Allergology International 71 (2022) 31e39

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Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Invited Review Article

Skin microbiome of atopic dermatitis

Li Fang Koh, Ruo Yan Ong, John E. Common*
A*STAR Skin Research Labs (A*SRL), Singapore, Singapore

a r t i c l e i n f o a b s t r a c t

Article history: The skin microbiome is a key component of pathogenesis in atopic dermatitis (AD). The skin of AD
Received 10 October 2021 patients is characterized by microbial dysbiosis, with a reduction of microbial diversity and over-
Available online 24 November 2021 representation of pathogenic Staphylococcus aureus (S. aureus). Recent exciting studies have elucidated an
importance of establishing an appropriate immune response to microbes in early life and uncovered the
Keywords: new mechanisms of microbial community dynamics in modulating our skin microbiome. Several mi-
Atopic dermatitis
crobes are associated with AD pathogenesis, with proposed pathogenic effects from S. aureus and
Biotherapeutics
Malassezia. The complex relationships between microbes within the skin microbiome consortia includes
Microbiome
Skin
various species, such as Staphylococcal, Roseomonas and Cutibacterium strains, that can inhibit S. aureus
Staphylococcus aureus and are potential probiotics for AD skin. Numerous microbes are now also reported to modulate host
response via communication with keratinocytes, specialized immune cells and adipocytes to improve
skin health and barrier function. This increased understanding of skin microbiota bioactives has led to
new biotherapeutic approaches that target the skin surface microenvironment for AD treatment.
Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction physicochemical properties, selecting for distinct groups of mi-

croorganisms adapted to the niche they occupy across body
The skin is an important interface that constantly interacts with, sites.3,4 This results in sebum-rich areas having an enrichment of
senses our environment and has evolved to maintain a homeostatic Cutibacterium spp. and fungal Malassezia spp. which are reliant
relationship with a community of microbes that form the micro- on lipids, and moist skin sites colonized by more Staphylococcal
biome. Atopic dermatitis (AD) is a pruritic inflammatory skin bar- and Corynebacterium species due to greater nutrient
rier disorder that affects approximately 20% of children, and 10% of availability.4e9 The collective microbial composition constitutes
adults in developed countries.1 AD is characterized by a defective our skin microbiota. Most of these microbial community mem-
barrier, which exacerbates microbiome stimulation of the immune bers are commensals with growing evidence for symbionts that
system, and the combination of these factors plays major roles in confer host benefits ranging from protection against pathobiont
AD pathogenesis. The complexity of pathophysiological drivers in invasion, and educating of host immune response to respond
AD underlies the heterogeneity of clinical presentation, such as age appropriately against pathogenic microbes that may break
of onset, disease severity, natural course of disease and the flare through the skin barrier.3 Microbiome studies in AD patients
cycle, which has distinct microbiome alterations and overgrowth of have consistently shown that lesional skin sites are abundantly
Staphylococcus aureus (S. aureus). colonized by S. aureus and have low microbial diversity. There-
Microbes coexist with humans and play an important role in fore, mechanistic understanding of how microbial communities
regulating health and disease. In the last decade, advances in contribute to AD across the flare cycle can offer patients an
microbial sequencing technologies have provided insight on the additional therapeutic avenue to maintain skin health.
multi-kingdom skin microbiome composition and characteristics Additionally, there are strong underlying genetic contributions
across the spectrum of skin health.2,3 Moreover, the skin surface as shown by numerous GWAS studies which flagged up over 30
has a wide range of microenvironments with unique risk loci for AD, with filaggrin null mutations and T helper 2 (Th2)
signalling molecules being significantly associated with AD.10e12 A
hallmark of AD is its strong association with an increased activa-
tion of the Th2 immune response, which includes increased
* Corresponding author. A*STAR Skin Research Labs (A*SRL), Immunos #6-10, 8A infiltration of CD4þ cells and elevated levels of prototypical Th2
Biomedical Grove, Singapore, 138648, Singapore.
cytokines. Furthermore, Th2 overactivation can impair the func-
E-mail address: [email protected] (J.E. Common).
Peer review under responsibility of Japanese Society of Allergology. tion of important skin barrier proteins such as filaggrin and

