The Association of the Skin Microbiota With

Health, Immunity, and Disease

M Egert1, R Simmering2 and CU Riedel3

The human skin is densely colonized by a highly diverse microbiota comprising all three domains of life. Long believed to
represent mainly a source of infection, the human skin microbiota is nowadays well accepted as an important driver of
human (skin) health and well-being. This microbiota is influenced by many host and environmental factors and interacts
closely with the skin immune system. Although cause and effect are usually difficult to discriminate, changes in the skin
microbiota clearly play a role in the pathobiology of many types of skin disease and cosmetic disorders. Consequently, treat-
ment and prevention strategies have to respect this role, rendering pre- and probiotic and even transplantation therapies an
additional option to the use of antibiotics.

THE HUMAN SKIN: NOT ONE BUT MANY MICROBIAL
HABITATS
The human skin represents one of the largest and most versatile
organs of the human body. It functions as a protective interface
between the largely sterile interior of the human body and the
unsterile outer environment. Like other epithelial interfaces with
the external environment, the human skin is densely colonized
with a complex microbial community.1 The entire microbial
community of a given habitat is also referred to as “microbiota”
or “microbiome.” While “microbiota” rather refers to the micro-
bial taxa associated with a given environment, a “microbiome”
comprises the catalog of these microbes and their genetic material
(DNA/RNA). However, both terms are often used interchange-
ably.2 For the sake of consistency, and because we largely focus
on the interactions of different microbial taxa with the human
host, we use “microbiota” throughout this text. “Microflora” is
another widely used term for “microbial community,” particularly
in medical circles. However, it originates from a time when
microbiology was a subdiscipline of botany, and microorganisms
were categorized as a kind of plant. Therefore, we suggest avoid-
ing this term.
For a long time, this skin microbiota was seen as a source of
contamination and infection. However, the human microbiome
project and concomitant molecular, i.e., cultivation-
independent, research projects strongly suggested that the
human skin microbiota is of major importance for human health
and well-being.1,3
1
Faculty of Medical and Life Sciences, Institute of Precision Medicine, Microbiology and Hygiene Group, Furtwangen University, Villingen-Schwenningen,
Germany. 2Henkel AG & Co. KGaA, Corporate Scientific Services, Du
Germany. Correspondence: M Egert (Markus.Egert@hs-furtwangen.de)
Received 20 February 2017; accepted 28 March 2017; advance online publication 5 April 2017. doi:10.1002/cpt.698
Structural and functional characteristics of the human skin
The human skin provides a mechanical and biological barrier
against chemical, physical, and pathogenic threats, thereby main-
taining host homeostasis. It participates in thermoregulation, sup-
ports immunological functions, and protects against UV
radiation by melanogenesis. Anatomically, the skin comprises
three distinct compartments (Figure 1): the stratum corneum,
consisting of dead, keratinized epithelial cells, the avascular epi-
dermis, mainly composed of (living) keratinocytes, and the der-
mis, a fibroblast-rich network of collagen and elastin fibers
providing strength and elasticity. The dermis also contains capil-
lary and lymphatic vessels, which serve as the entry and exit por-
tals for immune cells. Additional skin appendages such as hair
follicles, sebaceous glands, and sweat glands, as well as nerve end-
ings, are also found in the dermis.4
Several factors contribute to the protective function of the skin
against colonization by pathogenic microorganisms and, in turn,
have to be overcome by the resident, commensal, or even mutual-
istic members of the skin microbiota. The relatively low tempera-
ture of the skin (29–348C compared to 378C in the core of the
human body) and its acidic pH of about 4.5 to 5.5 represent
rather unfavorable conditions for most skin pathogenic bacteria.
Moreover, the continuous proliferation of epithelial cells in the
dermis and shedding of dead, keratinized cells in the epidermis
provide protection against microbial infection and degradation.4
In addition to these chemical and physical mechanisms, the bar-
rier function of the skin is supported by a wealth of different cell
types that provide both innate and adaptive immunity.5
€sseldorf, Germany. 3Institute of Microbiology and Biotechnology, University of Ulm, Ulm,

62 VOLUME 102 NUMBER 1 | JULY 2017 | www.cpt-journal.com

Figure 1 Layers of the human skin and associated glands and vessels. Contrary to the historical notion that microbial life is restricted to the epidermis
and its appendages (hair follicles and glands), recent evidence suggest (skin) microorganisms to be also present in deeper layers. Interaction between
microbes and Langerhans cells leads to the induction of FoxP31 regulatory T cells (Treg). In deeper layers of the skin, contact of microorganisms with con-
ventional dendritic cell (cDC) subsets induces production of IL-1, IL-17, and IFN-g by T cells, migration of these T cells to the epidermis, activation of natu-
ral killer (NK) cells, and secretion of antimicrobial peptides (AMPs) by keratinocytes.

