Wageningen 

Academic 
Beneficial Microbes, 2014; 5(2): 201-215 P u b l i s h e r s

Bacterial skin commensals and their role as host guardians

G.J.M. Christensen and H. Brüggemann

Department of Biomedicine, Aarhus University, Wilhelm Meyers Allé 4, 8000 Aarhus C, Denmark; gmc@microbiology.au.dk
http://www.wageningenacademic.com/doi/pdf/10.3920/BM2012.0062 - Friday, May 11, 2018 6:40:53 PM - IP Address:190.173.71.69

Received: 13 November 2012 / Accepted: 13 June 2013

© 2013 Wageningen Academic Publishers

REVIEW ARTICLE
Abstract

Recent years’ investigations of the co-evolution and functional integration of the human body and its commensal
microbiota have disclosed that the microbiome has a major impact on physiological functions including protection
against infections, reaction patterns in the immune system, and disposition for inflammation-mediated diseases.
Two ubiquitous members of the skin microbiota, the Gram-positive bacteria Staphylococcus epidermidis and
Propionibacterium acnes, are predominant on human epithelia and in sebaceous follicles, respectively. Their successful
colonisation is a result of a commensal or even mutualistic lifestyle, favouring traits conferring persistency over
aggressive host-damaging properties. Some bacterial properties suggest an alliance with the host to keep transient,
potential pathogens at bay, such as the ability of S. epidermidis to produce antimicrobials, or the production of
short-chain fatty acids by P. acnes. These features can function together with host-derived components of the innate
host defence to establish and maintain the composition of a health-associated skin microbiota. However, depending
largely on the host status, the relationship between the human host and S. epidermidis/P. acnes can also have parasitic
features. Both microorganisms are frequently isolated from opportunistic infections. S. epidermidis is a causative
agent of hospital-acquired infections, mostly associated with the use of medical devices. P. acnes is suspected to
be of major importance in the pathogenesis of acne and also in a number of other opportunistic infections. In this
review we will present bacterial factors and traits of these two key members of our skin microbiota and discuss
how they contribute to mutualistic and parasitic properties. The elucidation of their roles in health-promoting
or disease-causing processes could lead to new prophylactic and therapeutic strategies against skin disorders and
other S. epidermidis/P. acnes-associated diseases, and increase our understanding of the delicate interplay of the
skin microbiota with the human host.

Keywords: Staphylococcus epidermidis, Propionibacterium acnes, bacteriocin, skin microbiota, Propionobacterium spp.

1. Introduction cutaneous host defence is mainly comprised of two ‘barriers’.

Prenatally a sterile milieu, human skin becomes colonised
by microorganisms after birth. With time, an increasingly
complex ecosystem forms, comprised of indigenous or
resident, and transient microorganisms (Rosenthal et al.,
2011). The microbial members of this community are
determined by several environmental and physiological
parameters such as anatomic location, local humidity,
the production of sebum and sweat, and the hormonal
status and age of the host. This microbial community,
the human skin microbiota, includes bacteria, viruses,
fungi and protozoa, and its stability is based on a delicate
balance between the properties of the microbial inhabitants
and the human host with its defence mechanisms. The
Firstly, the stratum corneum of the skin acts as a ‘physical
barrier’ that adds mechanical rigidity to the skin. The lower
temperature of the skin and its slight acidity slow down or
prevent the growth of some microorganisms. In contrast
to mucosal surfaces, most skin areas are dry, creating an
unfavourable environment for bacterial propagation. The
permanent desquamation of epithelial cells in the stratum
corneum leads to a permanent renewal of the skin surface
and simultaneous removal of the microorganisms adhering
to these layers. Secondly, the host skin defence is mediated
by a ‘chemical barrier’, which consists of several host defence
molecules that are synthesised by epithelial cells and
expressed at different parts of the epidermis. These can be
inducible or constitutively expressed antimicrobial peptides,