https://doi.org/10.1016/j.alit.2021.11.001
1323-8930/Copyright © 2021, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
32 L.F. Koh et al. / Allergology International 71 (2022) 31e39

loricrin, exacerbating an already impaired skin barrier.13,14 exotoxins, phenol soluble modulins (PSMs), as well as proteases
Although AD is predominantly Th2-skewed, there is heterogene- that trigger inflammation alongside skin barrier dysfunction in AD
ity in the immune dysregulation profile of AD patients, with some as reviewed29e32 (Fig. 1).
patients presenting an increased Th17 polarization as well as Th2 An altered skin barrier is susceptible to S. aureus coloniza-
activation.15e18 tion,33,34 as there is a preferential binding of S. aureus to AD skin
due to a redistribution of fibronectin in the stratum corneum of AD
skin.35 AD patients with filaggrin (FLG) mutations typically harbor
Microbes and atopic dermatitis less FLG-breakdown products such as urocanic acid and pyrroli-
done carboxylic acid, leading to an increase in pH favoring prolif-
S. aureus colonization aggravates skin barrier dysfunction eration of S. aureus. Increased pH also promotes the expression of
secreted and cell wall-associated proteins involved in immune
The skin microbiome in healthy individuals is generally stable evasion and adherence (i.e. clumping factor B, fibronectin-binding
over time,2 but patients with AD display strong dysbiosis especially protein), further aiding the colonization of S. aureus on AD skin.36
during flares, characterized by a reduction in microbial di- Upon colonization, S. aureus virulence factors driving AD patho-
versity.19,20 Amongst the Staphylococcal species, S. aureus is often genesis causes further breakdown of the skin barrier and immune
found enriched in AD, with the extent of S. aureus colonization stimulation.
correlating with the severity of AD.19,21e24 S. aureus isolates from
AD patients also express higher levels of virulence factors,23,25 and
have a greater propensity for producing biofilms to help promote Cutaneous malassezia can drive AD pathogenesis
its colonization26e28 and immune evasion.26 S. aureus is a gram-
positive opportunistic bacterium that causes both superficial and Malassezia spp. are the most abundant fungi on mammalian skin
invasive skin infections. It expresses various factors promoting and are associated with AD.37,38 Malassezia spp. exists as a
colonization and virulence, including superantigens (SAgs) like commensal on healthy skin but overgrowth of multiple Malassezia
enterotoxins (i.e. SEA, SEB), toxic shock syndrome toxin 1 (TSST1), spp. such as Malassezia furfur and Malassezia sympodialis among

Fig. 1. Crosstalk between skin and microbiome in healthy and atopic dermatitis conditions. The presence of commensals on the skin interacts with the host to establish a functional
immune response and prevents the overgrowth of pathogenic microbes. On healthy skin (Left), there is high microbial diversity, which includes Dermacoccus and Corynebacterium
as well as other commensals. Secretion of AMPs and production of lantibiotics by commensals shape the microbial community on healthy skin to prevent colonization of pathogens
like S. aureus. On AD skin in a non-flare state (Middle), microbial dysbiosis occurs with a reduction of Dermacoccus and an increased abundance of Streptococcus and Gemella species.
The skin of AD patients during flares (Right) is characterized by the overgrowth of pathogenic microbes such as S. aureus, and reduced microbial diversity. Biofilm production by
S. aureus promotes its colonization and drives pathogenesis. Commensals including Dermacoccus are depleted. Epicutaneous defects can be exacerbated by genetic mutations of skin
barrier proteins such as filaggrin, S. aureus virulence factors, and Th2 cytokines. S. aureus virulence factors including d-toxin and superantigens trigger IgE-mediated mast cell
degranulation, and the resulting increase in Th2 cytokines perpetuates AD. Concurrently, there is a marked reduction of AMPs expressed, leading to the overgrowth of pathogens
such as S. aureus and Malassezia.
 L.F. Koh et al. / Allergology International 71 (2022) 31e39 33