Secretion of sweat and sebum
In particular, the uneven distribution of different gland types cre-
ates many different habitats across the human body, which differ
significantly in environmental conditions. Sebaceous parts, such
as the scalp, forehead, neck, and the upper part of the back, are
greasy and contain a large number of sebaceous glands responsible
for secretion of sebum. A few hours after birth, secretion of
sebum strongly increases, which lasts for a couple of days and
then decreases again. Normally, in late childhood (starting
approximately at the age of 9 years), sebum production rises again
and lasts until the adult level is reached. The sebaceous gland is a
target organ, but also an important production site of hormones,
especially of active androgens.6
While some parts of the human body, such as armpits, the
genital area, and feet, are rather occluded, moist, and warm,
there are also large areas on forearms, legs, and the lower part of
the back which are relatively exposed and dry. Perspiration, i.e.,
secretion through sweat glands, is crucial for the regulation of
body temperature, which represents an important factor for
body homeostasis.7,8 Sweat glands are specialized exocrine glands
that are appendages of the skin and can be categorized into
eccrine, apocrine, and intermediate, i.e., apoeccrine sweat glands
(Figure 1).
Eccrine sweat glands are the most abundant sweat glands of
the human body. On average, 100 to 200 glands per cm2 are dis-
tributed virtually all over the body surface. While palms and soles
show higher densities (600 glands per cm2), other parts of the
body, e.g., lips and nail beds, are depleted of eccrine glands.8
Thermoregulatory perspiration by eccrine sweat glands is effective
from birth on and is affected by environmental parameters, such
as temperature, humidity, skin and body temperature, but also by
physical fitness, circadian rhythm, and the menstrual cycle. Secre-
tion by eccrine glands is mainly triggered by temperature but also
by pain, stress, fear, and anxiety, resulting in emotional sweating.
Digestion is also speculated to induce eccrine sweating. Another
crucial function of eccrine sweat is the control of microbial colo-
nization and growth by acidification of the skin surface.1 Eccrine
sweat is a largely translucent liquid mainly composed of water,
sodium and potassium salts, as well as amino acids, sugars, lactate,
and glycoproteins.9 Its exact composition depends on hormonal
activity, physical condition, acclimatization to environmental
conditions, as well as secretion rate.8

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 102 NUMBER 1 | JULY 2017 63

