Review Article

Dermatology 2019;235:287–294 Received: December 13, 2018

Accepted after revision: March 25, 2019
DOI: 10.1159/000499858 Published online: May 21, 2019

Staphylococcus epidermidis:
A Potential New Player in the
Physiopathology of Acne?
Jean-Paul Claudel a Nicole Auffret b Marie-Thérèse Leccia c Florence Poli b
       

Stéphane Corvec d Brigitte Dréno e
   

a Private
Practice, Tours, France; b Private Practice, Paris, France; c Department of Dermatology, Allergology and
   

Photobiology, CHU A. Michallon, Grenoble, France; d CHU Nantes, Service de Bactériologie-Hygiène Hospitalière,
 

CRCINA, INSERM, U1232, Université de Nantes, Nantes, France; e UF dermato-cancérologie, CHU Nantes-Hôtel-Dieu,
 

Inserm U1232, CIC Biothérapie Inserm 05031, Nantes, France

Keywords
Acne vulgaris · Acne · Cutibacterium acnes · Dysbiosis ·
Microbiota · Pilosebaceous unit · Sebum · Staphylococcus
epidermidis
Abstract
Background: Cutibacterium acnes has been identified as one
of the main triggers of acne. However, increasing knowledge
of the human skin microbiome raises questions about the
role of other skin commensals, such as Staphylococcus epi-
dermidis, in the physiopathology of this skin disease. Sum-
mary: This review provides an overview of current knowl-
edge of the potential role of S. epidermidis in the physiopa-
thology of acne. Recent research indicates that acne might
be the result of an unbalanced equilibrium between C. acnes
and S. epidermidis, according to dedicated interactions. Cur-
rent treatments act on C. acnes only. Other treatment op-
tions may be considered, such as probiotics derived from S.
epidermidis to restore the naturally balanced microbiota or
through targeting the regulation of the host’s AMP media-
tors. Key Messages: Research seems to confirm the benefi-
cial role of S. epidermidis in acne by limiting C. acnes over-
colonisation and inflammation. © 2019 S. Karger AG, Basel
Introduction
Two different types of microorganisms are present on
the skin and appendages. One of them consists of resident
microorganisms or commensals, which, most of the time,
are harmless and non-pathogenic, and sometimes may
even have beneficial effects for the host. The second group
consists of transient microorganisms, which may be
harmful and pathogenic and colonise the skin after injury
or trauma, and lead to infections and inflammation [1–3].
With the availability of bioinformatic tools leading to
new phylogenetic approaches, important advances have
been made over the last years either to investigate the di-
versity and the topology of skin microbiota or to identify
the different commensal microorganisms present on the
skin, to evaluate the relative abundance of each popula-
tion, and to understand their beneficial role or contribu-
tion to dermatological conditions such as acne [4–6].
Metagenomic analysis and sequencing of the 16S ribo-
somal RNA gene are the predominant bacteriological
sampling methods employed for analysing the bacterial
composition of microbial communities, and choosing the
most effective study design is crucial for obtaining mean-
ingful analysis results [7]. Thus, physiological character-

© 2019 S. Karger AG, Basel Brigitte Dréno

UF dermato-cancérologie, CHU Nantes-Hôtel-Dieu
Inserm U1232, CIC Biothérapie Inserm 05031
E-Mail karger@karger.com
Place Alexis Ricordeau, FR–44093 Nantes Cedex 01 (France)
www.karger.com/drm E-Mail brigitte.dreno @ atlanmed.fr

