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Review
The Skin Microbiota: Balancing Risk and Reward
Laurice Flowers1 and Elizabeth A. Grice1,*
1Department of Dermatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

*Correspondence: [email protected]
https://doi.org/10.1016/j.chom.2020.06.017

The skin microbiome is an ecosystem comprised of a multitude of microbial species interacting with their sur-
roundings, including other microbes and host epithelial and immune cells. These interactions are the basis of
important roles within the skin microbiome that provide benefit to the host, boosting multiple aspects of bar-
rier function, a critical function of this essential organ. However, with reward always comes risk; resident skin
microbes function in a context-dependent manner, set on the backdrop of a dynamic host and microbial
milieu. Here, we discuss the reward of hosting a microbial ecosystem on the skin, including protection
from pathogens and tuning of the skin microenvironment. We also give consideration to how these skin res-
idents, often termed ‘‘commensals’’ can cause disorder, damage, and promote skin disease.

Introduction the skin microbiome. Early studies using bacterial 16S ribo-
The skin is an epithelial barrier to the external environment that somal RNA (rRNA) gene amplicon-based sequencing methods
also supports diverse microbiota comprised of bacteria, fungi, emphasized the topographical diversity of skin microbial com-
viruses, and microeukaryotes. The skin microbiota is adapted munities and the influence of microenvironment. The pivotal
for life in the unique microhabitats that define the environmental study of 20 different anatomical skin sites revealed unique mi-
and nutrient conditions of this ecosystem. Interacting together crobial compositional differences that occur across body sites
and through mutualistic or commensal interactions with (Grice et al., 2009). Sebaceous sites were enriched in sebum-
mammalian host cells, the skin microbiota promotes defense loving Cutibacterium, while the fastidious and slow growing
and immune responses, inhibits colonization and infection by Corynebacterium localized to moist sites. Overall, Staphylo-
opportunistic or pathogenic organisms, and promotes tissue coccal species were prevalent throughout, consistent with cul-
repair and barrier functions. In this review, we will discuss the in- ture-based assessments of skin microbiota. Sequencing of
teractions within this ecosystem and the resulting reward of ho- fungal ribosomal RNA gene amplicons demonstrated that Ma-
meostasis, or alternatively, the risk of disorder and disease that lassezia is the overwhelmingly dominant member of the fungal
might occur as a result of disrupting the skin ecosystem. microbiota on the majority of body sites (Findley et al., 2013).
The skin offers protective niches and nutrients for microbial The one exception was the feet, which harbored greater diver-
survival, competition, and cooperation (Fredricks, 2001; Roth sity of fungal species.
and James, 1988). On the microscopic scale, the pilosebaceous With the advent of shotgun metagenomics, an even more
unit is a protective invagination that provides a microaerophilic nuanced view of the skin microbiome has emerged. Unlike
environment for obligate and facultative anaerobes. On the 16S rRNA gene sequencing which relies on PCR-amplification
macroscopic scale, folds such as the umbilicus offer an of a specific gene, in shotgun metagenomics the genomic
occluded environment that retains moisture and resists outside DNA in a sample is fragmented and deeply sequenced. Bio-
perturbation. Sebum, secreted through the sebaceous gland, informatic methods are then used to assemble the heteroge-
is a source of lipids that may be utilized as a nutrient source neous microbial genomes that are recovered and then
(Figure 1). For example, the skin bacterium Cutibacterium acnes compared to reference databases to identify species. This
(C. acnes, reclassification of the previous Propionibacterium type of analysis allows for species- and strain-level interroga-
acnes) produces lipases that break down sebum lipids allowing tion of microbiota, a multi-kingdom analysis that is inclusive
it to utilize the resulting fatty acids as nutrients. These fatty acids of fungi and viruses as well as bacteria, and the analysis of
also acidify the skin surface, thereby creating an environment the genetic content and genes and pathways that are enriched
inhibitory of colonization by exogenous microorganisms. Other (Grogan et al., 2019). These methods revealed the strain-level
nutrients available on the skin include salts secreted from sweat variation of skin microbiota and its stability over time. Given
(eccrine and apocrine) glands and cellular debris rich in proteins the frequent perturbations encountered by skin microbes on a
and lipids resulting from desquamation, or sloughing, of the cor- daily basis, the microbiota was surprisingly stable (Oh et al.,
nified layer of the epidermis through a process of terminal differ- 2014, 2016).
entiation. Although the skin surface is mostly desiccated with a Metagenomic techniques have also enhanced our under-
few notable exceptions, the lipids, salts, and cellular debris pro- standing of viral communities associated with the skin. Unlike
vide sufficient nutrients for survival, especially for those mi- bacteria and fungi, there is not a common ‘‘marker gene’’
crobes that are adapted to the generally inhospitable conditions that can be broadly amplified and sequenced to infer viral iden-
(Figure 1). tify. In the healthy skin virome bacteriophages dominate, which
DNA sequencing-based methods to identify and survey mi- like their hosts, are associated with skin microenvironment
crobes have illuminated the vast diversity of species within (Hannigan et al., 2015). Eukaryotic viruses, especially human