others, may cause AD pathogenesis.6,39e42 There is increased levels and induction of immunoregulatory molecules. Furthermore,
of Malassezia-specific IgE in AD patients43 and a correlation of AD different isolates with slight alterations in microbial genome
severity with amount of Malassezia species present.44 Several harbored differential immunomodulatory capacities, showing the
studies have elucidated pathogenic mechanisms driven by Malas- potential of S. cohnii strains as a biotherapeutic.53
sezia. M. sympodialis releases extracellular vesicles that can induce In addition to CoNS, other non-staphylococci microbes have
IL-4 and TNF-a cytokines in AD patients.45 M. sympodialis can also shown antagonistic properties towards S. aureus. For example,
induce the release of cysteinyl leukotrienes in IgE-sensitized bone Streptococcus spp. was shown to have an inhibitory effect on
marrow-derived mast cells (BMMCs) and enhance IgE-mediated S. aureus growth,20 while Corynebacterium spp. was shown to
degranulation of BMMCs. As the skin barrier is often defective in constrain S. aureus through accessory gene regulatory (agr) quorum
AD patients, percutaneous sensitization with allergens produced by sensing inhibition.54 Malassezia can act as a protective commensal.
M. sympodialis then perpetuate inflammation through mast cells Metagenomic profiling of AD patients show that Malassezia is
activation.46 Fungal protein MGL_1304, secreted by Malassezia depleted from the skin of AD-susceptible individuals.20 Skin
globosa and found in the sweat of AD patients, causes type 1 allergy commensal M. globosa secretes protease MgSAP1 to restrict
in AD patients.47 And IL-23/IL-17 pathways are found to be S. aureus biofilm formation by hydrolyzing S. aureus protein A, a
important for maintaining a healthy balance for Malassezia-host virulence factor that is important in immune evasion and biofilm
coexistence; IL-23/IL-17 pathways exert protective functions that generation.55 This shows a mechanism of a fungalebacterium
prevent the overgrowth of skin fungus colonization but these exact interaction, illustrating how various microbial community mem-
pathways can also exacerbate Malassezia-induced inflammation in bers can influence each other.
atopic conditions.48 Not all commensals confer protection against S. aureus. While
Cutibacterium acnes was shown to inhibit the growth of S. aureus
Community dynamics and skin commensals with byproducts from fermentation of glycerol,56 it was also found
that some Cutibacterium species (including C. acnes) could facilitate
Temporal stability in skin microbiome of healthy individuals S. aureus colonization by promoting S. aureus aggregation, and
suggests strong selective control on the microbial constituents. This biofilm formation.57 Chng et al. identified a microbial signature
can be driven by host factors (e.g. skin physiology), environmental comprising of Streptococcus spp., Gemella spp., and a depletion of
exposure (e.g. UV exposure, temperature), and products secreted by Dermacoccus spp. In subjects prone to AD. In the same study, it was
other microbes through interactions or metabolism. found that the skin microbiome of these subjects has increased
Within the Staphylococcal species, the coagulase-negative capacity for ammonia production,20 suggesting that the metabolic
Staphylococci (CoNS) commensals such as Staphylococcus epi- activity of commensals may predispose individuals to S. aureus
dermidis, Staphylococcus hominis, and Staphylococcus lugdunensis colonization.
are of importance. Certain strains of S. epidermidis were found to The non-lesional skin and non-flare states of AD presents a state,
carry and express the gene that produces serine protease glutamyl which is in between that of a healthy skin and diseased lesional
endopeptidase (Esp), which inhibits the production of biofilms and skin. Non-lesional skin is altered from normal skin as there is an