ISSN 1876-2833 print, ISSN 1876-2891 online, DOI 10.3920/BM2012.0062201

 G.J.M. Christensen and H. Brüggemann
proteases, cytokines and chemokines that can either
directly inhibit microbial growth or serve as activators and
mediators of the innate and adaptive immune responses.
Together, these features contribute to maintaining a healthy
human skin.
The relationship between the human skin and the colonising
microorganisms can have various features ranging from
mutualistic and commensal to saprophytic and parasitic
relationships. The nature of this relationship and in
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particular the consequences for skin health depend largely
on the host status and to an extent also on the species
composition and the strain identities of the skin microbiota.
Another layer of complexity is the relationship between
different species and strains of the skin microbiota; these
interactions can also impact on skin homeodynamics.
This review focuses on features of two of the most common
skin microorganisms, Staphylococcus epidermidis and
Propionibacterium acnes, thereby explaining functional
principles of human skin-bacteria interactions with special
emphasis on beneficial effects of the skin microbiota.
2. Composition of the human skin microbiota
The human microbiota consists of more than 1000 bacterial
species; these encode approximately 150-fold more genes
than are present in the human genome (Bäckhed, 2012;
Grice and Segre, 2012). Recent years’ intense investigations
within the framework of the human microbiome project
(HMP; http://www.hmpdacc.org) have disclosed a major
impact of the microbiota on physiological functions of
the human host, including protection against infections,
reaction patterns in the immune system, and disposition for
autoimmune and other inflammation-mediated diseases.
Sequencing of the skin microbiome showed that the human
skin microbiota comprises around 113 phylotypes that
belong to six bacterial divisions (Grice and Segre, 2011;
Grice et al., 2009). The skin microbiota composition varies
with the topography of the human skin. Distinct habitats
are characterised by differences in densities of cutaneous
invaginations and appendages, including sweat glands
(eccrine and apocrine), sebaceous glands, and hair follicles,
and are associated with their own unique microbiota.
Abundant resident bacterial genera on the surface layers of
the human skin include Staphylococcus, Propionibacterium,
Micrococcus and Corynebacterium. Coagulase-negative
staphylococci are major skin commensals of humans, and
S. epidermidis is one of the most frequently isolated species
from human epithelia with an ubiquitous presence on the
skin. Sebaceous glands, mainly located on the face, chest
and back, secrete lipid-rich sebum, a hydrophobic coating
that protects and lubricates hair and skin. They constitute
a selective environment allowing growth of P. acnes and
Malassezia species (Bek-Thomsen et al., 2008; Coelho et
202
al., 2013; Grice and Segre, 2011). While sebum generally
serves as an antibacterial coating, organisms such as P.
acnes can hydrolyse triglycerides present in sebum, one
factor which may explain their successful colonisation of
sebaceous units.
3. Staphylococcus epidermidis
S. epidermidis belongs to the group of coagulase-negative
staphylococci, which is distinguished from the coagulase-
positive Staphylococcus aureus. The species shows a high
level of diversity; multilocus sequence typing studies
currently classify S. epidermidis into 492 sequence types
(http://sepidermidis.mlst.net), and most isolates belong
to clonal complex 2 (Miragaia et al., 2007). While S.
epidermidis is a commensal of the skin, it may act as an
opportunistic pathogen when it breaches the skin surface
and enters the bloodstream. It is a leading cause of hospital-
acquired infections, mostly associated with the use of
medical devices in seriously ill or immunocompromised
patients. This high incidence is mainly due to its ubiquitous
presence on the human skin and its capacity to stick to
surfaces of indwelling medical devices during device
insertion where it forms biofilms (Otto, 2008, 2009, 2013).
The detachment of bacterial cells from biofilms on these
devices can lead to bacteremia (Wisplinghoff et al., 2004),
and S. epidermidis is the most frequently isolated species
of coagulase-negative staphylococci from nosocomical
bloodstream infections (Rupp and Archer, 1994).
Biofilm as an important trait of invasive strains
Analysis of the S. epidermidis genome revealed that there
are fewer toxins, degradative enzymes, and surface proteins
compared to the more virulent relative, S. aureus (Zhang
et al., 2003). S. epidermidis pathogenesis relies instead
on the ability of the bacteria to form thick multilayered
biofilms on a wide variety of polymers, metal surfaces and
host tissues (Otto, 2009). However, S. epidermidis strains
differ significantly in their virulence potential and their
capacity to form biofilm. Moreover, they can rapidly change
their phenotypic features. For example, the expression
of the four-gene icaADBC operon and, as a result, the
production of polysaccharide intercellular adhesin, PIA
(or poly-N-acetyl-glucosamine, PNAG) (Table 1), is highly
variable among staphylococcal strains (Ziebuhr et al., 1997).
This ability to alternately express the icaADBC operon is
mediated through a mechanism of alternating insertion
and excision of the insertion sequence (IS) element IS256
into different sites of the icaADBC operon (Ziebuhr et
al., 1999). This phenomenon, termed phase variation,
seems to regulate the virulence potential of the bacterium
and is believed to be the mechanism responsible for the
long persistence and relapse of S. epidermidis biofilms.
Epidemiologic studies have shown that the majority of
commensal S. epidermidis isolates from healthy individuals
Beneficial Microbes 5(2)
  Skin microbiota in health and disease

lack the icaADBC operon, whereas clinical strains obtained
from device-associated infections harbour the icaADBC
operon in addition to multiple copies of IS256 and the
methicillin resistance gene, mecA (Cho et al., 2002;
Kozitskaya et al., 2004). This genetic difference between
commensal and disease-associated strains is supported
by the observation that S. epidermidis icaADBC mutants
are less virulent in animal models (Rupp et al., 1999). It
could be speculated that S. epidermidis strains without the
icaADBC operon are ‘true’ commensal strains, with no or
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Resistance to and evasion from host defences
Host defence mechanisms on the skin comprise, among
others, skin tissue-derived antimicrobial peptides (AMPs)
and reactive oxygen species (ROS). S. epidermidis has
evolved strategies to evade such host defences. Again, the
biofilm-associated polysaccharide PIA/PNAG plays a role
and partially explains the inefficiency of host defences to
eradicate persistent S. epidermidis infections. The large
amount of PIA/PNAG in the biofilm acts as a mechanical

little chance of being converted into pathogenic strains.
In contrast, icaADBC-positive S. epidermidis strains can
easily convert into biofilm-forming strains by insertion or
excision of insertion sequences in the icaADBC operon,
or by environmental changes. However, the pathogenic
potential of S. epidermidis does not solely rely on the
expression of the icaADBC operon, as studies have reported
biofilm-positive, but PIA/PNAG-negative staphylococcal
clinical isolates (Kogan et al., 2006), suggesting the existence
of PIA-independent biofilm/adherence mechanisms (Mack
et al., 2009).
barrier to block the effects of host defences, including
neutrophil killing, complement deposition, immunoglobulin
opsonisation, and AMP activity (Cerca et al., 2006; Kristian
et al., 2008; Vuong et al., 2004a). The importance of PIA/
PNAG in the resistance of S. epidermidis to host defences
has been verified through the generation of ica deletion
mutants that, compared to the wild-type strain, had a much
lower survival after exposure to AMPs and neutrophils
(Vuong et al., 2004a). The underlying resistance mechanism
regarding AMPs may include electrostatic repulsion of
cationic AMPs. However, PIA/PNAG also protects against
the anionic AMP dermcidin, suggesting that the mechanism
of protection is not solely based on electrostatic repulsion
(Vuong et al., 2004a). In addition, the anionic exopolymer