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Figure 1. Microbiota-Host Interactions Promote Skin Homeostasis and Immune Response

Multiple microbial species residing in skin promote immune tolerance, elicit pro-inflammatory response, and aid in skin maintenance; in turn, the host provides
nutrients to sustain microbial survival. Staphylococcus epidermidis, a model example of the intimate relationship microbiota has with the host, can both stimulate
and suppress inflammation. Such microbial-host interactions contribute to stability of the microbial ecosystem and skin integrity. Other species such as
Roseomonas mucosa, Malassezia spp., or Corynebacterium accolens can also tune keratinocyte and host immune responses in a context-dependent manner.
Lastly, even the often-problematic skin resident microbe, Cutibacterium acnes, has beneficial interactions with the host as it metabolizes sebum secretions,
which in turn aides in maintaining an acidic skin pH, making the skin suitable for select organisms.

papillomaviruses (HPVs) seem to be controlled to some degree Cutibacterium acnes: Friend in Health, Foe in Acne,
by immune surveillance, as HPVs expand and dominate the or Both?
skin virome in patients with primary immunodeficiencies (Tirosh Cutibacterium acnes is one of the most abundant bacterial spe-
et al., 2018; Pastrana et al., 2018). cies in the adult skin microbiome (Fitz-Gibbon et al., 2013).
A picture of a diverse resident microbiota has emerged, but Formerly known as Propionibacterium acnes, C. acnes is an
key questions remain regarding the function of the skin micro- aerotolerant anaerobe that utilizes lipid-rich sebum as its
biome and which members are beneficial, neutral, or harmful. nutrient source (Brown and Shalita, 1998). Comprising minimal
Similarly, how do changes in the composition of the skin mi- abundance in pre-pubertal skin, C. acnes begins to appear in
crobiota relate to disease, and are these changes causal? the human skin microbiota concomitant with maturation of
Here, we focus on members of the healthy human skin micro- the sebaceous gland and sebum secretion during puberty
biota, which we consider as those taxa that stably reside (in- (Oh et al., 2012). In its role as a commensal component of
transient) on the normal skin in the majority of humans. We the skin microbiota, C. acnes produces propionic acid, which
examine roles for skin microbes within this ecosystem and helps to maintain the acidic pH of healthy skin, thus inhibiting
how these roles present risk as well as reward in the context colonization by more pathogenic microbes (Youn et al., 2013).
of the host. Finally, we consider how changes in the normal Adapted to the nutrient conditions of the human pilosebaceous
skin microbiota can predispose to or exacerbate skin disease unit, C. acnes secretes an extracellular lipase that cleaves
and infection. sebum triglycerides, thus freeing glycerol as a growth substrate

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Figure 2. Risk: Diseases with Causative Agents from or Associated with Skin Microbiota
Microbiota that are most abundant and commonly found in skin microbiome datasets have been identified as the causative agents of the skin disorders and
diseases shown here. The species contributing to disease are often body site dependent, a reflection of microbial niche specificity. For instance, both Malassezia
spp. and Cutibacterium acnes prefer sebum rich environments, thus high abundance of these species at sebum rich sites, such as the scalp or the face, can lead
to host disease. Unfortunately, many species can cause serious systemic disease if given the opportunity to transit to deeper tissue. This occurs most often in
immunocompromised host in the form of bacteremia, surgical site soft tissue infections (SSTI), osteomyelitis, and/or chronic wounds.

