermatitis: Clinical, Cosmetic and Investigational Dermatology Dove

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Microbiome in atopic dermatitis


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This article was published in the following Dove Press journal:


Clinical, Cosmetic and Investigational Dermatology
22 February 2017
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Uwe Wollina Abstract: Atopic dermatitis (AD) is a common chronic inflammatory skin disease affecting
Department of Dermatology and
~10–20% of the general population. AD is characterized by disturbances in epidermal barrier
Allergology, Academic Teaching function and hyperactive immune response. Recently, changes in the skin and intestinal micro-
Hospital Dresden-Friedrichstadt, biome have been analyzed in more detail. The available data suggest a link between disturbed
Dresden, Germany
For personal use only.

skin microbiome and course of the disease. Flares of the disease are associated with an expan-
sion of Staphylococcus aureus on lesional skin and a substantial loss of biodiversity in skin
microbiome. Staphylococci exoproteins and superantigens evoke inflammatory reactions in the
host. Skin microbiome includes superficial stratum corneum that is affected by environmental
factors such as exposure to germs and cleansing. Available evidence argues for a link between
epidermal barrier impairment and disturbances in skin microbiome in AD. In contrast to skin
microbiome, intestinal microbiome seems to become stabilized after infancy. There is also a
significant heritable component for intestinal microbiome. The microbial taxa, relative percent-
ages and quantities vary remarkably between the different parts of the intestinal tract. Early
intestinal microbial colonization may be a critical step for prevention of further development
of AD. Skin barrier-aimed topical treatments help to develop a neo-microbiome from deeper
compartments. Probiotics, prebiotics and synbiotics have been investigated for the treatment
of AD, but further investigations are needed. Targeted treatment options to normalize skin and
intestinal microbiome in AD are under investigation.
Keywords: atopic dermatitis, microbiome, staphylococci, skin, intestine, antimicrobial peptides

Introduction
On skin and mucous membranes (intestine, airways), microbial genomes outnumber
those of the human host by a factor of 100. The microbiome (microbiota), i.e., the
bacteria, viruses, archaea and fungi, living on and within the human body contributes to
health and disease. The microbiome is individual and changes with age. The crosstalk
between the microbiome and the human host is realized by secretion of metabolites
from microbes and the human immune system scanning the microbiome for informa-
tion about metabolic state and colonization. Thereby, bacteria-derived molecules such
Correspondence: Uwe Wollina
as short-chain fatty acids may influence human epigenomic pathways.1,2 This article
Department of Dermatology and reviews the role of the human microbiome in atopic dermatitis (AD).
Allergology, Academic Teaching Hospital
Dresden-Friedrichstadt, Friedrichstrasse
41, 01067 Dresden, Germany AD
Tel +49 451 480 1685
Fax +49 351 480 1219
AD is a common chronic inflammatory skin disease affecting ~20% of children.
Email [email protected] In 95% of cases, initial manifestation of AD occurs within the first 5 years of life.

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Approximately a quarter of these children continue to have Table 1 Normal human skin microbiomea
AD during adulthood.3 Skin type Normal microbiome
In the pre-school age, 30% of children with AD suffer (most abundant bacterial groups)

from food allergies (eggs, cow’s milk, peanuts). Those with Sebaceous skin Propionibacteria spp., Corynebacteria spp.,
other Actinobacteriales spp., Staphylococci spp.
moderate to severe AD have a 50% risk of developing asthma
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Moist skin Corynebacteria spp., Staphylococci spp.,


and 75% risk of developing hay fever.4,5 b-Proteobacteria, g-Proteobacteria
AD diagnosis is made by almost exclusively clinical Dry skin b-Proteobacteria, Corynebacteria spp.,
criteria.6–8 Genetic and epigenetic factors modulate AD. Envi- Flavobacteriales
Note: aAccording to Costello et al.32
ronmental factors such as (perinatal) exposure to indoor and
outdoor allergens and pollutants, nutrition and microbiome
are considered as influential for the manifestation and sever- Among the Gram-positive Staphylococcus species,
ity of AD. Environmental factors regulate gene expression Staphylococcus epidermidis is the dominant type in healthy
through microRNA (miR) and genomic DNA modification. skin with the ability to inhibit the growth of Staphylococcus
Among genetic factors, filaggrin (FLG) null gene mutations aureus.17 In children, colonization of skin by S. epidermidis
are the most significant risk factor for AD. Furthermore, and S. cohnii during the first year of life has a protective
genes in T helper lymphocyte type 2 (Th2) signaling path- effect on the development of AD.18
ways represent a second important genetic risk factor for Disturbances in cutaneous microbiome represent an inde-
AD, although predominant Th2 response is limited to the pendent risk factor for the development of AD. In ~90% of
For personal use only.