TLRs
a b
Fig. 1. Healthy skin and skin with acne lesion in formation. a
Healthy skin. In healthy skin S. epidermidis controls the prolifera-
tion of C. acnes. b Formation of a microcomedone after over-col-
onisation of the skin by C. acnes leading to dysbiosis. Over-colo-
istics of different skin sites sampled have been associated
with different levels of bacterial diversity including Acti-
nobacteria such as Propionibacteria, very recently re-
named Cutibacteria (comprising Cutibacterium acnes
and also Cutibacterium granulosum and Cutibacterium
avidum), Proteobacteria, Bacteroides and Firmicutes;
Staphylococcus epidermidis belongs to the latter group [5,
6, 8, 9]. Of these, C. acnes and S. epidermidis are two of
the main commensal skin bacteria [3, 10–12]. Until very
recently, research in acne has mainly focused on the role
of C. acnes while the role of S. epidermidis in acne has
been discussed for several years but still remains to be
elucidated [10, 13].
The aim of the present article is to review published
data concerning the role of S. epidermidis in the physio-
pathology of acne and to present future treatment per-
spectives based on available data and evidence.
Methodology
A review of the literature published between the beginning of
2000 and 2018 and available from PubMed was carried out using
the following key words: acne, acne vulgaris + microbiota, skin +
microbiota, acne + microbiota + Propionibacterium acnes + Staph-
ylococcus epidermidis, bacterial resistance, skin commensal + Pro-
pionibacterium acnes + Staphylococcus epidermidis.
288 Dermatology 2019;235:287–294
DOI: 10.1159/000499858
AMPs TLRs PAR
AMPs
C. acnes
S. epidermidis
Corynebacterium
Other commensal
bacteria
S. aureus
M. furfur
nisation of C. acnes during puberty leads to dysbiosis and acne.
AMP, antimicrobial peptides; TLR, Toll-like receptors; PAR, pro-
tease-activated receptors.
Results
The Interplay of Host Skin and the Cutaneous
Microbiota
The interplay of host skin and the cutaneous microbi-
ota in the skin’s immune system is able to differentiate
between harmless commensal microorganisms including
Corynebacterium sp., Staphylococcus sp. excluding S. au-
reus, Cutibacterium sp., Malassezia furfur, and transient,
harmful pathogenic microorganisms such as S. aureus,
Streptococcus pyogenes, and Enterobacteriaceae. Even
though it seems as if this recognition involves the host’s
immune response, this mechanism is not fully under-
stood. Toll-like receptors (TLRs) have been reported to be
desensitised through prolonged exposure to commensal
microorganisms, either through a decreased expression of
TLR on the cell surface or by activation of the TLR path-
way inhibitors interleukin-1 receptor-associated kinase 3
(IRAK3) and the suppressor of cytokine signalling 1
(SOCS1) [14, 15]. Moreover, specificity may be achieved
by a combined recognition of pathogen-associated mo-
lecular patterns through pattern recognition receptors [6].
Thus, both such recognised commensals C. acnes and
S. epidermidis seem to interact with the host, helping to
protect the healthy skin from colonisation by pathogens
[9, 16]. Figure 1 provides visual support.
Claudel/Auffret/Leccia/Poli/Corvec/
Dréno
 However, the composition of the cutaneous microbi-
ota evolves constantly and changes over time. As an ex-
ample, a disturbed balance or dysbiosis of previously
healthy skin caused by exogenous factors such as injury,
stress, or pollution, or endogenous factors (hormonal
changes, changes of pH) may induce inflammatory skin
disorders such as acne, atopic dermatitis, rosacea, and
psoriasis [13, 17–21]. Specifically, during puberty, the in-
crease and qualitative modification of sebum due to hor-
monal modifications may lead to an unbalanced skin mi-
crobiota via an increased colonisation of the piloseba-
ceous unit and of the skin surface by C. acnes [6]. This
over-representation may be due to a selective advantage
linked to the nutritive substance availability [22].
The Role of C. acnes
In healthy skin, C. acnes plays a beneficial role in the
cutaneous microbiota of the pilosebaceous unit. It limits