and free fatty acids that further acidify the skin (Brown and Sha- et al. showed that C. acnes genomes recovered from acne skin
lita, 1998) (Figure 1). were different than C. acnes genomes from healthy controls
However, C. acnes may be more notorious for its role in the (Fitz-Gibbon et al., 2013). C. acnes from acne patients harbored
inflammatory skin disorder acne vulgaris. Acne affects the pi- unique genomic elements encoding virulence factors that were
losebaceous unit, which consists of small hair follicles associ- rarely present in C. acnes genomes from healthy controls, sug-
ated with a sebaceous gland and is localized to the face, gesting that genomic diversification may drive pathogenicity of
chest, and back (Brown and Shalita, 1998). Here, C. acnes the organism. Strain-specific differences in promoting immune
has the potential to directly and indirectly cause inflammation responses have also been observed, where C. acnes isolated
and tissue damage (Figure 2). Free fatty acids freed from from acne skin induced higher production of the pro-inflamma-
sebum triglycerides by C. acnes are also pro-inflammatory. tory cytokines interferon (IFN)-g and interleukin 17 (IL-17) from
C. acnes are also capable of producing a variety of pro-inflam- peripheral blood mononuclear cells, whereas strains from
matory virulence factors including proteases and factors that healthy skin were more robust in inducing the anti-inflammatory
activate complement and recruit neutrophils (Burkhart cytokine IL-10 (Yu et al., 2016). Comparative proteomic analysis
et al., 1999). of bacterial secreted factors provided mechanistic clues, as
Comparative genomic analysis of C. acnes isolates cultured acne strains were found to produce higher levels of an adhesin
from acne and normal skin has shed some light on the elusive na- and a cell wall hydrolase compared with C. acnes strains isolated
ture of this bacterium’s relationship with the skin. Fitz-Gibbon from healthy individuals.

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Figure 3. Reward: Microbiota Targeting of
Pathogens Associated with Skin Disorders
or Disease
Microbial-microbial interactions between the skin
microbiome (white circles) and pathogens (pink
circles) demonstrate the powerful benefit the skin
microbiome can have for the host. CoNs, Cory-
nebacterium spp, and Roseomonas mucosa target
(arrows point from the source to the target)
Staphylococcus aureus. These bacteria can either
directly kill through the secretion of antimicrobial
factors or limit the virulence of Staphylococcus
aureus through the secretion of an inhibitor or
suppressor of a major S. aureus virulence regu-
lator. Other skin microbial species can target and
limit Cutibacterium acnes, Streptococcus pyo-
genes, and Streptococcus pneumoniae.

context-dependent relationships among

skin microbes and their effects on
the host.
Coagulase-Negative Staphylococci:
Bacterial Warfare on the Skin
To ensure survival, skin resident bacteria
must compete to maintain colonization of
their niche and access to nutrients. As in
any ecosystem, competitive interactions
Porphyrin production by C. acnes may be an important viru- are continuously occurring between microorganisms. In the
lence mechanism that promotes skin inflammation. C. acnes skin, resident microbiota protect the skin from invading, patho-
strains isolated from acne skin have been observed to produce genic, or opportunistic microbes through the process of coloniza-
higher levels of the pro-inflammatory porphyrin molecule than tion resistance (Figures 3 and 4). One manner in which bacteria