flare-ups. Genome-wide association studies have identified patients suffering from AD, the skin becomes colonized by
>30 risk loci for AD for genes involved in epidermal bar- S. aureus of which 50% are toxin producing. These toxins
rier function and immune response. Gene profiling assays can contribute to inflammation and skin barrier dysfunction
revealed overexpression of Th2, Th17 and miR-155.9,10 via activating the host inflammasomes.19
Epigenetic studies in AD have demonstrated significant Using whole metagenome profiling, distinct signatures
changes in the methylation status of skin lesions, e.g., enriched for Streptococcus and Gemella but depleted for
hypomethylation of gene promoters and alterations in miR Dermacoccus were identified in subjects prone to AD. This
profile.11–13 Genetic and epigenetic studies suggest that two was accompanied by changes in the innate and Th1 adaptive
major pathways are involved in AD, i.e., innate and adaptive immune responses to S. epidermidis and S. aureus.20
immune systems and epidermal barrier function.9–13 In lesional AD, however, the proportions of both S. aureus
Levels of the antimicrobial metabolite sphingosine and and S. epidermidis increase. Since these species produce
antimicrobial peptides cathelicidin and defensins B2 and antibacterial compounds such as antimicrobial peptides and
B3 are reduced in the skin of AD subjects.14 These factors bacteriocins, a relative decrease in other species, including Pro-
contribute to the increased risk of cutaneous infections in AD. pionibacterium, Corynebacterium and Streptococcus, occurs
during AD flares. After successful topical AD treatment, there
Cutaneous microbiome and AD is an increasing biodiversity of cutaneous microbiome that
Resident skin bacteria are influenced by topological and arises from taxa already present in cutaneous microbiome.21,22
endogenous factors of skin and can be modulated by exter- In AD, S. aureus is capable of inducing flares of the dis-
nal factors such as clothing, hygiene, topical treatments and ease. There is an increased colonization of lesional skin in AD
skin care products (Table 1). There are gender differences in patients. Membrane vesicles released from these bacteria can
skin microbiome as well. Skin microbiomes differ between penetrate the epidermis and induce a massive infiltration of
children and adults (described in the following). Bacteria inflammatory cells with a mixed Th1/Th2 immune response.23
are not uniformly distributed in skin. There is a superficial S. aureus itself is capable of penetrating the epidermis in case
and a deeper compartment in the human stratum corneum. of increased cathelicidin expression and increased expression
After injury, a neo-microbiome is produced from the deeper of interleukin (IL)-4, IL-13, IL-22, and other cytokines.24 S.
compartment, which can be regarded as the indigenous aureus can directly impair skin barrier function by stimulating
microbiome. Furthermore, bacteria are consistently detect- the production of keratinocyte endogenous serine protease.
able also in deeper skin layers such as the dermis and the This diminishes FLG and other epidermal proteins and
subcutaneous adipose tissue. A balanced resident skin flora contributes to disturbed lipid lamellar function.25 S. aureus-
is a protective measure.15,16 associated, microbial-associated molecular patterns bind to

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Toll-like receptor 2 (TLR2) heterodimers and induce long- distinct in the youngest patients, leading to a decreased intes-
lasting and self-perpetuating T-cell inflammation.26 tinal concentration of butyrate and propionate.41
On the other hand, AD is a risk factor for colonization Another study used microarray analysis of intestinal
of nasal mucous membranes and the skin by methicillin- microbiome in infants with and without AD at 6 and
resistant S. aureus (MRSA).27 MRSA prevalence on lesional 18 months of age. Although the authors did not find signifi-
Clinical, Cosmetic and Investigational Dermatology downloaded from https://www.dovepress.com/ by 193.93.194.201 on 02-Aug-2018

skin has been reported from 13 to 24%.28,29 This can cause cant differences at 6 months, healthy children at 18 months
recurrent MRSA infections in patients with AD.30 harbored threefold greater number of Bacteroidetes. Infants
Staphylococcus epidermidis secretome, on the other hand, with AD showed increased numbers of Clostridiae.42
promotes the activity of regulatory T-cells (Treg), suppressing Intestinal microbiome is dynamic during the first 3 years of
the proliferation of CD4-positive T cells. Furthermore, S. epi- life before stabilizing.43 In contrast to skin microbiome, intesti-
dermidis induces the release of IL-10 by skin dendritic cells.31 nal microbiome demonstrates heritability as demonstrated by a
It becomes obvious that changes in skin microbiome are recent metagenomics shotgun sequencing study in adult twins.44
most critical during early life time, when skin barrier function
and immune system are rather immature. Skin microbiome is Microbiome in the treatment of AD
dynamic since it changes with time. Operational taxonomic Therapies targeting skin microbiome
unit (OTC) stability of skin microbiome has been found less There is much evidence suggesting a link between impairment
abundant and therefore more instable than that of intestinal of epidermal barrier function and disturbed skin microbiome.15,22
microbiome, probably due to cleaning and other extrinsic Antibiotics and antiseptics may decrease skin coloniza-
For personal use only.

