Skin microbiome in AD
AD is characterized by a waxing and waning course, in which worsening of
AD lesions (flares) occur periodically followed by a period of clinical
improvement with treatment.5Microbes on the skin are thought
to play an important role in skin homeostasis by modulating the immune
system,8 providing colonization resistance against
pathogens,9 or, in the case of Staphylococcus
aureus (S. aureus), exacerbating skin inflammation.10The skin microbiome composition changes dramatically across the AD flare
cycle, with microbial diversity dropping as disease severity increases,
and a concomitant increase in abundance of S. aureus in the
majority of cases.11 A predominant S. aureusstrain is often observed in the flare state, while heterogenousStaphylococcus epidermidis strain communities are seen in both
the flare and post-flare states. On non-flare AD skin, microbial
diversity remains high; however, the composition and functional
potential of the AD subjects’ microbiome are distinct from healthy
individuals, highlighting potential microbiome-related factors that
could increase the susceptibility to flares.12 This
altered microbiome signature in the non-flare skin of AD patients is
more pronounced in individuals with high levels of circulating IgE and
also associates with molecular changes in the skin surface
microenvironmental niche.13 There is growing evidence
that commensal microbes may play a mechanistic role in skin barrier
repair and attenuate inflammation during AD via AhR-dependent signalling
and glucocorticoid-related pathways.14, 15
The predominance of S. aureus strains in flares and relative
reduction of commensal microbes are linked with skin barrier disruption
and inflammation in AD skin.16 A meta-analysis
reported that around 70% of individuals across all ages with AD are
colonized with S. aureus on lesional skin, 30-40% in
non-lesional skin, and 62% in the nares.17 AD
patients have significantly higher odds of S. aureus colonization
than healthy controls at all sites compared.17
There is a need for greater understanding of the initiators and drivers
of the altered skin microbiome and why S. aureus predominates on
AD skin. The contribution is likely complex and multifactorial, driven
by Th2 skewing of the immune milieu, disruption to the skin barrier by
mutations in genes such as FLG , and alterations in lipid and
protein production in the epidermis that increase S. aureusadherence.18-20 There is also strong evidence from
genetic disorders that either impact the immune system (such as inborn
errors in immunity), or disrupt skin barrier function (such as
congenital ichthyosis), resulting in overrepresentation ofStaphylococcus species as a common feature in microbial
communities.21, 22 Thus, both host and microbiome
factors likely contribute to AD pathogenesis in susceptible individuals.
S. aureus has long been associated with AD23and shown to demonstrate its pathogenic effects through various
mechanisms such as disruption of barrier integrity, intrinsic host
immune dysregulation, and expression of virulence genes. (Figure 1)
Virulence factors such as α-toxin, protein A (SpA), lipotechoic acid
(LTA), phenol soluble modulin (PSM)-α, and proteases can damage
keratinocytes.24 While AD-associated S. aureusstrains have been isolated, several studies have investigated the
differences between S. aureus strains isolated from children with
AD as compared to other S. aureus strains to potentially identify
specific strains that may contribute to AD skin
disease.20, 25, 26
Viral-host interactions also mediate AD morbidity. AD patients with a
history of S. aureus skin infections are at greater risk of
eczema herpeticum (EH), a severe blistering cutaneous infection caused
by herpes virus.27, 28 Some mouse and in vitrostudies have raised the possibility that S. aureus strains which
produce staphylococcal toxic shock syndrome toxin-129or α-toxin30 may enhance viral entry. Conversely, AD
host factors such as genetics, immune dysregulation, and barrier defects
also increase susceptibility to EH compared to healthy individuals.
Differences in fungal composition have also been described in AD.
Cross-sectional sequencing studies demonstrated lower relative
abundances of Malassezia spp . Correspondingly, the higher
prevalence of non-Malassezia fungi such as Cladosporium,
Alternaria , and Aspergillus in AD skin12, 31may be attributed to environmental selection pressures asMalassezia spp grow best in lipid-rich conditions, which are
deficient in AD skin. Certain Malassezia species perform
protective functions, whereas others may induce skin
inflammation.32, 33 A small study (n=17) demonstrated
that Malassezia globosa, a commensal yeast from healthy adult
volunteers, secretes a protease (Malassezia globosa Secreted
Aspartyl Protease 1 - MgSAP1) which disrupts S. aureus biofilms
by hydrolyzing SpA.34 A murine AD model, however,
showed that M. pachydermatis, M. sympodialis , and M.
furfur activated IL-23 and IL-17 inflammatory pathways, and this was
corroborated by the presence of Malassezia -specific production of
these cytokines by memory T cells in adult AD
patients.33 These targeted studies were designed to
investigate the specific inflammation-associated mechanisms exerted by
commensal Malassezia spp, mostly in in vitro or in
vivo models. There is, however, little direct data on how yeast
interact with other skin microbiota or influence human host responses.