colonization by S. aureus.49 This inhibitory effect of Esp turns increased presence of inflammatory T cells, decreased hydration,
bactericidal, when Esp acts together with beta-defensin 2 (hBD2),49 impaired synthesis of lipids, altered expression of differentiation
a host antimicrobial peptide (AMP). Interestingly, strains capable of markers. Non-lesional skin also has a similar transcriptional profile
attenuating S. aureus were typically found in subjects with low to as lesional AD skin, although it expresses less immune-mediated
no S. aureus carriage, hinting at a competitive exclusion between inflammation compared to lesional skin58 (Fig. 1). Our work on
commensals and pathobionts. S. lugdunensis was found to effi- the skin microbiome of AD-prone individuals defined microbial
ciently inhibit S. aureus growth through the production of lugudi- signatures of AD susceptibility, that were termed “Dermotypes”,
nin, a novel class of macrocyclic thiazolidine peptide antibiotics.50 A highlighting a distinct microbial community on the skin of AD
follow up study has demonstrated lugudinin's ability to promote patients during a non-flare state and altered skin surface compo-
immune responses through inducing host production of AMP nents.20,59,60 Interestingly, one of these dermotypes was associated
cathelicidin (LL-37) and enhance the recruitment of phagocytes. In with the AD endotype that has high IgE, so called “extrinsic AD”.
addition, lugudinin was shown to act synergistically with LL-37 and This clinically more severe dermotype is characterized by reduced
dermicidin-derived peptides, potentiating lugudinin's antimicro- microbial diversity, depletion of C. acnes, Dermacoccus and Meth-
bial effects against S. aureus.51 Following a screen of CoNS isolates ylobacterium species, along with overgrowth of Staphylococcus
collected from the skin of healthy and AD subjects, S. epidermidis species. It remains to be seen what is driving these various endo-
and S. hominis were found to possess antimicrobial activity against types and dermotypes in AD patients that provides differences in
S. aureus. Selected strains from both species were able to produce allergic biomarkers and could be linked to the atopic march.
lantibiotics efficacious against S. aureus, but did not affect the The complex host-microbe and microbeemicrobe relationships
growth of other commensals, highlighting its therapeutic potential that shape the eventual pathogenicity of each microbe is described
in treating AD. S. hominis strain ShA9 was also shown to be capable in a concept introduced by Chen et al., termed contextual patho-
of effecting host protection in an AD mouse model through genesis. Suggesting that all microbes in the body fall somewhere
lantibiotic-independent means by induction of AMP LL-37 gene within the spectrum of being potentially pathogenic (aggressive)
expression. Concomitantly, Th2 and Th17 T cell recruitment was and mutualistic (passive), with some microbes being generally
suppressed; highlighting ShA9's potential in regulating host im- beneficial to the host, but under certain circumstances can turn
mune responses.52 invasive, while some microbes may primarily be virulent.61
Ito et al. used a mouse model of dermatitis, with a variety of
agents to induce skin inflammation including S. aureus; MC903, a Skin microbiota of pediatric AD patients
vitamin D3 analog that models AD; and Imiquimod, a TLR7 agonist
that models psoriasis-like dermatitis. In these models, Staphylo- As AD is a disease that has an early onset in the early years of life,
coccus cohnii treatment showed amelioration of dermatitis and skin studying the skin microbiome in this time scale is very relevant. Shi
inflammation, along with suppression of immune responses et al. investigated the skin microbiome differences between pediatric
including upregulation of anti-inflammatory glucocorticoid genes, and adult AD patients. Their cohort includes young children aged
34 L.F. Koh et al. / Allergology International 71 (2022) 31e39