the growth of S. aureus, such as community-acquired
methicillin-resistant S. aureus, as well as that of S. pyo-
genes in maintaining an acidic pH of the pilosebaceous
follicle by hydrolysing sebum triglycerides and by secret-
ing propionic acid [6, 23, 24].
However, during puberty, over-colonisation of the pi-
losebaceous unit by C. acnes may lead to a loss of diversi-
fication and dysbiosis, potentially causing acne [6, 25–
27]. A recent clinical study using the single-locus se-
quence typing method investigated C. acnes subgroups
on the face and back in patients with severe acne and in
healthy subjects [28]. In almost 75% of the acne patients,
C. acnes phylotypes were identical on the face and back,
whereas this was only the case in about 45% of the healthy
subjects. In the healthy group, phylotypes IA1 (39%) and
II (43%) were the main phylotypes, whereas in the acne
group IA1 (84%), especially on the back (96%), was the
main phylotype. This may confirm the hypothesis that
acne severity may be associated with a loss of diversity of
C. acnes phylotypes, following a selection of phylotype
IA1/clonal complex (CC) 18 present in all acne patients
[28–30].
Therefore, different inflammatory profiles, depending
on the phylotype (i.e., phylotype IA1, which has been
mainly observed on the face and back of acne patients and
cluster of C. acnes activating the innate immunity via the
expression of protease-activated receptors (PARs), tu-
mour necrosis factor-α, and the production of interferon-γ
and interleukins [IL-8], have been observed [28, 31–37].
Moreover, C. acnes activates the release of lipases, matrix
metalloproteinases, and hyaluronidases, leading to hy-
perkeratinisation of the pilosebaceous unit and finally to
Staphylococcus epidermidis and Acne
comedones, papules, and pustules [31–34, 38]. Figure 1
shows the difference between healthy microbiome and
microbiome suffering from dysbiosis.
The Role of S. epidermidis
S. epidermidis is the most frequently isolated commen-
sal species from human epithelia [25, 39]. It colonises pre-
dominantly axillae, the head, and nares, and has gener-
ally a non-pathogenic relationship with its host [11, 39].
S. epidermidis belongs to the group of coagulase-neg-
ative staphylococci, which differs from coagulase-posi-
tive staphylococci such as S. aureus by lacking the enzyme
coagulase. According to multi-locus sequence typing, the
species showed a high degree of diversity with more than
400 identified sequence types (STs) compared to 155 for
C. acnes [40, 41]. Most clinical isolates belong to CC2,
which comprises the most frequently isolated ST2. Pos-
sibly, the successful spread of ST2 may be due to the fact
that all ST2 isolates contain IS256 insertion sequences
and ica genes, two factors found to be correlated with S.
epidermidis invasiveness [42, 43]. Nevertheless, contro-
versy still exists about the fact that icaA is a useful marker
for S. epidermidis biofilm [44].
In the past, S. epidermidis has been considered an in-
nocuous commensal microorganism on the human skin.
Nowadays it is seen as an important opportunistic patho-
gen. It is the most frequent cause of nosocomial infec-
tions, at a rate about as high as that due to its more viru-
lent cousin S. aureus. In particular, S. epidermidis repre-
sents the most common source of infection on indwelling
medical devices [45].
Treatment is complicated by specific antibiotic-resis-
tant genes and the formation of biofilms, multicellular
agglomerations that have intrinsic resistance and toler-
ance to antibiotics and mechanisms of host defence [46].
Furthermore, investigations have identified specific mo-
lecular determinants allowing S. epidermidis immune in-
vasion and its ability to cause chronic diseases [47]. These
causes are believed to have original functions in the non-
infectious lifestyle of this microorganism, emphasising
the accidental nature of S. epidermidis infections allowing
differentiating between portage, contamination, and in-
fection. A better understanding of the physiology of S.
epidermidis is important to evaluate therapeutic strate-
gies against S. epidermidis infections [39].