factors.32,33 tion by S. aureus but fail to improve the microbiome. On


the other hand, topical treatments with corticosteroids,
Intestinal microbiome and AD calcineurin inhibitors or even moisturizers and emollients
The fetal intestine becomes colonized before delivery by are capable to restore barrier function and normalize skin
bacterial transmission from the mother through the placental microbiome.22,45,46
barrier. The mode of delivery has further impact on intesti- To restore cutaneous microbiome in AD, transplantation
nal microbiome. It has been demonstrated that delivery by of microbiota from healthy volunteers might become an
cesarean section decreases the colonization by Bacteroides option. Skin culturable Gram-negative microbiome differs
but increases the number of Clostridiae.34 between AD patients and healthy controls. In a mouse model
It has been assumed that small intestine permeability of AD, culturable Gram-negative bacteria such as Roseomo-
may be increased in AD patients.35,36 Intestinal permeability nas mucosa from healthy volunteers reduced the growth
is one factor in acquired food allergy.37 of S. aureus, enhanced skin barrier function and activated
Disturbances in intestinal microbiome could be a risk innate immune function.47 In the future, such a treatment
factor of further AD development. Intrapartum antibiosis for may become available for human patients.
>24 h increased the relative risk for AD infants at the age of Textiles serve as our second skin. Functional textiles may
2 years by 1.99.38 improve skin quality. Chitosan-coated long-sleeve pyjama tops
Staphylococcus aureus was isolated from rectal swabs and pants worn overnight for 8 weeks improved the severity
from infants aged 0 to 2 months. S. aureus strains of infants scoring of atopic dermatitis index from baseline in 43.8% of
who developed AD were different from the strains of infants patients whereas only 16.5% improved with the uncoated pyja-
who were not affected at the age of 18 months. A combination mas. A significant decrease in coagulase-negative Staphylococci
of expression of superantigen SEIM and adhesin elastin- was observed on the skin with the chitosan-coated product.48
binding protein by S. aureus was protective for AD.39 Another open trial investigated the effect of ZnO fab-
High fecal calprotectin at the age of 2 months is a risk rics on AD severity in adult patients. The fabric was used
factor for AD. There is an inverse correlation to intestinal overnight on three consecutive days. ZnO has antibacterial
Escherichia coli colonization. It can be concluded that early activity and serves as an oxygen radical scavenger. Severity
intestinal colonization by E. coli has long-term health impli- of AD, pruritus and sleep quality of patients improved even
cations and is a protective measure for AD.40 after short-time application of the functional textile.49
A South Korean study investigated the intestinal micro- A meta-analysis evaluated published studies about func-
biome in 90 AD and 42 non-AD subjects. They observed an tional textiles in AD. Fabrics based on silk, silver-coated
enrichment of Faecalibacterium prausnitzii F6 in AD, most cotton, borage oil and ethylene vinyl alcohol (EVOH) fibers

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were analyzed. Silk and silver-coated cotton demonstrated Prebiotics are defined as selectively fermented nutrients
the strongest effects on AD severity, but only silver-coated that cause specific changes in composition and/or activity
cotton reduced S. aureus colonization of skin.50 of intestinal microbiome.61 The first randomized controlled
On the other hand, it is questionable whether this attempt trial in infants at high risk for AD included 259 patients
would have any impact on dermal and subcutaneous adipose during their first 6 months of life. The verum group got a
Clinical, Cosmetic and Investigational Dermatology downloaded from https://www.dovepress.com/ by 193.93.194.201 on 02-Aug-2018