strains from healthy subjects (Johnson et al., 2016). Linking can eliminate competition is through direct killing of competing
genomic variation to molecular mechanism, these phenotypic microbes. The full extent of these interactions is unknown, but
changes could be explained by loss of a repressor gene in the the most studied are those where coagulase-negative Staphylo-
porphyrin biosynthetic pathway. Porphyrin production also ap- coccus (CoNS) species inhibit their close but pathogenic relative,
pears to be positively regulated by vitamin B12, driving S. aureus (O’Sullivan et al., 2019). CoNS species are highly abun-
increased porphyrin in acne-associated strains, but with no ef- dant across the skin microbiome. These Gram-positive, faculta-
fect in healthy strains (Barnard et al., 2020). These findings are tive anaerobes are distinguished from S. aureus, which is coagu-
consistent with metatranscriptomic profiling of acne skin, which lase positive, or capable of coagulating blood. On human skin, the
was depleted in expression of vitamin B12 biosynthesis genes CoNS species largely comprise S. epidermidis, S. capitis,
compared with normal skin (Kang et al., 2015). Oral supplemen- S. caprae, S. hominis, S. lugdunensis, and S. haemolyticus.
tation of healthy humans with vitamin B12 over a course of two Some species of CoNS directly kill their S. aureus competitors
weeks similarly resulted in decreased expression of C. acnes by secreting antimicrobial peptides (summarized in Figure 3). For
vitamin B12 biosynthesis genes in their skin microbiota. These example, some strains of S. hominis secrete lantibiotics that
findings together provide evidence for a microbially mediated were shown to be protective against S. aureus colonization in
link connecting acne pathogenesis with porphyrin and vitamin murine models and human subjects with the inflammatory skin
B12 supplementation (Kang et al., 2015). condition atopic dermatitis (Nakatsuji et al., 2017). Nasal strains
C. acnes may also serve as an accomplice to skin pathogenic of S. lugdunensis were found to produce lugdunin, a novel thia-
species, namely S. aureus. Coproporphyrin III (CIII), the most zolidine-containing cyclic peptide that also has potent anti-
abundant extracellular porphyrin molecule produced by S. aureus activity (Zipperer et al., 2016). Phenol-soluble modulins
C. acnes, was shown to induce aggregation of S. aureus and (PSM) are produced by several different CoNS species including
biofilm attachment to abiotic (plasma free) surfaces (Wollen- S. epidermidis, S. capitis, and promote killing of Streptococcus
berg et al., 2014). Other studies have shown that C. acnes en- pyogenes and S. aureus, and C. acnes, respectively (Cogen
hances S. aureus hemolytic and cytolytic activity; these effects et al., 2010; O’Neill et al., 2020).
translated to heightened lesion severity in a murine model of Bacterially produced AMPs may enhance or synergize with
co-infection, and were dependent on pore-forming toxins host immune responses, in addition to their direct killing activity.
from these bacteria, notably C. acnes CAMP (Christie, Atkins, S. epidermidis PSMs work in concert with the host derived anti-
Munch Peterson) factor and S. aureus b-hemolysin (Lo et al., microbial peptide LL-37 to enhance host immune defense (Co-
2011). These studies highlight how microbes regarded as skin gen et al., 2010). Similarly, combining S. hominis lantibiotics
commensals may cooperate with traditional pathogens to with LL-37 enhanced the antimicrobial activity against
enhance their virulence and are yet another example of the S. aureus (Nakatsuji et al., 2017).