2e12, teenagers aged 13e17 and adults above 18 years old. The important in host protection. Indeed, neutrophils were demon-
healthy and AD non-lesional skin microbiome of children was strated to be responsible in early control of S. aureus numbers on
significantly more diverse compared to adults. AD lesions of children the superficial layers of the skin, thereby preventing S. aureus
and adults were significantly decreased in microbial diversity, with colonization.71 Interestingly, in a separate study, in vivo NET for-
greater abundance of S. aureus.62 Similarly, Meylan et al. assessed the mation by neutrophils was found to aid S. aureus colonization
skin microbiome of infants and found those that developed AD had an through an unidentified mechanism.72 While both studies utilized
increased S. aureus prevalence on their skin during the onset of AD at 3 epicutaneous model of S. aureus infection, Bitschar et al. involved
months old, and 2 months before the onset of AD.63 In a group of AD tape stripping to induce skin inflammation rather than passive
pediatric patients aged 2e18 years old, Byrd et al. found overgrowth topical application by Schulz et al., suggesting that the microenvi-
S. aureus clonal strains abundance correlated to severe AD flares and ronment (e.g. inflammation versus homeostasis) plays a role in
heterogenous S. epidermidis strains correlated with less severe AD.23 affecting neutrophil's control of S. aureus colonization.
Nakamura et al. found that although the colonization with S. aureus It has also been shown that gd T cells secrete IL-17 and IL-22 that
on the cheeks of infants at 1 month old did not predict AD outcome, at restrict S. aureus infections.73,74 These cytokines control S. aureus-
6 months old skin colonization by S. aureus could predict the risk of driven abscesses, influence T cell and neutrophil infiltration, as well
developing AD. 6 months old infants who did not develop AD had as preventing S. aureus colonization.75 Loss of conventional den-
S. aureus strains with impaired agr function rendering them unable to dritic cells (cDCs) exacerbates AD skin inflammation and acceler-
grow and colonize.64 In contrast, Kennedy et al. did not detect S. aureus ates S. aureus colonization, thereby implicating cDCs in maintaining
in the AD lesions of their pediatric cohort, which was tracked at 4-time immune homeostasis, and preventing S. aureus colonization.76
points; day 2, month 2, month 6, and 1 year old. They found that in the In addition to immune cells, keratinocytes respond to S. aureus
first year of life, infants who suffer from AD did not differ from control infection by increasing metabolic stress, with HIF1a activation.
infants in terms of their Shannon diversity and neither had their skin HIF1a signaling led to the production of inflammatory cytokines
colonized by S. aureus. The most significant difference between the AD such as IL-1b and IL-18, which are associated with inflammasome
and control infants were that infants affected with AD at 12 months activation. Inhibiting glycolysis resulted in decreased IL-1b pro-
old had significantly fewer commensal staphylococci compared to duction, and a larger S. aureus-induced skin lesion with delayed
control infants, suggesting a potentially protective function of healing. Hence, the role of glycolysis in immunometabolism is
commensal staphylococci against AD development.65 Taken together, important to control S. aureus overgrowth.77 Human dermal adi-
the skin microbiota of pediatric AD patients may not always be pocytes were also observed to regulate the invasion of S. aureus by
characterized by the presence of S. aureus colonization or reduced producing LL-37. Inhibiting adipogenesis reduced LL-37 production,
microbial diversity, and this could be because microbiome is still and increased susceptibility to S. aureus infection,78 demonstrating
developing throughout the first year of life.66 the role of adipocytes in innate immunity against S. aureus.