Table 1. Staphylococcus epidermidis factors mentioned in this review.1

Factor Gene Function Reference

Protective exoploymers
PIA/PNAG icaADBC Polysaccharide intercellular adhesin; protects from IgG, Handke et al., 2004; Vuong et al., 2004a
AMPs, phagocytosis and complement deposition
PGA capABCD Poly-γ-DL-glutamic acid; protects from AMPs and Kocianova et al., 2005
phagocytosis
PSMs
PSM δ psmδ Cytolytic activity, antimicrobial activity Mehlin et al., 1999; Cheung et al., 2010;
Cogen et al., 2010b
PSM γ psmγ (hld) Antimicrobial activity Cheung et al., 2010; Cogen et al., 2010a,b
PSM β psmβ1, psmβ2 Biofilm structuring and detachment Mehlin et al., 1999; Yao et al., 2005; Wang
et al., 2011
Host interacting factors
SepA protease sepA Involved in AMP degradation Teufel and Götz, 1993; Lai et al., 2007
Aps system apsR, apsS, apsX AMP sensor, regulator of AMP resistance mechanisms Li et al., 2007
Dlt dltABCD D-alanylation of teichoic acids Perego et al., 1995; Li et al., 2007
MprF mprF Lysylation of phospholipids Peschel et al., 2001; Li et al., 2007
VraFG vraFG Putative AMP export Li et al., 2007
Bacteriocins
Epidermin epiA Lantibiotic, active on Gram-positive bacteria Schnell et al., 1988
Pep5 pepTIAPBC Lantibiotic, active on Gram-positive bacteria Meyer et al., 1995
Epilancin K7 elkA Lantibiotic Van de Kamp et al., 1995
Epicidin 280 eciABCIOP Natural variant of Pep5 Heidrich et al., 1998
Epidermicin NI01 edcA Unmodified bacteriocin Sandiford and Upton, 2012

1Abbreviations used; AMP = antimicrobial peptide; Aps = antimicrobial peptide sensor; IgG = immunoglobulin G; PGA = poly-γ-glutamic acid; PIA =
polysaccharide intercellular adhesin; PNAG = poly-N-acetylglucosamine; PSM = phenol-soluble modulin.