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Figure 4. Colonization Resistance, a Collective Contribution of the Skin Microbiome

The skin microbiome is composed of a diverse microbial community; as also defined in Figure 1, this diversity spans through domains, from kingdom to strain. A
recently recognized essential function of the skin microbiome is to provide protection against pathogens, termed colonization resistance. The skin microbiome
achieves this through the capability to directly kill or alter the virulence of pathogens through the secretion of antimicrobial peptides and other molecules.
Additionally, as many species are capable of stimulating keratinocytes, the microbiome can signal to the host to mount a protective immune response to invading
pathogens. Importantly, the combined microbial-microbial and microbial-host interactions play a critical role in maintaining host health.

Another mechanism of bacterial warfare on the skin involves protective, introduction of Esp producing strains into the nasal
interfering with cell-to-cell communications of the pathogenic cavity of S. aureus carriers effectively eliminated S. aureus, while
S. aureus, referred to as quorum sensing. All staphylococci the isogenic Esp mutant did not.
communicate through quorum sensing, specifically through the The above described competitive interactions highlight the
accessory gene regulator (agr) system, and this system is neces- role of microbial competition as a force in shaping the skin micro-
sary for S. aureus skin infection and damage (Wright et al., 2005). biome. Among the staphylococci, genomic diversification
This system also provides a target for commensal bacteria to though mobile genetic transfer may also shape the skin micro-
inhibit the growth and virulence of their competition. For biome and its risk versus reward. The diverse species in the
example, S. caprae inhibited methicillin-resistant S. aureus agr skin microbiome represent a reservoir of genetic material, in
activity in an intradermal skin infection model, thereby improving particular pathogenicity islands, transposons, plasmids, and
infection outcome (Paharik et al., 2017). Such mechanisms of other mobile elements that are transferrable among staphylo-
cross talk have also been identified in atopic dermatitis skin, cocci (Otto, 2013). In fact, the chromosomal cassette carrying
where CoNS such as S. hominis interfere with S. aureus quorum methicillin resistance and other virulence factors likely originated
sensing to prevent S. aureus toxin production and associated tis- from S. epidermidis and potentially other CoNS species. Diversi-
sue destruction and inflammation (Williams et al., 2019). fication through horizontal gene transfer represents a potential
Production of proteases is another potential mechanism mechanism whereby resident skin commensal bacteria could
whereby CoNS species interfere with S. aureus virulence. become more virulent or invasive.
S. epidermidis is capable of producing a serine protease, Esp, Corynebacterium
that inhibits biofilm formation and disrupts intact biofilm of The Corynebacterium are also prevalent and abundant members
S. aureus (Iwase et al., 2010). In addition to epidemiological ev- of the skin microbiota, in particular in moist and occluded areas
idence suggesting that colonization with Esp producing strains is of the body. Corynebacterium, of the phylum Actinobacteria and