Certain strains of S. epidermidis may modulate the
host innate immune response, especially of TLR 2, and
thus allow the host to fight against pathogens [6, 28]. Phe-
nol-soluble modulins produced by S. epidermidis were
shown to selectively inhibit skin pathogens, such as S. au-
Dermatology 2019;235:287–294 289
DOI: 10.1159/000499858
reus and Group A Streptococcus, and, together with host
antimicrobial peptides (AMPs), enhanced their elimina-
tion [48–50]. Moreover, S. epidermidis activates the AMP
expression of keratinocytes through a TLR2-dependent
mechanism [51]. This confirms that this skin commensal
interacts closely with the host innate immune mechanism
[48, 49]. This was also shown through the microdissec-
tion of epidermal compartments of the dermis and of the
adipose tissue followed by 16S ribosomal RNA sequenc-
ing demonstrating that colonisation with S. epidermidis
tunes T-cell homing and function in an IL-1-dependent
manner [52, 53].
Other very recent research work reported that S. epi-
dermidis may also protect against skin neoplasia through
the production of 6-N-hydroxyaminopurine, a molecule
that inhibits DNA polymerase activity [54]. Moreover,
butyric acid, released by S. epidermidis, allows adipose-
derived stem cells to differentiate into adipocytes and lip-
id accumulation in the cytoplasm, resulting in an in-
creased dermal layer [55].
The Interplay between S. epidermidis and C. acnes in
Acne
S. epidermidis and C. acnes use glycerol as a shared car-
bon source to produce different short-chain fatty acids
(SCFAs) used as antimicrobial agents to compete against
each other. They are both present in acne lesions. This
concomitant presence has raised questions about their re-
spective role in the pathogenesis of acne [56, 57]. While
there is no evidence that S. epidermidis plays an active role
in the onset of acne, C. acnes is currently associated with
acne [9].
Some S. epidermidis isolates have been shown through
an antagonism assay to possess antimicrobial activity
against C. acnes [27, 56]. Among the S. epidermidis strains
with an elevated antimicrobial activity, differences in inhi-
bition zone diameter and appearance were observed, indi-
cating that the antimicrobial substances were of a different
nature. Most of the S. epidermidis strains displayed small
zones of inhibition (2–4 mm) against C. acnes and some
strains produced opaque zones of inhibition. One strain,
FS1, produced very large inhibitory zones (>10 mm), but
was not active against all C. acnes strains tested. Another
strain, 14.1.R1, inhibited all C. acnes strains, but produced
only small zones of inhibition (2–5 mm). No difference in
prevalence and intensity was noted in the antimicrobial
activity of S. epidermidis strains isolated from normal and
acne-affected skin, respectively. Likewise, the origin of C.
acnes strains did not determine their susceptibility to the
antimicrobial activity of S. epidermidis, since strains iso-
290 Dermatology 2019;235:287–294
DOI: 10.1159/000499858
lated from acne lesions and healthy skin, respectively, were
not significantly different in their susceptibility patterns
towards S. epidermidis. Conversely, the study showed a
higher frequency of antimicrobial activity among certain
C. acnes strains, such as I-2 phylogroup, against S. epider-
midis. The authors hypothesised a likely possible presence
and secretion of a bacteriocin or bacteriocin-like substance
specific to C. acnes phylogroup I-2 [13]. C. acnes strains
and their antimicrobial activities against S. epidermidis
have also been investigated. However, regarding the skin
status origin (healthy, moderate, or severe acne), the anti-
microbial activity ranged from 29 to 39%. Consequently,
type IA1 CC18 C. acnes strains largely involved in acne did
not present higher activity compared to healthy strains
[13].
Different antagonism investigations demonstrated
that, in vivo, S. epidermidis controls the proliferation of
C. acnes via the release of succinic acid, a fatty acid fer-
mentation product, which inhibits surface TLRs of kera-
tinocytes and tumour necrosis factor and suppresses C.