Beneficial Microbes 5(2) 203

 G.J.M. Christensen and H. Brüggemann
poly-γ-glutamic acid (PGA), which is synthesised by the
gene products of the cap locus, is crucial for S. epidermidis
resistance to neutrophil phagocytosis and AMPs, facilitating
bacterial survival (Kocianova et al., 2005). In contrast to
the icaADBC operon, which is found only in some strains,
the cap gene locus and correspondent PGA production
are ubiquitous among S. epidermidis strains. Its ubiquity
and the fact that it also contributes to resistance to high
salt concentrations, a condition encountered in the natural
habitat of S. epidermidis, i.e. the human skin, suggests that
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PGA might serve as an important factor in enhancing the
fitness of the bacteria.
Resistance to AMPs is also mediated through the actions
of the protease SepA, which mainly mediates resistance
to anionic AMPs (Lai et al., 2007), and the cationic AMP-
responsive three-component sensor/regulator apsRSX
(antimicrobial peptide sensor), a system composed of a
classical two-component histidine kinase and response
regulator (ApsS, ApsR) and a third protein of unknown
function (ApsX) (Li et al., 2007). The ApsS protein
represents the sensor part of the apsRSX system and
interacts with the cationic AMPs. Specifically, a single,
9-amino acid extracellular loop of ApsS with a high density
of negative charges is responsible for cationic AMP binding
and induction of an AMP-mediated signal transduction
cascade that activates the expression of the two main
resistance mechanisms to cationic AMPs in Gram-positive
bacteria, i.e. the dlt operon and the mprF gene. The dlt-
operon-mediated D-alanylation of teichoic acids (Perego et
al., 1995) and MprF-mediated lysinylation of phospholipids
(Peschel et al., 2001) introduce positive charges to the cell
wall and cell membrane components, respectively, resulting
in a decreased interaction between cationic AMPs and the
S. epidermidis cell surface (Otto, 2009; Peschel, 2002). In
addition, the apsRSX system regulates the vraFG genes,
encoding an ABC transporter that probably functions as
an AMP exporter (Li et al., 2007).
Host-interacting phenol soluble modulins
A family of molecules with multiple functions in S.
epidermidis are the phenol soluble modulins (PSMs).
These are amphipathic, α-helical peptides with surfactant
properties that are produced in virtually all staphylococcal
species, albeit with a varying pattern of expression and
with amino acid sequence differences between species.
PSMs are characterised by common physicochemical
properties rather than similarity at the amino acid sequence
level. PSMs have proinflammatory capacities; some PSM
peptides, such as the PSM-α peptides of the pathogenic
relative S. aureus, have a high capacity to attract, stimulate
and efficiently lyse human neutrophils and other cell types,
such as erythrocytes, hereby contributing significantly to
virulence (Wang et al., 2007). The PSM-δ peptides of S.
epidermidis share the ability to lyse human neutrophils
204
(Cheung et al., 2010); both the PSM-α peptides from
S. aureus and PSM-δ of S. epidermidis have the basic
structural requirements for membrane perturbation and
pore formation. However, the overall low cytolytic activity
of S. epidermidis compared to S. aureus can be explained
with the observed low production of PSM-δ and a PSM
expression pattern favouring the non-cytolytic β-peptides
(Cheung et al., 2010).
Instead of damaging host cells, it has been found that S.
epidermidis PSM-γ and PSM-δ peptides selectively reduce
survival of Streptococcus pyogenes and S. aureus, but not
S. epidermidis, by cooperating with human host AMPs in
killing the bacteria (Cogen et al., 2010a,b). Both PSM-γ
and PSM-δ cause membrane leakage in target bacteria,
which indicates that they function like host-derived AMPs
such as cathelicidins and defensins. This is supported by
structural similarities of PSM-γ and PSM-δ peptides to
native human AMPs. Notably, this co-operation against
bacterial pathogens only seems to take place between
established commensals and the host, as the closely related
δ-toxin of S. aureus does not possess antimicrobial activity,
even though the physicochemical properties of the δ-toxin
are comparable to properties of PSM-γ of S. epidermidis
(Dhople and Nagaraj, 2005).
Another class of PSMs are the non-cytolytic β-peptides of
S. epidermidis. The psmβ operon consists of three to four
genes encoding the three different forms of β-type PSMs:
PSMβ1 (whose gene is often duplicated in the psmβ operon),
PSMβ2 and PSMβ3 (a hypothetical product that has never
been detected in culture filtrates). The function of β-type
PSMs was recently elucidated (Wang et al., 2011): PSM β1
and PSM β2 promote S. epidermidis biofilm structuring and
detachment. Acting as surfactants, PSM β1 and PSM β2
at low concentrations facilitate the formation of channels
in the structure of the biofilm, favouring its increased
formation. Conversely, higher concentrations of β-type
PSMs determine the detachment and reduction of biofilm
mass. In biofilm-forming pathogens, biofilm detachment
processes have significance, as they are believed to lead to
the systemic dissemination of infection.
Bacteriocins
Bacteriocin production by S. epidermidis is assumed to have
beneficial effects for the human skin, since it might restrict
the colonisation of pathogenic organisms. Bacteriocins are
bacterial antimicrobial peptides that are classically defined
as proteinaceous compounds with bactericidal activity
(Cotter et al., 2013; Heng et al., 2007). The inhibitory
spectrum of these substances is predominantly directed
towards bacteria that are closely related to the producer
strain, while the producer strain is immune to its own
product. A bacteriocin classification scheme was proposed
(Heng and Tagg, 2006): class I, the lantibiotics; class II,
Beneficial Microbes 5(2)
  Skin microbiota in health and disease
the unmodified peptides; class III, the large proteins; and
class IV, the cyclic peptides. As a frequent producer of
bacteriocins, S. epidermidis appears to have a particular
tendency to produce lantibiotics, peptide antibiotics that
contain the characteristic amino acids lanthionine or
methyllanthionine. All lantibiotics are ribosomally produced
as prepeptides that undergo extensive post-translational
modifications to form biologically active peptides, which
are polycyclic and less than 5 kDa in size.
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Several lantibiotics of S. epidermidis are well characterised,
such as epidermin, Pep5, epilancin K7 and epicidin 280
(Bastos et al., 2009; Sahl and Bierbaum, 1998). They
share the ability to inhibit methicillin-resistant S. aureus
(MRSA) and coagulase-negative staphylococci involved in
human infections, hereby conferring a selective advantage
to the producing S. epidermidis strain. Pep5, produced
by S. epidermidis strain 5, is a 34-amino-acid lantibiotic,
which inhibits the abilities of clinical S. epidermidis and S.
aureus isolates to adhere to catheters (Fontana et al., 2006).
Inhibition can also be observed after initial colonisation
with clinical adherent strains, implying a promising
potential for Pep5 to be applied at the time of placement
of the catheters, hereby avoiding potentially dangerous
nosocomial bloodstream infections. The same effect is true
for epidermin, produced by S. epidermidis Tü3298, which
also inhibits bacterial adhesion to catheters, albeit not with
the same broad potency (Nascimento et al., 2006). The
biosynthesis of Pep5 and epidermin proceeds from plasmid-
located structural genes that encode prepeptides, which are
enzymatically modified to form the mature lantibiotics. The
above mentioned staphylococcal lantibiotics all belong to
the linear type A lantibiotics (Bastos et al., 2009). These
bacteriocins exert their activity by disruption of the
barrier function of the microbial cytoplasmic membrane,
a mechanism of action that they share with the unmodified
type II bacteriocin epidermicin NI01 from S. epidermidis
strain 224 (Sandiford and Upton, 2012). Epidermicin NI01
also displays antimicrobial activity against a wide range of
Gram-positive pathogens, including MRSA and biofilm-
forming S. epidermidis strains. The potential of these S.
epidermidis bacteriocins to eliminate human pathogens has
nurtured a therapeutic interest in bacteriocins as a treatment
option (Cotter et al., 2013). Sandiford and Upton (2012)
demonstrated that the structural gene of epidermicin NI01
could be cloned into Escherichia coli and expressed as an
active peptide, thus allowing for heterologous production.
Another advantage of a target-directed bacteriocin therapy
(compared to the use of broad-spectrum antibiotics) is that
the normal, commensal microbiota of the patient will not
be compromised.
Beneficial Microbes 5(2)