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family Actinomycetales, are Gram-positive, aerobic, ‘‘club- ering the overlap in microbiome species composition, and
shaped’’ microorganisms. Corynebacterium species have been demonstrate the role of microbial-microbial interactions in
implicated in producing odorous volatile compounds character- sculpting the overall composition of the microbiome.
istic of axillary sweat (Kligman and Strauss, 1956), though While widely regarded as a commensal bacterium, as usual,
emerging evidence suggests that CoNS species this relationship is context dependent. Multi-drug resistance
S. lugdunenesis, S. hominis, and S. haemolyticus are more effi- has been noted among Corynebacterium species, but especially
cient at sweat biotransformation to the malodourous free thioal- C. striatum, which is considered an emerging pathogen that
chohol (Bawdon et al., 2015). Because they grow slower than causes various device and skin and soft tissue infections in
other skin commensal species and have specialized nutritional immunocompromised, hospitalized, and chronically ill hosts
requirements, Corynebacterium can be difficult to isolate and (Figure 2) (Patel et al., 2016; Wang et al., 2019). Almost all spe-
cultivate under artificial growth conditions (Forbes et al., 1998). cies of Corynebacterium contain a mycolic acid layer, long-chain
Corynebacterium species and their role in competitive interac- fatty acids (usually C22 to C36 in Corynebacterium; Collins et al.,
tions with the skin pathogen S. aureus have been studied most 1982) with key roles in resisting stress, such as detergents, anti-
thoroughly in the nasal cavity. Many of the microbial species microbials, and even lysozyme, allowing colonization and sur-
residing in the nasal cavity are also found on the skin and vice vival across various conditions (Burkovski, 2018; Tauch and Bur-
versa (Human Microbiome Project, 2012; Grice et al., 2009), kovski, 2015). Mycolic acid also can influence host responses,
including Corynebacterium species. This is despite the nasal but this is also contextual. In a murine model of epicutaneous
cavity being occluded and comprised non-cornified stratified colonization, it was found that C. accolens only promoted inflam-
epithelium. The nasal cavity is also a reservoir of S. aureus car- mation in an IL-23-dependent manner when animals were fed a
riage, and nasal carriage is a well-established risk factor for high-fat diet (Ridaura et al., 2018). This effect was dependent on
infection (Kluytmans and Wertheim, 2005). Studies defining the mycolic acid in the cell envelope and demonstrates how the
human nasal microbiota have led to the identification of microbial metabolic state of the host can influence its relationship with
community determinants influencing the competitive exclusion components of the skin microbiota.
of S. aureus in the nasal cavity (Yan et al., 2013). One such spe- Staphylococcus epidermidis: A Model Commensal to
cies, C. pseudodiphtheriticum, was identified from culture-inde- Probe Homeostatic Immune Responses
pendent sequencing and random forest-supervised learning The majority of studies that probe immune responses to
models as a predictor that was strongly negatively correlated commensal bacteria have utilized Staphylococcus epidermidis
with S. aureus carriage. In vitro co-culture confirmed the predic- as a model skin commensal. Study designs in murine models
tive model, as cultured isolates of C. pseudodiphtheriticum typically use topical association procedures to colonize the
demonstrated strong inhibition of S. aureus. More recent studies skin. Liquid cultures of the bacterium, usually 107–109 CFU,
have built on these findings to show a novel direct killing mech- are concentrated and swabbed onto the skin multiple times
anism of C. pseudodiphtheriticum that was dependent on over a time-course of several days to several weeks. This design
S. aureus virulence components (Hardy et al., 2019). is typically used when colonizing murine skin with bacterial
Skin commensal Corynebacterium species may also limit the strains isolated from human skin. Due to differences in nutrient
virulence of S. aureus through modulating the agr quorum availability, pH, and other microenvironment parameters, iso-
sensing system and expression of agr-inducible virulence genes lates specialized to life on human skin may be recalcitrant to
(Figure 3). In vitro co-culture of C. striatum or C. striatum cell-free colonization of murine skin. Thus, optimization and experimental
conditioned media with S. aureus resulted in decreased expres- confirmation of colonization are critical to robust experimental
sion of S. aureus genes regulated by agr, reduced hemolytic ac- designs.
tivity, and increased epithelial adhesion, characteristic of viru- In neonatal life, colonization is of particular importance during
lence attenuation. In a dermal murine abscess infection model, a critical window of hair follicle morphogenesis. Scharschmidt
co-infection of S. aureus with C. striatum reduced S. aureus mi- et al. observed that S. epidermidis colonization of murine
crobial burden compared with infection with S. aureus alone neonatal skin provided protection, or immune tolerance, later
(Ramsey et al., 2016). While it is unknown how C. striatum elicits in life when challenged (Scharschmidt et al., 2015). This effect
such interference, these findings demonstrate how mechanisms was dependent on a migratory wave of activated regulatory
of microbial interference have the potential to limit S. aureus T cells (Tregs) into neonatal skin, which was concomitant with
colonization and virulence. hair follicle morphogenesis (Scharschmidt et al., 2017). The
Corynebacterium species have also been shown to inhibit mechanism underlying this selective wave of Treg infiltration is
streptococcal pathogens. The observation that children with dependent on S. epidermidis stimulation of the hair follicle-
high relative abundances of nasal Corynebacterium were free derived chemokine Ccl20 and its receptor Ccr6, which is ex-
of Streptococcus pneumoniae (pneumococcus) informed further pressed on Tregs (Scharschmidt et al., 2017). This work demon-
mechanistic investigations of microbial antagonism (Bomar strates how skin morphogenic processes coordinate with the im-
et al., 2016). C. accolens, commonly found in adult and human mune system to establish tolerance to our commensal
nasal cavity, depends on a lipase for its inhibitory activity that microbiota (Figure 1).
cleaves triacylglycerols that are found in skin and sebum. In hy- In adult murine skin, microbial colonization has been shown to
drolyzing these triacylglycerols, free fatty acids are released that control the local inflammatory milieu and T cell function (Naik
inhibit S. pneumoniae (Bomar et al., 2016). Biological observa- et al., 2015, 2012). For example, infection of germ-free mice
tions, such as these regarding microbial-microbial interactions with the parasitic pathogen leishmania resulted in uncontrolled
from nasal isolates are likely to be relevant to the skin, consid- parasite growth and blunted protective immune response,