tissues, which are a substantial part of cutaneous microbiome.16 mixture of prebiotic galacto-oligosaccharides and long-chain
fructo-oligosaccharides. At the end of this trial, 9.8% in the
Therapies targeting intestinal microbiome verum group and 23.1% in the placebo group developed
Probiotics are defined as live microbial food ingredients that AD, demonstrating a preventive effect of prebiotics. On the
confer health benefits for the consumer.51 In most AD studies, other hand, severity of AD was not affected by prebiotics.62
probiotics have not shown a beneficial effect, independent of Two prospective randomized and placebo-controlled trials
the age of AD patients.52 Two recent meta-analyses, however, in infants using either prebiotic galacto-oligosaccharides or
found best evidence for probiotic supplementation in mothers a mixture of prebiotics failed to reduce severity of AD.63,64
and infants for Lactobacillus rhamnosus GG in long-term Another trial in low-risk infants suggested a temporary pre-
prevention of AD.53,54 ventive effect on AD.65
In a prospective randomized trial, the oral application of Most of these trials observed changes in intestinal micro-
Lactobacillus salivarius LS01 and Bifidobacterium breve biome with increased numbers of Bifidobacteria but reduced
BR03 for 12 weeks to adult patients with AD improved severity numbers of Clostridiae.63–65
For personal use only.

(as measured by the SCORAD index), quality of life (derma- Daily intake of Lactobacillus plantarum YIT 0132-fer-
tology quality of life index) and ratio of Th17 to Treg cells and mented citrus juice (LP0132-fermented juice) alleviated AD
diminished immune activation and microbial translocation.55 symptoms in adults during 8 weeks of treatment and further
In a mouse model, AD was improved by oral administra- 8 weeks off treatment in two open trials.66
tion of Lactobacillus casei var. rhamnosus (LCR35), which Fecal microbiome transplantation has been successful in
increased the gut population of Bacteroides fragilis, Lacto- some intestinal diseases such as recurrent Clostridium diffi-
bacilli, Bifidobacterium and Enterococcus, while Clostridium cile-induced pseudomembranous enterocolitis and Crohn’s
coccoides became less frequent. The treatment also restored disease, but data on AD are still missing.47,67
the Th1/Th2 balance.56
Oral administration of the probiotic Bifidobacterium Conclusion
animalis subsp lactis (LKM512) alleviated pruritus in AD is a common inflammatory skin disease. Recent investi-
adult AD patients in a placebo-controlled prospective trial. gations suggested a role of skin and intestinal microbiome in
Metabolomic analysis suggested that the antipruritic effect AD. Most data have been observed from infants, and those
was due to increased production of fecal kynurenic acid.57 from other age groups are rather limited. Furthermore, data
In an open trial, 130 pregnant women were treated with from populations less often affected by AD than Caucasians
B. breve M16V and Bifidobacterium longum BB536 1 month and Asians are almost nonexistent.
before delivery; 36 mother–infant pairs served as controls. Skin microbiome includes not only superficial stratum
After delivery, the infants were treated for 6 months with corneum that is affected by environmental factors such as
the same combination of probiotics. The risk of AD was exposure to germs and cleansing. Available evidence argues
significantly reduced within the first 18 months of life (odds for a link between epidermal barrier impairment and distur-
ratio at 18 months: 0.304). Temporary changes in intestinal bances in skin microbiome in AD.
microbiome were noted in infants who developed AD.58 Until today, studies considering the different compart-
A meta-analysis of randomized controlled trials suggested ments/tissue layers populated by skin microbiome in AD
the highest efficacy in reduction of severity of AD and pre- have not been investigated in detail.
vention of AD by synbiotics, i.e., a combination of prebiotics In contrast to skin microbiome, intestinal microbiome
and probiotics with a mixture of different microbial strains, seems to become stabilized after infancy. There is also a
in children >1 year of age.59 significant heritable component for intestinal microbiome.
Primary prevention of AD in infants by probiotic supple- The microbial taxa, relative percentages and quantities
mentation of their breast-feeding mothers 2–4 weeks before vary remarkably between the different parts of the intes-
delivery failed in a randomized, double-blind trial.60 tinal tract.

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Skin barrier-aimed topical treatments help to develop a neo- 17. Iwase T, Uehara Y, Shinji H, et al. Staphylococcus epidermidis Esp
inhibits Staphylococcus aureus biofilm formation and nasal coloniza-
microbiome from deeper compartments. Probiotics, prebiotics tion. Nature. 2010;465(7296):346–349.
and synbiotics have been investigated for the treatment of AD, 18. Kennedy EA, Connolly J, Hourihane JO, et al. Skin microbiome before
but further investigations are needed. Current understanding development of atopic dermatitis: early colonization with commensal
staphylococci at 2 months is associated with a lower risk of atopic
suggests that there may be a window of time to gain best results
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dermatitis at 1 year. J Allergy Clin Immunol. 2017;139(1):166–172.


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bacterial toxins on atopic dermatitis. Toxins (Basel). 2016;9(1):pii:E3.
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intestinal microbiome in AD are under investigation. Nat Microbiol. 2016;1(9):16106.
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The author reports no conflicts of interest in this work. 22(5):850–859.
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