Regulation of Staphylococcus epidermidis traits
The agr (accessory gene regulator) quorum-sensing system
in S. epidermidis is known to regulate the production of
fitness factors including surface adhesins and PSM peptides
(Otto, 2013). Regarding the latter, direct binding of the agr
response regulator AgrA to the PSM promoter regions
controls their expression (Vuong et al., 2004b). Thus, the
S. epidermidis agr system exerts a regulatory effect on
biofilm dynamics, indirectly influencing attachment of
staphylococcal cells to surfaces. Also controlled by the agr
system is the production of bacteriocins in S. epidermidis,
which is generally associated with the shift from the
logarithmic to the stationary growth phase (Kies et al.,
2003). The study of Yao et al. (2006) identified members
of the agr quorum-sensing regulon; besides genes for
possible virulence factors such as degradative exoenzymes,
it contains general and oxidative stress-response factors,
including detoxifying enzymes of ROS. Consequently, the
importance of the agr system for S. epidermidis survival
has been demonstrated; experiments using an isogenic agr
mutant strain showed that the presence of agr provided a
significantly increased resistance to host-derived ROS and
AMPs (Yao et al., 2006).
The agr-regulated responses are activated by extracellular
pheromone peptides, the agr pheromones. In addition to
triggering agr-regulated responses in the S. epidermidis
producer strain, agr pheromones can display cross-
inhibition of the agr system in S. aureus, hereby silencing
the virulence potential of this opportunistic pathogen (Ji,
1997; Otto et al., 1999, 2001). This might give rise to a
selection advantage for S. epidermidis, which partially
explains its ubiquitous abundance on the human skin
and its predominance in infections on indwelling medical
devices. In support of this notion, the development of S.
aureus-induced lesions in mice was efficiently suppressed
when the infecting S. aureus strain was injected together
with the inhibiting pheromone of a foreign subgroup (Otto
et al., 1999, 2001).
Immunomodulatory properties of S. epidermidis
It was reported that pattern recognition receptors such as
Toll-like receptors (TLRs) of the innate immune system
sense and react to S. epidermidis components. For example,
both PSM peptides and PIA were reported to trigger TLR2-
dependent responses (Hajjar et al., 2001; Stevens et al.,
2009). Activated TLR2 signalling can induce antimicrobial
peptide expression of the host, which is important to
fight off the colonisation of pathogenic strains (Lai et al.,
2010). Wanke et al. (2011) extended these findings; they
showed that S. epidermidis triggers TLR2 and thus NF-κB
activation in primary human keratinocytes whereas S.
aureus activates the mitogen-activated protein kinase and
phosphatidylinositol 3-kinase/AKT signalling pathways
205
 G.J.M. Christensen and H. Brüggemann
and suppress NF-κB activation. Another study has revealed
that lipoteichoic acids produced by S. epidermidis can
suppress skin inflammation during wound repair (Lai et
al., 2009). The normal skin microbiota is thus responsible
for controlling and fine-balancing cutaneous inflammatory
responses, emphasising its important role in maintaining
skin homeodynamics.
Conclusions
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S. epidermidis’ successful colonisation of the human skin is a
result of its commensal lifestyle, favouring traits that confer
persistency over aggressive host-damaging properties. The
low cytotoxicity and the ability to evade host defences
ensure an overall low host immune response. This could be
regarded as a mutual non-aggression pact. Some properties
suggest even an alliance of the host with S. epidermidis to
keep transient, potential pathogens at bay. The ability to
produce selectively antagonising molecules is important for
retaining a normal microbiota and bacterial antimicrobial
substances probably function together with host-derived
components of the innate host defence to establish and
maintain the composition of a health-associated skin
microbiota. These synergistic features are likely a product
of the long-term co-evolutionary history of S. epidermidis
and its human host. It is important to keep in mind that it
is only during conditions of compromised host situations,
such as injury, changes in immune status, or surgery, that
S. epidermidis can display an opportunistic pathogenic
side. The factors responsible for the establishment of S.
epidermidis’ pathogenic properties often have roles in both
the commensal and pathogenic lifestyle of the bacterium.
For example, adhesion properties are considered to be an
important characteristic during both lifestyles, as biofilm
formation via bacterial aggregation by PIA/PNAG is vital
in an environment such as the human skin, where the
bacteria experience considerable mechanical stress, but
also in an opportunistic pathogenic scenario where invasive
bacteria stick to tissue in a thick biofilm in order to resist
host clearance.
4. Propionibacterium acnes
The Gram-positive bacterium P. acnes is intimately
associated with humans, mainly residing within sebaceous
follicles of the face and back. Studies on the microbiota
of human follicles suggest that P. acnes is often the sole
bacterial inhabitant of such areas (Bek-Thomsen et al.,
2008). Several studies reported that P. acnes can be found
in other parts of the human body as well, such as intestine,
stomach, lungs, oral cavity, conjunctiva, prostate and urinary
tract (Delgado et al., 2011; Fassi Fehri et al., 2011; Perry
and Lambert, 2011; Sharon et al., 2012). Due to different
methods of isolation and detection it is somewhat difficult
to assess if the presence of P. acnes at non-skin sites is
(always) a true finding or a problem of skin-derived sample
206
contamination. However, more recent studies included
means to avoid skin-derived contamination. Thus, it is
highly likely that P. acnes is indeed a successful coloniser
of different human tissue sites, and this ubiquity might
indicate that the human host benefits from the presence
of P. acnes. Indeed, some properties, as outlined below,
suggest a mutualistic role of the bacterium.
On the other hand, the bacterium is frequently isolated
from inflamed tissues. An overview of P. acnes-associated
infections at non-skin sites is given in a recent review
(Perry and Lambert, 2011). P. acnes is also isolated from
inflamed and cancerous prostates (Alexeyev et al., 2007;
Fassi Fehri et al., 2011; Mak et al., 2013); this association is
currently under investigation and it remains to be seen if a
causative or supportive association of P. acnes with prostate
cancer can be proven. P. acnes’ most famous association
with acne vulgaris, a highly prevalent skin condition with
an inflammatory component that affects up to 80% of
adolescents, is still controversial. Several recent reviews
summarise our knowledge of the association of P. acnes with
acne vulgaris; some arguments suggest a direct, causative
role of P. acnes, others suggest a rather insignificant
contribution of P. acnes to disease formation (Dessinioti and
Katsambas, 2010; Shaheen and Gonzalez, 2011; Williams
et al., 2012). Despite this on-going debate, genome and
proteome analyses, together with cell culture and in vivo
experiments, have supported the view that P. acnes has
features of an opportunistic pathogen (Brüggemann et
al., 2004; Brzuszkiewicz et al., 2011; Holland et al., 2010;
Lomholt and Kilian, 2010; Mak et al., 2012; McDowell et
al., 2012; Tomida et al., 2013). We will summarise selected
properties of P. acnes in the next section, with special
emphasis on possible host beneficial properties.
Metabolic features of Propionibacterium acnes
Due to its successful and apparently exclusive colonisation
of human follicles, the bacterium must be equipped with
unique metabolic traits to occupy this ecological niche.
P. acnes has saprophytic properties; it acquires nutrients
for growth from within sebaceous follicles, such as lipids
of the sebum, which is mainly composed of triglycerides
(~40%). A lipolytic activity of P. acnes has been shown,
and a secreted lipase, the triacylglycerol lipase GehA, was
investigated (Miskin et al., 1997) (Figure 1 and Table 2). It is
so far not known if other lipases are involved. The genome
of P. acnes encodes at least 12 putative lipases, but only
two possess a signal peptide for secretion (Brüggemann
et al., 2004). Other nutrients can be made available by
host component-degrading enzymes of P. acnes. Secreted
or surface-exposed enzymes comprise two putative
endoglycoceramidases that might catalyse the hydrolysis
of the glycosidic linkage between oligosaccharides and
ceramides of glycosphingolipids (Holland et al., 2010).
A sialidase of P. acnes can cleave sialoglycoconjugates to
Beneficial Microbes 5(2)
  Skin microbiota in health and disease