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despite lesser infection pathology compared to conventionally Despite being an integral part of the resident skin microbiota,
raised control mice (Naik et al., 2012). Notably, these responses Malassezia species have a clear connection to skin disease.
could be rescued in germ-free mice by colonization with Dandruff, a frequent scalp issue, and seborrheic dermatitis are
S. epidermidis (Naik et al., 2012). Thus, S. epidermidis not only most commonly associated with M. globose, M. furfur, and M.
promotes tolerance to the commensal microbiota but also tunes restricta (Han et al., 2019; Johansson et al., 2018). In this case,
protective immune responses appropriately when a pathogen is Malassezia spp. metabolize sebum to different fatty acids, which
encountered. then act as irritants, causing flaking and irritation (DeAngelis
S. epidermidis also has demonstrated roles in modulating et al., 2005). Malassezia spp. have also been tied to atopic
innate immune responses during tissue repair and wound heal- dermatitis, and recent studies have shed light on how orchestra-
ing of the skin. Like other Gram-positive bacteria, tion of anti-fungal immunity may go awry to promote IL-17 and
S. epidermidis cell membrane and/or wall contains lipoteichoic IL-23-dependent inflammation under conditions of barrier
acid (LTA), an adhesion molecule that is released upon bacteri- impairment (Sparber et al., 2019). Furthermore, unchecked colo-
olysis (Ginsburg, 2002). LTA from Staphylococcal species sup- nization by M. globosa and M. restricta can result in pityriasis,
pressed inflammation during tissue injury through a TLR2- skin that is considered to be infected and characterized by
dependent mechanism to prevent excessive damage (Lai rash and inflammatory signals, such as skin redness and thick-
et al., 2009). Staphylococcal LTA may also have applications ening (Pradhan et al., 2018). Finally, M. furfur is an emerging
for the treatment of inflammatory disease. In an acne model of culprit in invasive fungal infections in infants (Chen et al., 2020).
P. acnes induced skin inflammation, staphylococcal LTA appli- Indeed, Malassezia spp. can be the causative agents in dis-
cation abrogated inflammatory effects via induction of a micro- ease and are often framed as such, but there is abundant evi-
RNA, miR-143, which destabilizes the TLR2 mRNA and de- dence of positive impact on the skin microbiome and the host.
creases protein production (Xia et al., 2016). Many Malassezia spp. secrete extracellular vesicles that signal
S. epidermidis interactions with its host exist against the back- keratinocytes to secrete pro-inflammatory cytokines (Vallhov
drop of a complex microbial milieu that may not always behave in et al., 2020; Watanabe et al., 2001; Zhang et al., 2019). Like other
the interest of the host. The mechanisms that S. epidermidis use skin resident microbes, Malassezia spp. are able to inhibit and
to compete in the skin microbial community may double as viru- compete with the pathogen S. aureus. The dominant secreted
lence mechanisms that promote the adherence, survival, and protease of M. globosa (MgSAP1) not only cleaves the
dissemination in certain situations. For example, the S. aureus protein A, a major virulence factor, but also is able to
S. epidermidis protease Esp may prevent S. aureus biofilm for- dissociate biofilms (Li et al., 2018). These studies suggest that
mation, but it also degrades human complement component despite the risk, there is potential for Malassezia in promoting
C5 and fibrinogen, critical proteins for the complement and skin health.
coagulation cascade which forms a pillar of the innate immune The Microbiome and Skin Disease
response (Moon et al., 2001). S. epidermidis PSMs have potent Changes in the skin microbiota are often investigated in cuta-
anti-bacterial activity but are also essential for structuring and neous disease and disorders. It is possible that these searches
dissemination of biofilm in S. epidermidis indwelling device will identify a novel and/or previously unsuspected species in as-
infection (Le et al., 2019). S. epidermidis also produces prote- sociation with disease. More often, they reveal ‘‘dysbiosis’’ or an
ases that promote its adherence to plastic (EcpA), degrade imbalance of microbial inhabitants on the skin. This terminology
host AMPs, and evade elimination by immune cells (SepA, is imprecise and inaccurate for multiple reasons, as fully elabo-
APS) (Cheung et al., 2010; Martı́nez-Garcı́a et al., 2018). These rated by Oleson et al. (Olesen and Alm, 2016); namely, dysbiosis
mechanisms highlight potential reasons why S. epidermidis is suggests that (1) a ‘‘balanced’’ skin microbiome has been
prone to cause device-associated infections and is the most defined; (2) a ‘‘balanced’’ skin microbiome is equivalent to skin
common microbe associated with such (Zheng et al., 2018). health; and (3) an ‘‘imbalance’’ is causal of disease. Demon-
Recently, the S. epidermidis protease EcpA was identified as a strating causality of dysbiotic states presents challenges as
factor contributing to tissue destruction and inflammation in appropriate model systems may not be readily available and/or
the monogenetic skin disorder Netherton syndrome (Williams there is difficulty isolating microbes in culture. Furthermore, the
et al., 2020), highlighting how host-dependent interactions with relevance of ‘‘Who is there?’’ is less relevant than ‘‘What are
the resident skin microbiota can impact disease severity. they doing?,’’ as highlighted by our discussion thus far of the
Malassezia context-dependent risk versus reward of microbial colonization.
Malassezia are the most abundant fungi found on human skin Thus, while associations are abundant in the literature, the rele-
(Findley et al., 2013). In a similar fashion as other resident skin mi- vance of such changes is often ambiguous.
crobes, Malassezia spp. are highly evolved for life on the skin and A species that repeatedly appears and dominates the micro-
exhibit niche specificity where nutrients necessary for survival biota in association with skin disorders is S. aureus, often found
are readily available. Malassezia sp. thrive in lipid-rich environ- where there is a breach in the skin barrier, such as atopic derma-
ments; thus, they are commonly found in skin sites enriched titis (AD) or wounds. While the current discussion is focused on
with sebaceous glands such as the face, scalp, and outer ears resident skin microbiota, this pathogen deserves mention with
(Kaneko et al., 2010). The human-associated species of Malas- regard to skin disease as it is also the leading cause of skin
sezia include M. dermatis, M. furfur, M. globosa, M. restricta, and soft tissue and surgical site infection and a major antimicro-
and M. sympodialis. The role of this species in the skin micro- bial resistance threat (Tong et al., 2015). Yet, S. aureus is some-
biome is quite nuanced because they frequently dominate times characterized as having a commensal relationship in the
diseased skin with varying levels of disease severity (Figure 2). skin microbiome (Krismer et al., 2017). Indeed, S. aureus can