acnes-induced IL-6 [27, 56, 58].
With both C. acnes and S. epidermidis being present on
the skin, the inhibition of C. acnes-induced inflammation
by S. epidermidis may potentially be dependent on staph-
ylococcal LTA-induced miR-143 on keratinocytes,
known for limiting inflammation. Research suggested
that the mechanism for LTA-miR-143-mediated sup-
pression of TLR2 signalling is accomplished by miR-143
targeting the 3′UTR of TLR2. It thereby decreases the
TLR2 protein production, which plays a major role in the
inhibition of C. acnes-induced cutaneous inflammation
[58–60]. Thus, it helps to regulate skin homeostasis and
to suppress the pathogenic inflammation that is induced
by C. acnes [58, 61].
Accordingly, an unbalanced equilibrium between C.
acnes and S. epidermidis in pilosebaceous units of acne
patients in favour of phylotype IA1 CC18 C. acnes strains
(75–80 of cases) may not allow S. epidermidis to fully play
its role as a regulator of the natural skin homeostasis in
limiting the growth of C. acnes. Figure 2 shows visually
the interplay between C. acnes and S. epidermidis.
S. epidermidis and its Implication in the Choice of
Current and Future Acne Treatments
Current topical acne treatments principally include
different retinoids, such as adapalene and tretinoin,
which reduce inflammation by modulating the innate im-
munity activated by C. acnes [62–65]. Apart from ben-
zoyl peroxide, the use of topical antibacterials such as
erythromycin and clindamycin in monotherapy resulted
Claudel/Auffret/Leccia/Poli/Corvec/
Dréno
 Dysbiosis Balanced microbiome
C. acnes releases
coproporhyrin III
promoting
S. aureus
X X
biofilm
X X
S. aureus
biofilm
Fig. 2. Bacterial interactions on the skin. AMP, antimicrobial peptides.
in the development of antibiotic-resistant strains of not
only C. acnes but also of S. epidermidis in 4–6 weeks [30,
57, 66]. Systemic antibiotics have been reported to cause
only little resistance but can lead to collateral damage in
gut microbiota [30, 33, 67]. Oral isotretinoin normalises
the response of the innate immune system to C. acnes by
inhibiting its proliferation [68].
Thus, eliminating only C. acnes may favour the prolif-
eration of S. aureus, triggering inflammatory acne flare-
up and proliferation of S. epidermidis, leading to another
unbalanced skin homeostasis and a risk of nosocomial
infections.
AMPs are effector molecules of the innate immune
system of the skin. They are amphipathic and disrupt the
lipid membrane of the bacterium, leading to cell lysis and
death by interacting preferentially with negatively charged
bacterial membranes rather than with neutrally charged
mammalian cell membranes. The importance of the
AMPs’ contribution to host immunity is undeniable as
alterations in AMP expression have been associated with
various pathologic processes. Nevertheless, data regard-
ing the role of AMPs in acne vulgaris are limited. A re-
cently published study reports that the AMPs hBD-1 and
cathelicidins play an important role in the pathogenesis
of acne [69]. AMPs have shown activity against a broad
Staphylococcus epidermidis and Acne
S. epidermidis inhibits
S. aureus biofilm
C. acnes inhibits proliferation of
X
X S. epidermidis through hydrolyzing
sebum triglycerides and release
of propionic acid
S. epidermidis inhibits proliferation
of C. acnes through glycerol and
succinic acid
S. epidermidis induces keratinocytes
to produce AMPs to kill S. aureus
CoproporphyrinIII
Antimicrobial peptides
C. acnes
S. epidermidis
S. aureus
spectrum of Gram-positive and Gram-negative bacteria,
as well as some fungi, parasites, and enveloped viruses
[70]. They are produced as a response by keratinocytes
and sebocytes. However, they also promote additional
inflammatory responses. The production of AMPs com-
prises ß-defensins, RNase 7, the S100-protein psoriasin,
and cathelicidins, and is mediated by the MyD88 pathway
and IL-1 signalling. In addition, it has been demonstrated
that more cells express TLR-2 as acne severity increases
[33]. This may be one explanation why agents that target
TLR-2, such as topical retinoids, have a greater efficacy in