Skin surface skin tissue (follicular wall, adjacent keratinocytes)

Blackhead

TLR2 | Ma
Enlarged jor i
mm
follicle opening uno
LTA, PG, rea
cti
lipoproteins ve
DsA1/DsA2 p
Sebaceous gland

rot
ein
so
f P.
Follicle HtaA

acn
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es |
CAMPs

Poly- Lipases

| – – – – –
ketides

Sialidases

– –
Thio-
Endoglycocer-

Deg
peptides
amidases

rad
ative
SCFAs

en
Hyal-

zy
me
(Propionic uronidase
s
Porphyrins
–
acid), CLA ––
–
– –
– |

Figure 1. Factors of Propionibacterium acnes involved in human skin-bacterium interactions with possible disease- or health-
promoting functions. P. acnes is able to trigger innate immune responses via Toll-like receptor 2 (TLR2). TLR2 ligands could
be cell wall-attached lipoteichoic acids (LTA), peptidoglycan (PG) fragments, and/or cell surface-exposed lipoproteins. Major
immunoreactive proteins, i.e. dominant B cell and T cell antigens, of P. acnes are: dermatan-sulphate adhesins DsA1 and DsA1
and two HtaA-domain proteins. Degradative enzymes are predicted to degrade human host tissue components. For example,
surface-attached endoglycoceramidases and sialidases might hydrolyse host cell membrane-exposed gangliosides. Christie-
Atkins-Munch-Peterson (CAMP) factors have co-hemolytic activity and have been described as cytotoxins. Putative antimicrobial
and/or probiotic factors are shown in white; these include short-chain fatty acids (SCFAs) as fermentative products; conjugated
linoleic acids (CLA) as product of the P. acnes linoleic acid isomerase; secreted thiopeptides and polyketides (their biosynthesis
is predicted from genome analyses); secreted porphyrins as part of the cobalamin biosynthesis (these molecules might have a
dual role: induction of proinflammatory host molecules and scavenging of toxic host molecules) (Figure adapted and modified
from Brüggemann et al., 2004).

obtain sialic acids for use as carbon and energy sources
(Nakatsuji et al., 2008), and a hyaluronate lyase cleaves
hyaluronan, a polysaccharide and part of the extracellular
matrix of connective tissues (Ingham et al., 1979). However,
different P. acnes strains have distinguishable properties:
some enzymatic activities (glucosidase, neuraminidase,
hyaluronidase) are only present in a subset of P. acnes strains
(Lomholt and Kilian, 2010).
Fatty acids generated by lipase activities retard the
development of transient microorganisms on skin surfaces,
e.g. S. pyogenes and S. aureus, whereas indigenous skin
organisms such as P. acnes seem to be resistant to fatty acids;
the bacteria were reported to adhere with varying degrees to
fatty acids (Gribbon et al., 1993). Thus, fatty acids generated
by skin organisms appear to play a role in excluding
nonindigenous organisms from the skin ecosystem and
in maintaining the stability of the resident cutaneous
community. In this context, it is noteworthy that some
propionibacteria, including P. acnes, possess and express
a polyunsaturated fatty acid isomerase, which catalyses the
isomerisation of linoleic acid to 10,12-conjugated linoleic
acid (CLA) (Liavonchanka et al., 2006). CLAs have been
reported to regulate body fat gain, inhibit carcinogenesis,
and modulate the immune response and insulin tolerance in
animals. The physiological role of the linoleic acid isomerase
in P. acnes has not been unravelled, but the production of
CLAs on the skin might be a beneficial factor for skin health.

Beneficial Microbes 5(2) 207

 G.J.M. Christensen and H. Brüggemann

Table 2. Propionibacterium acnes factors mentioned in this review.1

Factor Gene2 Function/comment Reference

Degradative enzymes
Triacylglycerol lipase gehA (PPA2105) Secreted lipase, putatively hydrolysing lipids in sebum Miskin et al., 1997
Putative endoglyco- PPA2106, PPA0644 Secreted enzymes, possibly hydrolysing glycosphingolipids Unpublished
ceramidase
Sialidase PPA1560 Possibly cleaves sialoglycoconjugates Nakatsuji et al., 2008
Hyaluronate lyase PPA0380 Possibly cleaves hyaluronan Ingham et al., 1979
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Immunoreactive proteins
Dermatan sulphate dsa1, dsa2 (PPA2127, Dermatan-sulphate binding activity Lodes et al., 2006; McDowell et
adhesin PPA2210) al., 2011
HtaA-like protein PA-4687, PPA0786 Putative iron acquisition factor Lodes et al., 2006
HtaA-like protein PA-21693, PPA0779 Part of a putative ABC iron transport system Lodes et al., 2006
CAMPs
CAMP1-5 PPA1340, PPA0687, Putative co-hemolysins, cyotoxins Valanne et al., 2005; Sörensen
PPA2108, PPA1231, et al., 2010; Liu et al., 2011;
PPA1198 Nakatsuji et al., 2011
Others
Linoleic acid isomerase pai, PPA1039 Catalyses the isomerisation of linoleic acid to Liavonchanka et al., 2006
10,12-conjugated linoleic acid
Cobalamin biosynthesis PPA0418-43/ B12 synthesis; coproporphyrin III is secreted Brüggemann et al., 2004; Borelli
PPA0301-0310 et al., 2006
Acnecin ? Bacteriocin-like substance Fujimura and Nakamura, 1978
Putative thiopeptide PPA0859-PPA0866 Precursor identical to berninamycin Wieland Brown et al., 2009