Microbes and immunity Early exposure to commensals trains the immune system

Patients with primary immunodeficiency disorders commonly have Commensal microbiota have a protective function in early life, as
eczema reduced exposure to microbes increases susceptibility to AD and
other allergic conditions in early childhood.65 Neonatal skin colo-
Patients suffering from primary immunodeficiency (PID) dis- nization by commensal S. epidermidis induces immune tolerance
eases commonly have skin disorders, including AD.67 Oh et al. through specific regulatory T cells (Tregs). In contrast, S. aureus
examined the skin microbiome of PID patients who have a common minimally induces the development of specific Tregs and this is in
feature of suffering from AD-like eczema and recurrent microbial part due to S. aureus a-toxin's activation of IL-1b.79 A diverse
infections, despite the different immunological deficiencies.68 The community of skin commensals is therefore important to educate
PID patients examined include those with hyper-IgE (STAT3- the immune system, and allow the host to develop tolerance and be
deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 able to appropriately respond to environmental stimuli.
(DOCK8) syndromes. The skin of PID patients have increased per- Immune education begins in utero; the gestational environment
missivity to bacterial and fungal colonization, dysbiosis in microbial is not sterile80e85 and the presence of microbes in the gestational
diversity, and unique bacterial-fungal colocalization compared to environment influences the fetal immune system. Mishra et al.
healthy controls. PID patients show a correlation of microbial detected live, culturable bacterial strains in fetal tissues that are
presence and skin disease severity, and in addition to S. aureus, capable of triggering activation of memory T cells in vitro, indicating
Clostridia spp. and Corynebacterium spp. also correlate with disease that immune priming, and the interplay between microbiome and
presentation. In contrast to AD patients who have significant immune regulation may already commence during gestation.
overburden of S. aureus, PID patients primarily have S. epidermidis Studies from the same group demonstrated vertical transmission of
and Staphylococcus haemolyticus, shown capable of driving AD as allergic disease through maternal IgE sensitization of fetal mast
well.68 Skin microbial dysbiosis on PID patients indicate that cells.86 These findings of in utero immune priming and
crosstalk between our immune system and commensals impacts maternalefetal transmissions may explain in part, the observation
the microbial community on the skin. that family history of atopy is the strongest predictor of AD risk in
children,87,88 as the contributions of both maternal immune86 and
Host immune responses to skin microbes microbial components85 potentially shapes early immune re-
sponses to microbes.
Neutrophils are a major part of the host innate immune
response against pathogens, and S. aureus has been reported to Microbiome-based biotherapeutics
inhibit effector functions of neutrophils, including prevention of
recruitment by blocking extravasation, suppressing priming, acti- Targeted therapies to treat AD microbiota dysbiosis
vation, and phagocytosis, as well as neutrophil extracellular traps
(NETs) formation.69,70 The investment of resources by S. aureus to Next generation microbiome-based biotherapies have been
evade neutrophil effector functions suggests that this cell type is gaining traction over the past decade and are set to be a major
 L.F. Koh et al. / Allergology International 71 (2022) 31e39 35

growth area for new treatments for AD. The classical approach to populating AD lesions with S. epidermidis can encourage optimal
treating S. aureus infection in AD is through decolonizing using lipid levels and acidic skin pH to promote healthy skin microbiota.
broad-spectrum antibiotics that comes with risks of promoting Furthermore, Bayer AG, Germany and Azitra Inc., USA partnered to
antibiotic resistance and importantly, perturbing the commensal develop skin care products with selected S. epidermidis strains for
microbes.89,90 S. aureus can also use mechanisms to evade antibiotic AD prone skin showing how topical application of commensals can
killing.91 Dilute bleach baths were trialed as a potential accessible be harnessed for the lucrative skin care market. Next, S. epidermidis
method to manage S. aureus abundance, but results from multiple and S. hominis strains with antimicrobial activity against S. aureus
trials did not show a consistent effect on alleviating AD,92 and the were isolated and treatment of AD patients could decrease S. aureus
therapeutic effects that bleach baths have shown may not be due to colonization.99 S. hominis ShA9 can selectively kill S. aureus and
its antimicrobial effects.93 Hence, more targeted therapies such as promote beneficial bacteria to act as a bacteriotherapy for AD.52 AD
microbiome-based options are needed that aim to restore a healthy patients who received a 1-week treatment of topical ShA9 had
skin microbiome in AD patients, reduce overgrowth of pathogenic fewer adverse events related to AD, significant decrease in S. aureus
drivers of AD and promote the recovery of commensals. These abundance, inhibition of PSMa expression by S. aureus, but did not
therapies include probiotics treatment, repopulating AD lesions reduce AD severity. Microbial strain differences between isolates
with beneficial commensals, phage therapies, small molecules and derived from healthy versus AD patients are important to the
peptides that counteract S. aureus colonization, humanized outcome of microbial therapies. Treatments with isolates of cul-
monoclonal antibodies that target bacterial toxins, as well as turable Gram-negative bacteria (CGN) obtained from healthy in-
quorum sensing inhibitors that block virulence factors94e96 (Fig. 2). dividuals, but not AD patients, correlated with an improved skin
barrier and prevented S. aureus colonization.100 A first-in-human
trial used live topical Roseomonas mucosa from healthy in-
Probiotic and repopulating AD lesions with commensal microbes
dividuals to treat adult and pediatric AD patients101 to alleviate AD
(reduced SCORAD, pruritis and use of steroids). The alleviation of
Restoring a diverse microbiota that includes commensals will
AD symptoms was through the induction of a TNR-related epithe-
improve the community resistance to colonization with patho-
lial pathway.102 A potential therapy combining three strains of
bionts. S. epidermidis application on healthy individuals increased
R. mucosa (FB-401) is currently being developed by Forte Biosci-
skin lipid content and lowered skin acidic conditions.97 As
ence.96 Nitrosomonas eutropha (B244) is a bacterium that produces
epidermal lipid composition and an acidic skin pH correlate with a
nitric oxide, a potential anti-inflammatory molecule. Results from
healthy skin microbiome composition and diversity,20,98