 Apoeccrine sweat glands are far less abundant on skin than
eccrine glands. About 2,000 of them are distributed around the
eyes and ears and on chest skin, while the highest densities are
reported for axillae and groin. Apocrine glands release their secre-
tion into hair canals, and are restricted to hairy body surfaces.
They are activated with puberty and androgen stimulation and
are then stimulated by hormones.7–9
Apocrine sweat appears milky and viscous, and is known to
comprise lipids, lactates, nitrogen, electrolytes, steroids, proteins,
and vitamins in addition to other ions.8 However, the exact com-
position of apocrine secretion has yet to be elucidated due to the
lack of pure samples. Apocrine glands are suspected to be
involved in emotional sweating, but their original function
remains unidentified.7 In contrast to eccrine sweat glands, apo-
crine glands secret substances that can be transformed into mal-
odorous molecules upon lysis by bacteria and thus contribute
significantly to development of human body odor.7–10
The immune system of the skin
The skin harbors a wide range of different cell populations
including keratinocytes, macrophages, dendritic cells, innate lym-
phocytes, and different T-cell populations that belong to or per-
form functions of the innate and adaptive immunity. The
effector mechanisms of these cells include production of antimi-
crobial compounds, expression of innate recognition receptors to
sense and respond to microbe-associated molecular patterns, and
more specialized, antigen-specific responses.5 The primary innate
defense system of the human skin consists of an arsenal of anti-
microbial peptides (AMPs), and enzymes mainly produced by
keratinocytes.11 Enzymes with antimicrobial activity found on
human skin include lysozyme, RNAses, and S100 family pro-
teins.11 The main AMPs of the human skin are human b-
defensins (hBD-1, hBD-2, hBD-3, hBD-4), and the cathelicidin
LL-37.11 b-defensins are small cationic peptides (usually 4–
5 kDa) with a characteristic set of three disulfide bonds.12 LL-37
is a member of the cathelicidin family, which are host defense
peptides of vertebrates, of which LL-37 is the only human repre-
sentative. The active form of LL37 is derived from its precursor
hCAP18 by proteolytic cleavage, consists of 37 amino acids with
two leucine residues at the N-terminus, and has a broad range
antimicrobial activity against bacteria, fungi, and viruses.13
Expression of AMPs by keratinocytes is regulated by various
mechanisms. While hBD-1 is generally considered as being con-
stitutively expressed in the epithelium, hBD-2, hBD-3, and
LL-37 are induced during inflammation, e.g., in acne lesions and
psoriasis,14–16 and in response to microbial stimuli.17–20 Activa-
tion occurs via cytokines of the interleukin-1 family and the
nuclear factor kappa B (NF-jB) pathway.21,22 Polymorphisms in
an NF-jB binding site in the promoter of hBD-1 are associated
with reduced expression of hBD-1 and hBD-3 and increased
nasal carriage of S. aureus.23 Expression of LL-37 is induced by
vitamin D3, which is produced upon exposure to UVB light, in
combination with inflammatory stimuli and skin injury.11
The primary role of antimicrobial peptides and proteins of the
skin is to inactivate microorganisms by disruption of membrane
integrity, enzymatic degradation of the cell wall, or other, yet
64
unknown mechanisms.11 However, their effects are by far not
restricted to killing of microorganisms, but also include immuno-
modulatory functions. Some AMPs interact directly with Toll-
like receptors (TLRs), a family of innate recognition receptors,
and this interaction seems to limit excessive inflammatory
responses.11 Moreover, LL-37 and hBDs act as potent chemotac-
tic signals and attract monocytes, dendritic cells, neutrophils, and
T cells.11
Similar to the gastrointestinal immune system, the skin is rich
in a wide range of different cell populations of the innate and
adaptive immune system even in the absence of a pathogenic or
inflammatory stimulus (Figure 1). Cells of the adaptive immune
system in the skin include antigen-presenting cells (APCs),
CD41, and CD81 T cells.24 Several populations of APCs are
present in different layers of the skin, of which epidermal Langer-
hans cells are the most abundant.25 These different populations
of APCs have different functional properties. Langerhans cells
seem to have a rather immunosuppressive phenotype that coun-
terbalances excessive T-cell responses induced by conventional
dendritic cell (cDC) populations of the dermis.25 At the other
end of the spectrum, cDC subsets prime na€ıve T cells to differen-
tiate into appropriate effector T cells, depending on the stimu-
lus.25 As observed in the gastrointestinal tract, the skin
microbiota plays a major role in maintaining the skin immune
system in homeostasis under normal conditions. The skin, but
not the gut microbiota, is required to induce appropriate levels of
interleukin (IL) 17 and interferon g-producing T cells and
FoxP3-expressing regulatory T-cell populations.26 Early exposure
of human neonates to S. epidermidis induces S. epidermidis-
specific, FoxP31 regulatory T cells in the skin which are thought
to contribute to inhibition of excessive (proinflammatory)
immune responses to this commensal skin bacterium.27 More-
over, different dermal DC subsets cooperate in antigen presenta-
tion and induction of IL-17-producing CD8-positive T cells in