1 Abbreviationsused: CAMP = Christie-Atkins-Munch-Peterson; PAI = polyunsaturated fatty acid isomerase.

2 Gene nomenclature of the KPA171202 genome (GenBank # AE017283.1).

As main energy-conserving route the methylmalonyl-CoA
pathway has been studied in propionibacteria; this pathway
leads to propionate formation under anaerobic conditions.
The accumulation of propionate and other short-chain
fatty acids (SCFAs) can lower the pH and thus inhibit
the growth of other bacteria, which might be beneficial
for the host since it would prevent the colonisation of
(more) harmful pathogens. A recent study showed that
fermentative products of P. acnes can indeed suppress
the growth of S. aureus (Shu et al., 2013). Propionic acid
and its salts are commonly used in the preservation of
foods and manufacture of cellulose, perfumes, herbicides,
and pharmaceuticals (Poonam et al., 2012). To counteract
SCFA-dependent growth inhibition for P. acnes itself,
the bacterium can compensate the pH drop by utilising
arginine deiminase; this system is highly expressed when the
bacterium is grown in complex medium under anaerobic
conditions (Brzuszkiewicz et al., 2011). It generates NH3
and ATP, and thus counteracts the acidification in the
course of propionate formation, facilitating survival in
acidic conditions.
Genomic and transcriptomic data suggest that P. acnes does
not solely rely on energy conservation under anaerobic
conditions; the organism is not only aerotolerant, but can
actually employ oxidative phosphorylation to conserve
energy, as judged from the presence and the expression
of the respiratory chain with two respiratory endoxidases
(Brzuszkiewicz et al., 2011). This indicates that P. acnes
has a greater ability to react to changing oxygen conditions
than other propionibacteria, such as P. freudenreichii that
lacks cytochrome c reductase and oxidase.
Fermentation to propionate employs a key enzyme,
methylmalonyl CoA mutase. This enzyme is cobalamin-
dependent. P. acnes is able to synthesise this cofactor;
the cobalamin/B12 biosynthesis genes are organised in
a large cluster comprising 26 genes and a small cluster of
eight genes (Brüggemann et al., 2004). B12 precursors,
in particular coproporphyrin III, are secreted into the P.
acnes culture supernatant and coproporphyrin III was also
detected in human skin follicles (Borelli et al., 2006). The
consequences for the host are not known; this molecule
can induce an interleukin (IL)-8 response in cultured
cells (keratinocytes) and thus might contribute to the
development of inflammation (Schaller et al., 2005). On
the other hand, some studies reported a benefit of topical
B12 administration, for instance to treat atopic dermatitis
(Stucker et al., 2004). This effect might be due to the
property of B12 to efficiently scavenge nitric oxide and