Fig. 2. The process of bench to bedside for microbiome-based biotherapeutics for AD. (a) Skin sampling: Skin biomass is obtained from AD afflicted sites (e.g. antecubital fossa) of
healthy individuals and AD patients. (b) 16s rRNA sequencing or metagenomic sequencing: Sequencing is performed to uncover microbial taxonomy and strain diversity infor-
mation between healthy individuals and AD patients to identify microbes of interest; such as identification of commensals with certain characteristics or possible pathogenic
bacteria that exacerbates AD. (c) Targeted microbial culturing to specifically isolate and culture strains of potentially pathogenic bacteria or commensals for downstream testing. (d)
Testing hypotheses with 3D skin, skin explants, and mouse models to ascertain the mechanistic role of strain of interest. (e) Microbiome-based biotherapeutics include probiotics
treatment, repopulating AD lesions with commensals, phage therapies, small molecules and peptides that counteract S. aureus colonization, humanized monoclonal antibodies that
target bacterial toxins, and quorum sensing inhibitors that block expression of virulence factors.
36 L.F. Koh et al. / Allergology International 71 (2022) 31e39

clinical trials showed an improvement in pruritis and this treat- with high specificity, allowing genes that drive pathogenesis in
ment is being developed by AOBiome.96 Also, the treatment of pathogenic strains to be genetically removed. This technique of
Lactobacillus johnsonii NCC533 is a potentially beneficial treatment gene delivery can allow the integration of potentially useful genes
in atopic skin, as topical treatments on in vitro organoid skin model to restore antibiotic sensitivity and introduce biofilm dispersal
showed reduced S. aureus adhesion and increased the expression of enzymes. For the gut microbiome, Eligo Biosciences, France is
AMPs.103 moving to clinical trials with the “CRISPR Nanobits” combining
phage and CRISPR-Cas technologies to edit specific microbes with
Phage therapy, small molecules and peptides skin treatments an obvious potential next step. Like phages, genetic
manipulation can be introduced via plasmids and transposable
Staphefekt SA.100 is a recombinant phage endolysin that binds elements. Conjugation-mediated genetic engineering has a broader
to the cells walls of S. aureus and cleaves the bonds in the pepti- host range and can transfer more complex genetic material
doglycan walls to result in cell death. Clinical trials with topical compared to phage-mediated engineering.113
Staphefekt SA.100 produced conflicting results. It was effective in
suppressing clinical symptoms of AD in a small study of 3 AD pa- Using a mixed community of skin microbes to boost therapeutic
tients,104 but in a larger trial of randomized patients, endolysin potential?
treatment against S. aureus was not efficacious in reducing S. aureus
abundance nor did it reduce topical corticosteroid requirement.105 At present, microbiome therapies to repopulate AD lesions with
Clinical parameters of AD improved when a clinical isolate of commensals have focused on delivering a specific strain of bacteria.
staphylococcal phage, SaGU1, obtained from the skin of AD pa- Using human skin equivalents, Loomis et al. found that treatment
tients, was tested in combination with commensal bacteria with a mixed community of microbes resulted in significant
S. epidermidis on the back skin of a contact hypersensitivity mouse changes in transcriptomic and histological analyses more than
model.106 Phage SaGU1 is a potential AD therapeutic agent as it can treatment with single microbes. Mixed community treatment was
infect many S. aureus strains that have been isolated from AD pa- able to increase filaggrin expression, reduce actively proliferating
tients but does not kill commensal bacteria, such as S. epidermidis cells and increase the thickness of the epidermis more robustly
strains.107 In the small molecule space, Niclosamide ATx201 has than a single microorganism, reflecting how we could tap into
been shown to decolonize S. aureus, improve the skin barrier and community dynamics to enhance microbiome-based treatments
reduce inflammation markers.96 Synthetic peptides can also be for AD.114
effective against biofilms formed by S. aureus108 and Omniganan
(CLS001) is currently being developed as a drug for AD.96 Concluding remarks