Native skin commensals also form part of the innate host defence against
pathogenic organisms. S. epidermidis and Staphylococcus
hominis are examples of coagulase-negative staphylococci (CoNS) which
stimulate host production of antimicrobial peptides like cathelicidin
and human beta defensin (HBD), and also directly produce PSM-γ and
PSM-δ, which inhibit the growth of pathogenic
bacteria.35
An observational sequencing study (n=100 adult patients) detected
increased abundances of the Demodex folliculorum mite on AD skin
compared to healthy controls.36 However, no further
mechanistic studies were done to assess the role of Demodex mites
in inducing or perpetuating skin inflammation in these patients. While
house dust mites have been shown to trigger inflammation in AD murine
models,37 there is little data to show that they
trigger AD flares in AD patients. There is thus insufficient evidence to
conclude if skin mites play a major role in AD development.
Skin microbiome markers
of AD in early life
Early life exposure to the external environment may shape host-microbe
interactions that play roles in skin health and atopic disease
onset.38 Distinct fluctuations in neonatal and infant
skin physiology in the first year of life influence skin microbiota
colonization patterns. The skin microbiome in healthy neonates is
characterized by the predominance of Bacillota (formerlyFirmicutes ), such as Staphylococcus andStreptococcus , and fewer Actinomycetota (formerlyActinobacteria ) (Cutibacterium andCorynebacterium ). A small,
open, non-randomized, cross-sectional study found that soon after
delivery, vaginally born neonates (n=4) have skin microbiota that are
similar to their mothers’ vaginal fluid, predominantlyLactobacillus or Prevotella spp., while neonates born
through Caesarean section (n=6) acquire mainly maternal skin commensals
such as Staphylococcus, Corynebacterium, and Cutibacterium
spp .39 In a subsequent publication where infants were
followed up to 30 days of life, the authors reported that 4
Caesarean-born infants who were exposed to their mothers’ vaginal fluids
at birth continued to exhibit skin microbiota characteristics similar to
vaginal-born infants.6 A larger follow-on
observational study recruited n=98 vaginal-born infants and n=79
Caesarean-born infants, 30 of whom were swabbed with maternal vaginal
fluids after birth. Caesarean-born infants who underwent vaginal seeding
had a gut microbiota developmental trajectory up to age 12 months that
more closely resembled vaginal-born infants, compared to those who were
not seeded, suggesting that early life vaginal microbiota transfer had a
sustained effect up to 1-year post intervention.7 A
subsequent double-blind randomized controlled trial of 10 vaginal-seeded
infants vs 10 controls (seeded with sterile saline) found that
vaginal-seeded infants had significantly reduced alpha diversity in the
skin at day 1, as well as in transitional stool up to day 30 of
life.8 There has, however, been no longitudinal data
beyond 1 year of life, nor any data on whether this intervention had any
impact on infant disease outcomes. Furthermore, as the Caesarean
sections were all elective and non-emergent, there is little known about
how other peripartum factors may influence maternal and infant
microbiota and maternal-infant transmission.
Various factors such as maternal microbiome, mode of delivery, and early
environmental exposure may influence the maturation trajectories of the
infant skin microbiome, and from murine models, potentially infant skin
immunology as well. A systematic
review by Xiong et al found that studies examining the link between mode
of delivery and AD risk harboured significant heterogeneity that could
be attributed to differences in country, study design, and method of AD
ascertainment.40 No definite conclusions can thus be
made about the impact of delivery mode on AD risk.
Several longitudinal studies have demonstrated early skin microbial
signals that may be predictive of AD onset. A small longitudinal study,
nested within a birth cohort, found that infants who developed AD at age
1 year (n=10) had a much lower abundance of commensalStaphylococcus species detected by 16S rRNA gene sequencing at 2
months of age relative to controls (n=10) .41 A larger
prospective birth cohort study (n=146) found that early S. aureuscolonization (by culture-based methods) in the first few months of life
appeared to precede the onset of AD in infants.42Nakamura et al further observed that infants in the Chiba birth cohort
who had S. aureus strains harbouring dysfunctional mutations in
their Agr quorum-sensing (QS) system did not go on to develop AD
(n=24), postulating that this functional S. aureus virulence
mechanism may be important for AD pathogenesis.43Further studies are needed to examine the mechanistic pathways through
which early differences in microbiota composition may influence later
disease onset, such as the impact of microbiota on host immunological
responses, skin barrier protein expression, and barrier function.
Marked pubertal differences in the skin microbiome have been
demonstrated as children sexually mature through Tanner
stages.44, 45 Similarly, the skin microbiome
composition of young children with AD (2-12 years, n =59) differed from
adolescents (13-17 years, n =13) and adults (18-62 years, n=56) versus
age-matched nonatopic healthy controls.
Skin microbiome diversity was significantly higher in the non-lesional
skin of AD children than in adolescents/adults, corresponding to similar
patterns in healthy individuals.46 However,Staphylococcus was significantly more abundant in lesional as
well as non-lesional skin of children and adolescents with AD. Skin
commensals for AD and control subjects were also age-specific: such asStreptococcus spp enriched in children compared toCutibacterium and Corynebacterium in adults.
There are only a few observational studies describing changes in skin
microbiome signatures in early infancy that may be associated with AD
onset. Further mechanistic studies are needed to deconvolute the
potential role of the skin microbiota in AD pathogenesis and their
interactions with the host skin barrier and immune system in the
pre-clinical disease state.