208 Beneficial Microbes 5(2)

  Skin microbiota in health and disease
possibly also superoxide. Besides B12 synthesis, P. acnes
is, similar to dairy propionibacteria, equipped with genes
for the biosynthesis of other vitamins such as folate and
riboflavin.
Antimicrobial substances of Propionibacterium acnes
Bacteriocin production has been reported from a range
of Propionibacterium species: P. thoenii, P. jensenii, P.
freudenreichii and P. avidum can produce antimicrobial
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substances, designated e.g. thoeniicin, jenseniin and
propionicin (Faye et al., 2011; Poonam et al., 2012). These
bacteriocins usually act against closely related species, but
at least propionicin PLG-1, produced by P. thoenii P-127,
has a more widespread activity, inhibiting even some Gram-
negative pathogens and fungi (Lyon and Glatz, 1993). Some
strains of P. acnes produce a bacteriocin-like substance,
designated acnecin, which acts against other P. acnes strains
(Fujimura and Nakamura, 1978). Another substance with
bacteriocin-like properties, isolated from P. acnes strains
recovered from dental plague, is bacteriostatic and active
against both Gram-positive and Gram-negative anaerobes
(Paul and Booth, 1988).
Genome and transcriptome analyses of P. acnes highlighted
other bacteriocin-like factors, which are encoded in the
genomes of a subset of P. acnes strains. For example,
most type I-2 strains harbour a gene cluster involved in
bacteriocin/lanthionine biosynthesis. These genes were
identified in a bioinformatics search for genes involved
in the biosynthesis of thiazolylpeptides (Wieland Brown
et al., 2009). Thiopeptide antibiotics are potent inhibitors
of protein synthesis in Gram-positive bacteria. They are
synthesised from a precursor peptide that is subsequently
transformed by posttranslational modifications into the
final macrocyclic structure. Two precursor peptides are
encoded in the P. acnes genome; one precursor possesses the
15-aa structural peptide of berninamycin from Streptomyces
bernensis (Wieland Brown et al., 2009), and the associated
genes exhibit similarities to biosynthesis pathways of
thiopeptides such as nosiheptide of Streptomyces actuosus,
siomycin A of Streptomyces sioyaensis and TP-1161 of
Nocardiopsis sp. TFS65-07 (Engelhardt et al., 2010).
The bacteriocins and bacteriocin-like substances of P. acnes
may be (partially) responsible for the successful competition
of this microorganism in human follicles, which could
explain its dominant presence in healthy follicles.
Surface-exposed factors of Propionibacterium acnes
A study revealed four major immunoreactive proteins
of P. acnes (Lodes et al., 2006). Two of these antigens,
designated dermatan sulphate adhesins DsA1 and DsA2,
are cell surface-exposed, weakly similar to M-like protein
of Streptococcus equi and display dermatan sulphate
Beneficial Microbes 5(2)
binding activity (McDowell et al., 2011). Dermatan
sulphate is expressed in many mammalian tissues
and is the predominant glycan present in skin. This
glycosaminoglycan has been implicated in cardiovascular
disease, tumorigenesis, infection, wound repair and fibrosis.
Interestingly, DsA1 and DsA2 are associated with phase and
antigenic variation; the latter is due to a proline-threonine
rich repeat in the C-terminus of the protein, which can
result in a heterogenic phenotype of a clonal population
(Holland et al., 2010; Lodes et al., 2006; McDowell et
al., 2011). This could represent a strategy of P. acnes for
immune evasion. The two other immunoreactive proteins
both contain HtaA domains. They might be important for
iron acquisition and are probably part of a hemin ABC
transport system.
CAMP (Christie-Atkins-Munch-Peterson) factors are
another interesting class of proteins of P. acnes. These
factors are responsible for the co-haemolytic reaction of P.
acnes with both sheep and human erythrocytes (Choudhury,
1978). This response is similar to the CAMP reaction, a
synergistic haemolysis of sheep erythrocytes by the CAMP
factor from Streptococcus agalactiae strains and the β-toxin
(sphingomyelinase C) from S. aureus. P. acnes possess five
CAMP factor paralogs, designated CAMP1 to CAMP5
(Brüggemann et al., 2004; Valanne et al., 2005). CAMP1
has been shown to be a major surface-bound factor of P.
acnes. CAMP2 is a secreted CAMP factor and a knock-
out mutant of CAMP2 showed reduced co-haemolytic
activity in the CAMP reaction (Sörensen et al., 2010).
Moreover, inhibition of CAMP2 by neutralising antibodies
efficiently attenuated P. acnes-induced inflammation in
the mouse ear model (Liu et al., 2011). It was also shown
that CAMP2 can act as an exotoxin, exhibiting cytotoxic
activity on host cells (Nakatsuji et al., 2011). The latter
study further suggested that CAMP2 can act together
with host acid sphingomyelinase to amplify bacterial
virulence. Although their exact in vivo role remains to be
unravelled, the importance of CAMP factors is supported
by the conservation of all five CAMP paralogs across the
different P. acnes phylotypes.
Immunomodulatory properties of Propionibacterium
acnes
Immunomodulatory activities of P. acnes have been
reported. P. acnes can elicit a powerful Th1-type cytokine
immune response and injection of P. acnes in mice can
shift a dominant Th2 response to a Th1 type response
(Sugisaki et al., 2009; Kitagawa et al., 2011). Several studies
have used P. acnes as a typical Th1 response-inducing
antigen (Cervi et al., 2004). In experimental animals,
infection with live or administration of heat-killed P.
acnes leads to a strong activation of the mononuclear
phagocyte system. Observed effects include intra-hepatic
granuloma formation, splenomegaly, enhanced resistance
209
 G.J.M. Christensen and H. Brüggemann
to infection and malignant tumors and hypersensitivity to
lipopolysaccharide (Baum and Breese, 1976; Tchaptchet
et al., 2010).
These observations have led to investigations into the
innate immune response elicited by P. acnes. P. acnes-
induced production of pro-inflammatory cytokines, such
as interferon-γ, IL-1α, IL-6 and tumour necrosis factor-α,
has been reported for several cell culture models (Fassi Fehri
et al., 2011; Mak et al., 2012; Nagy et al., 2005, 2006). Host
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cell activation occurs via activation of pattern-recognition
receptors. A crucial role was assigned to extracellular
signalling via TLR2, which was shown to be sufficient for
NF-κB activation in response to P. acnes, and IL12- and
IL-8 production in P. acnes-stimulated keratinocytes was
inhibited by TLR2-blocking antibodies (Kim et al., 2002).
The P. acnes TLR2 ligand has not been identified but its
peptidoglycan was suggested; this peptidoglycan is distinct
from most Gram-positive bacteria, containing a cross-
linkage region of peptide chains with L,L-diaminopimelic
acid and D-alanine in which two glycine residues combine
with amino and carboxyl groups of two L,L-diaminopimelic
acid residues (Kamisango et al., 1982). Other studies
performed in mice implicated the involvement of TLR9
in the immunomodulatory activity of P. acnes (Kalis et al.,
2005). Since TLR9 is an intracellular receptor that senses
bacterial DNA and synthetic CpG oligodeoxynucleotide, the
cellular response via TLR9 might be related to the ability
of P. acnes to resist or delay intracellular degradation in
phagocytes (Pringle et al., 1982). Recently, it was shown
that P. acnes can invade epithelial cells and can be detected
intracellularly for weeks (Fassi Fehri et al., 2011; Furukawa
et al., 2009; Mak et al., 2012; Shinohara et al., 2013), which
might have consequences for the induction of cytokine/
chemokine production of infected cells.
Conclusions
P. acnes could be regarded as a chimeric organism. On one
hand it shares properties with dairy propionibacteria, such
as Propionibacterium freudenreichii, which is a ‘Generally
Recognised as Safe’ (GRAS) status microorganism. Such
GRAS microorganisms display a multitude of health
promoting properties such as modulation of gut microbiota,
improved gut physiology, and immunomodulation,
suggesting their probiotic potential. Potential health
promoting features shared between P. acnes and GRAS
propionibacteria are e.g. the biosynthesis of vitamin B12,
riboflavin and folate, the production of conjugated linoleic
acid, propionic acid and other SCFAs, and the secretion
of bacteriocins.
On the other hand P. acnes has features of an opportunistic
pathogen. It secretes host-tissue component degrading
enzymes, is usually haemolytic and possesses cytotoxic
CAMP factors. The immunomodulatory activities of
210
P. acnes are well recorded, but the consequences are
poorly understood. It is essentially not known if these
immunomodulatory properties have beneficial or
adverse effects to the host. It could depend on several
host preconditions such as tolerance status, genetic
predisposition, age, and hormone status. It might also
depend on the anatomical site of infection. Recently, it was
reported that P. acnes exhibits profound host cell tropism:
whereas the P. acnes-induced inflammation in skin cells is
acute but transient, the same strain triggers a delayed but
sustained inflammation in cultured prostate cells (Mak et
al., 2012).
The population structure of P. acnes has been resolved a
few years ago (Lomholt and Kilian, 2010; McDowell et al.,
2011; Tomida et al., 2013), revealing the presence of distinct
phylotypes of P. acnes, some of which are associated with
disease while others are predominately isolated from healthy
individuals. The immunomodulatory properties of P. acnes,
in particular the induction of innate immune responses,
have been suggested to account for an inflammation-
inducing role of P. acnes in acne vulgaris. However, it is
still unclear why the commensal P. acnes microbiota usually
does not lead to inflammatory responses. The restriction of
the P. acnes population size in human follicles might be one
factor, but it could also be possible that (health-associated
phylotypes of ) P. acnes produce so far unidentified factors
involved in the inhibition or suppression of innate immune
responses. The nature and consequences of human host-P.
acnes interactions, which comprise both mutualistic and
parasitic properties, likely depend on host cell type-specific
responses as well as bacterial strain identities.
Being part of the normal skin microbiota, both S.
epidermidis and P. acnes have evolved along with the human
host. Knowledge on the mutualistic roles of both organisms
will increase our understanding of the delicate balance of
our skin microbiota, and could be exploited for therapeutic
strategies to treat skin diseases or to fight more harmful
skin-associated bacteria, such as MRSA.
Acknowledgements
We would like to thank Mogens Kilian for critically reading
the manuscript.
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