patients with more severe acne [71]. Cytokines are also
produced as a result of the interaction between C. acnes
and TLR-2, defensins, and matrix metalloproteinase via
PAR-2R activation [72].
Another treatment approach could be the regular oral
or topical supplementation of the skin microbiota with a
beneficial microorganism (probiotics) for patients with
acne by re-equilibrating the cutaneous microbiota [73,
74]. In 2010, Arck et al. [75] suggested that not only a
brain-gut or brain-skin axis, but also a gut-skin axis ex-
ists. The authors showed that oral supplementation of a
Lactobacillus strain in mice dampens stress-induced neu-
rogenic skin inflammation and hair growth inhibition.
Their concept suggested that modulation of the micro-
Dermatology 2019;235:287–294 291
DOI: 10.1159/000499858
biota by deployment of probiotics reduces stress-induced
neurogenic skin inflammation. These observations raise
hope that the right kind of bacteria may have beneficial
effects on the skin homoeostasis, skin inflammation, and
peripheral tissue responses to perceived stress. Other
studies conducted in humans confirmed this hypothesis
[76–78]. Thus, probiotics may be efficient in acne and
other inflammatory skin diseases such as atopic dermati-
tis and potentially psoriasis [79–83].
In this perspective, studies indicate that S. epidermidis
may control dysbiosis caused by C. acnes, thus reducing
acne severity [27, 56]. However, it still remains unclear
which SCFA in the products of S. epidermidis glycerol fer-
mentation primarily contributes to the anti-C. acnes ef-
fect. It is also undetermined whether SCFAs act together
with other antimicrobial molecules in fermentation prod-
ucts to display their anti-C. acnes activities. The anti-C.
acnes activity of the fermented media persisted after boil-
ing the said media, thereby suggesting that the antimicro-
bial proteins/peptides may not be the major contributors
to the anti-C. acnes activity of fermented media [56].
Pro-drugs such as the SCFAs pivaloylomethyl butyrate
(AN-9) have been developed to achieve pharmacologic
concentrations of such SCFAs in vivo [84]. Moreover, live
S. epidermidis may potentially be used as an active com-
ponent in acne probiotics [27, 56].
tion [9, 33]. However, disequilibrium in favour of S. epi-
dermidis may also result in other health consequences
such as nosocomial infections. Therefore, a balanced skin
homeostasis should be the final aim in any acne treatment.
In this perspective, other treatment options may be
considered, such as probiotics derived from S. epidermi-
dis, allowing for a restoration of the naturally balanced
microbiota, and through the targeting of the regulation of
the host’s AMP mediators, without increasing the local S.
epidermidis population.
Key Message
S. epidermidis limits C. acnes-induced colonisation of the skin,
thus potentially playing a role in the physiopathology of acne.
Acknowledgements
The authors acknowledge the writing support of Patrick Göritz,
SMWS-Scientific, and Medical Writing Services.
Statement of Ethics
The authors have no ethical conflicts to disclose

Disclosure Statement
Discussion and Conclusion
The authors have no financial interest to disclose.
Acne is a chronic and multifactorial inflammatory dis-
ease of the skin and the pilosebaceous unit. Dysbiosis in
acne patients is associated with a decreased number of S. Funding Sources
epidermidis and an over-colonisation by selected C. acnes
phylotypes in the sebaceous unit, leading to different lev- This Expert Group was organised by Galderma International,
France.
els of activation of the innate immunity, thus resulting in
different severity levels of inflammatory acne. Recent re-
search seems to confirm the beneficial role of S. epidermi- Author Contributions
dis in the physiopathology of acne through limiting C.
acnes-induced colonisation of the skin and of inflamma- All cited authors contributed equally to this paper.

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294 Dermatology 2019;235:287–294 Claudel/Auffret/Leccia/Poli/Corvec/

DOI: 10.1159/000499858 Dréno