Future perspectives To summarize, the skin microbiome is a complex and constantly

evolving community that interacts across the skin barrier to
Measuring skin microbial diversity to monitor, stratify and treat communicate with the host. S. aureus overburden and reduced
patients? microbiome diversity has been shown by many studies to be a
characteristic of skin during AD flare. Emerging research have
Several studies have concluded that microbial diversity and pointed to early life being a pivotal period for the development of
S. aureus abundance correlates with AD severity.22,60 The use of appropriate immune response to microbes and this could be a
traditional AD therapies such as UVB results in an increase in skin critical time to initiate microbiome interventions. Investigations on
microbiota diversity on lesional skin.109 Likewise, recent biologic microbial community dynamics to differentiate healthy skin and
treatment regimens such as Dupilumab, also result in an increase in skin during AD flares, will drive innovation on how to sustainably
skin microbiota diversity and decreased S. aureus abundance.110,111 treat microbial dysbiosis of AD patients, which has led to several
Hence, using skin microbial diversity or the abundance of S. aureus clinical trials of biotherapeutics to correct the AD microbiome
could be a viable, objective measurement for AD severity compared dysbiosis. Results show that microbiome-based therapeutics have
to only SCORAD, the semi-quantitative scoring method that is multiple viable treatment possibilities for AD but the specific
currently widespread. Tracking the skin microbiome could be a strains of commensals that would produce lasting effects remains
non-invasive molecular diagnostic indicator for optimal treatment to be fully investigated.
regime and skin health.112
AD patients that are colonized by S. aureus present a more se- Acknowledgements
vere disease and epidermal impairments.24 Our laboratory has
recently identified two dermotypes (Dermotypes A and B) to This work was supported by funding from Agency for Science,
stratify AD patients. Dermotype B is characterized by patients with Technology and Research (A*STAR) Biomedical Research Council,
a higher IgE, more severe itch, recurrent flares and disease pre- A*STAR Graduate Academy and A*STAR BMRC EDB NRF IAF-PP
sentation, with reduced skin microbiome diversity that favors grants e H17/01/a0/004 “Skin Research Institute of Singapore” and
Staphylococcal species and S. aureus colonization.20,60 As AD is a H18/01a0/016 “Asian Skin Microbiome Program”.
heterogenous disease, stratification by dermotypes coupled with We thank Dr Stephen Wearne for proofreading this manuscript.
monitoring changes to skin microbiota could aid in monitoring AD Figures are created with BioRender.com
progression or recovery, which will contribute to a more person-
alized AD treatment linked to spatio-temporal skin condition. Conflict of interest
The authors have no conflict of interest to declare.
Possibility of personalized therapies?
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