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asymptomatically co-exist as part of the human microbiota and Conclusions

in the nares, about 30% of healthy individuals are asymptomat- The skin microbiome is home to thousands of microbial species
ically colonized; however, colonization is a significant risk factor that create a rich ecosystem providing many benefits to the host
for subsequent infection (von Eiff et al., 2001). In an example of as we have highlighted here. These benefits are derived from
how skin commensals cooperate with pathogens, Micrococcus their interactions with different components of the skin
luteus enhanced S. aureus pathogenesis in a murine sepsis ecosystem. Furthermore, strain-specific attributes are critical
model while M. luteus itself was cleared (Boldock et al., 2018). in the outcome of host-microbial interactions. Such interactions
Thus, while the risks are evident, it is less clear what ‘‘rewards’’ have the potential to provide novel, translatable targets for the
S. aureus has to offer in the human skin microbiota. prevention and treatment of skin disease and disorders. Thus,
At the genomic level, specialization and diversification of one must consider the potential risks along with the rewards,
S. aureus is also a significant factor that can drive skin disease including how changing one component of a highly dynamic, in-
and clinical variation and outcomes. In pediatric atopic derma- tertwined consortium will affect other interactions.
titis flares, shotgun metagenomic profiling approaches have al- Here, we have highlighted ways in which the most abundant
lowed strain-level analysis of S. aureus and S. epidermidis pop- and stable (‘‘resident’’) skin microbial species may be detri-
ulations (Byrd et al., 2017). In this cohort, S. aureus strains were mental to the host. Thus, we ponder the question, as others
clonal within each patient and highly personal, suggesting strain have posed, is it fair and accurate to refer to these microbes
variation in driving different disease outcomes. In a murine model as ‘‘commensals’’? Given the opportunity or if forced into a sur-
of cutaneous colonization, S. aureus isolates from more severe vival state, any commensal may become pathogenic. However,
AD flares elicited increased epidermal thickening and promoted this ‘‘switch’’ in lifestyle can be true of many organisms in eco-
T cell infiltration in the skin, compared with strains from less se- systems beyond the microbiome. Therefore, we surmise that
vere disease and/or healthy individuals (Byrd et al., 2017). Simi- classification of a given microbial species as a commensal is
larly, in chronic wounds, shotgun metagenomics in a prospective dependent on its interaction state with the host. Furthermore,
cohort study of diabetic foot ulcers revealed that S. aureus rela- both strain and host specificity are highly relevant as has been
tive abundance was significantly increased in non-healing demonstrated by CoNS and S. aureus studies.
wounds, and that some S. aureus strains were exclusively linked Importantly, the wealth of data generated from DNA-based
with non-healing outcomes (Kalan et al., 2019). Unlike atopic techniques combined with culturing techniques has set the
dermatitis, ‘‘generalist’’ strains of S. aureus were also present groundwork for asking the persistent but fundamental questions,
across both healing and non-healing outcomes. These findings ‘‘What microbial species compose a healthy skin microbiome?
suggested that S. aureus strain-level variation was associated How is a healthy skin microbiome maintained’’? In order to answer
with poor healing outcomes. Using a murine model of diabetic these questions, future studies examining understudied species
wound healing coupled with matched patient wound isolates, and their molecular and biochemical mechanisms of interacting
these associations were shown to be biologically relevant and in their ecosystem are needed. At the same time, it is critical to
suggested mechanisms whereby the same species can cause consider that these mechanisms exist against a backdrop of the
differential disease outcomes (Kalan et al., 2019). entire ecosystem and thus are one of many, many ‘‘conversa-
One of the thrilling aspects of the skin microbiome is the abun- tions’’ that are taking place at the same time. A challenge to the
dance of microbes still to be identified. Excitingly, now with in- field will be to demonstrate that these mechanisms have biological
sights from DNA-based microbiome analysis, targeted culturing and clinical relevance, when considered outside of model systems
has yielded the successful isolation and classification of new and in the complex ecosystem of the human skin microbiome.
species within genera—Roseomonas is a prime example (Rihs
et al., 1993). Guided by genomic analyses of the skin microbiota, ACKNOWLEDGMENTS
targeted culturing approaches uncovered Roseomonas mucosa
as inhibitory to S. aureus. Roseomonas are pink Gram-negative We thank the members of the Grice lab for their underlying contributions and
bacteria found on the skin, the teeth, and in aquatic environ- the funding sources that make our work possible. Support to E.A.G. includes
grants from the National Institutes of Health (R01NR015639, R01AI143790,
ments; dominant strains identified on human skin include: and R01AR066663), the Linda Pechenik Montague Investigator Award, and
R. gilardii, R. cervicalis, and R. mucosa (Han et al., 2003). Similar awards from the Burroughs Wellcome Fund (PATH Award) and the Derma-
to other skin microbiota discussed in this review, they have the tology Foundation (Sun Pharma Research Award). L.F. was supported by a
NIH/NIAMS training grant (T32AR007465).
potential to be pathogenic and have previously been identified All figures were created with BioRender.com.
as the causative agent in bacteremia and wound infections
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