response to S. epidermidis in an IL-1-dependent manner. These
IL-17-producing T cells then migrate to the epidermis and stimu-
late expression of AMPs by keratinocytes.28
THE SKIN MICROBIOTA IN HEALTH AND DISEASE
Structure of the skin microbiota of healthy adults
In the last decade, high-throughput sequencing technologies have
greatly facilitated the in-depth taxonomic analysis of the commu-
nity structure of the human skin microbiota. It is now well estab-
lished that this microbiota comprises prokaryotes, eukaryotes
(fungi, metazoic parasites), and viruses.1,3,29,30 The prokaryotic
community is dominated by Bacteria, however, Archaea are
clearly also present.31 Thus, the skin microbiota comprises all
three domains of life. Metazoic parasites (mostly arthropods, e.g.,
mites) and viruses will not be discussed here, as they do not repre-
sent microorganisms in a narrower sense (mites) or living micro-
organisms (viruses), respectively.
Assuming a skin surface of 2 m2 and maximum microbial
(bacterial) cell densities of 106 cm-2, the skin of healthy adults
can be estimated to be colonized by a maximum of 1010 micro-
organisms in total. However, bacteria are distributed very
unevenly across the different niches of the human skin. Cell
VOLUME 102 NUMBER 1 | JULY 2017 | www.cpt-journal.com
numbers range from 102 cm22 (fingertips, back) to 106 cm22
(forehead, axilla). Owing to its physicochemical conditions, the
human skin is typically colonized by mesophilic, xerophilic, aci-
dophilic, osmotolerant, and facultative aerobic microorganisms.
However, depending on the respective niche, also microbes with
other physiological traits can occur. While it was long believed
that on healthy skin microbial life is restricted to epidermis, hair
follicles, and sebaceous and sweat glands, recent analyses32 suggest
that viable microbes are found also in deeper skin layers, i.e., the
dermis and underlying fat tissue (Figure 1). This finding is
important from an immunological point of view, because it sug-
gests direct communication between host and microbial cells in a
tissue previously thought to be sterile, unless injured and contam-
inated with bacteria from upper skin parts or the environment.
At present, molecular high-throughput studies (see below, and
Supplementary Table S1) allowed detection of more than 25
bacterial phyla on human skin, although mostly in low abun-
dance. The vast majority of skin bacteria are affiliated with three
phyla: Actinobacteria, Firmicutes, and Proteobacteria. Moreover,
the human skin microbiota proved to be individual (particularly
on genus and species-level), body site-dependent, and to change
with time and age.
Investigated over a period of 8–10 months, the superficial volar
forearms of six healthy adults contained 247 operational taxo-
nomic units (OTUs, here used in the sense of “species”) belong-
ing to 119 genera and 10 phyla.33 On average, 48 species were
detected per human individual. Actinobacteria, Firmicutes, and
Proteobacteria accounted for 95% of the clones. Only four
(3.4%) of the 119 genera (Propionibacterium, Corynebacterium,
Staphylococcus, Streptococcus) were observed in those subjects, who
were tested twice over the period, albeit these genera represented
54% of all clones.
Over a period of 4–6 months, 20 different body sites of 10
healthy adults harbored 19 bacterial phyla, but most sequences
were assigned to just four of them: Actinobacteria (52%), Firmi-
cutes, (24%), Proteobacteria (17%), and Bacteroidetes. (6%).34 Of
205 identified genera, represented by at least five sequences, three
accounted for more than 62% of the sequences: corynebacteria
(23%, Actinobacteria), propionibacteria (23%; Actinobacteria),
and staphylococci (17%; Firmicutes). Sebaceous sites were domi-
nated by propionibacteria and staphylococci. Corynebacteria and
staphylococci were predominant in moist habitats. Rather unex-
pectedly, in particular in view of earlier cultivation-dependent or
small-scale cloning-based community analyses, a mixed popula-
tion of bacteria resided in dry sites, with a greater prevalence of
b-Proteobacteria and Flavobacteriales. Species diversity and tem-
poral stability of the skin microbiota were also site-dependent:
the latter was higher for protected sites (nares, external auditory
canal) than for exposed sites (buttock, popliteal). The effect of
skin niche on the composition of the skin microbiota was more
dependent on the investigated skin site than on the individual.
The left and right palmar surfaces of 27 healthy men and 24
healthy women contained more than 4,700 bacterial phylotypes
(“species”) representing an overall microbial diversity similar to
that of the human intestinal tract.35 On average, every hand was
colonized by 158 different phylotypes. More than 25 phyla were
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 102 NUMBER 1 | JULY 2017
detected; however, Actinobacteria, Firmicutes, and Proteobacteria
again accounted for 94% of the sequences; the most abundant
genera were Propionibacterium (31.6% of all sequences), Strepto-
coccus (17.2%), Staphylococcus (8.3%), Corynebacterium (4.3%),
and Lactobacillus (3.1%). Hands from the same individual shared
only 17% of their phylotypes, with different individuals sharing
only 13%. Women had a significantly higher diversity than men,
and community composition was significantly affected by hand-
edness, time since last hand washing, and an individual’s gender.
While most studies on the skin microbiota addressed the epi-
dermis and its appendages, knowledge about the microbiota of
subepidermal compartments of normal skin is scarce. Using a
multiphasic approach,32 probably active bacteria have been
reported from the dermis and dermal adipose tissue. Interestingly,
this microbiota was dominated by Proteobacteria, while Actino-
bacteria and Firmicutes were much less abundant. Although fur-
ther studies are needed to substantiate and better interpret this
finding, theses data suggest that the commensal skin microbiota
extends within the dermis, which allows physical contact between
bacteria and various cells below the basement membrane, i.e.,
that normal commensal bacterial communities directly communi-
cate with the host in a tissue previously thought to be sterile.
Finally, still relatively little is known about nonbacterial mem-
bers of the human skin microbiota, e.g., fungi and archaea. Of 14
investigated skin sites in 10 healthy adults, 11 core-body and arm
sites were dominated by Malassezia yeasts, showing differences
only on the species level. By contrast, three foot sites showed a
higher fungal diversity, comprising also genera such as Aspergillus,
Cryptococcus, Rhodotorula, Epicoccum, and others, and a lower sta-
bility over time. Fungal communities were also influenced
by skin topography, but—in comparison to bacterial skin
communities—less clearly by skin physiology.36 For a long time,
Archaea were thought to be absent from human skin. However, a
recent report31 suggested that they can represent more than 4% of
the human prokaryotic skin microbiota. Phylotypes detected by
polymerase chain reaction (PCR) and fluorescence in situ hybridi-
zation (FISH) were mostly affiliated with Thaumarchaeota, and
to a lesser extent also with Euryarchaeota. So far, their physiologi-
cal role is obscure. According to the function of Thaumarchaeota
in many environmental ecosystems, a role in skin ammonia
metabolism has been suggested.36
A wealth of intrinsic (host) and extrinsic (environmental,
behavioral) factors have been identified that influence the com-
position of the skin microbiota of the human body on a spatial
and temporal scale.1,3,37 Intrinsic factors include age, gender,
genetic predisposition, immune status, underlying diseases (skin
and nonskin disease), skin site, and microbe–microbe interac-
tions. Extrinsic factors include, for instance, life style, domestic
and personal hygiene, cohabitation, and environmental factors
such as place of living (geography) and solar radiation. Supple-
mentary Table S1 represents an updated version of a recently
published table37 containing select examples of recent studies
investigating various factors that shape the overall composition of
the skin microbiota. In addition to the factors mentioned in
Table S1, several others are likely to influence the composition
of the human skin microbiota, such as diet, climate, occupation
65
(clothing), stress, etc.; however, appropriate studies are still
missing.
Protective functions of the human skin microbiota
Given the high interindividual variation in the composition of
the (skin) microbiotas of healthy subjects, it is difficult to define
a “healthy” skin. However, it is generally believed that a healthy
skin microbiota is characterized by a considerable diversity of
commensal or even beneficial (symbiotic) bacteria.38 In contrast,
illness is thought be associated with a disturbed (imbalanced)
microbiota characterized by a loss of microbial diversity and
increased absolute numbers or relative abundance of pathogenic
bacteria; a state called dysbiosis.39 Colonization of the skin with
a balanced or healthy microbiota is generally recognized as benefi-
cial because it is thought to contribute to protection against
infections, a phenomenon known as colonization resistance.
Moreover, the microbiota may also play a role in other, noninfec-
tious disease, e.g., by immunomodulatory effects. However, given
the pronounced temporal, spatial, and interindividual variations
in microbial diversity, assigning beneficial functions to distinct
taxonomic groups of the complex skin microbiota, which also
comprises large numbers of yet uncultured species, is challenging.
The acidic pH of normal healthy skin, also termed the “acid
mantle,” represents an important line of defense against patho-
genic microorganisms. Facultative anaerobes, such as Propionibac-
terium acnes, reside in sebaceous glands where their lipolytic
enzymes release free fatty acids from sebum. Together with
sebum, these free fatty acids are continuously shed onto the skin
surface and contribute to the acidic pH.1
Another mechanism by which commensal bacteria contribute
to colonization resistance is the production of bacteriocins and
other antimicrobial factors, which are produced to increase com-
petitive fitness in a densely populated environment. With respect
to the skin ecosystem, staphylococci, and in particular S. epider-
midis, can be regarded as the best-investigated bacteriocin-
producers.40 Some commensal strains of. S. epidermidis can
protect their host from colonization with S. aureus by means of a
serine protease (Esp) that destroys S. aureus biofilms; for instance,
in the anterior nares.41 Nasal S. lugdunensis was recently shown to
produce lugdunin, a cyclic peptide antibiotic that inhibits nasal
colonization with S. aureus.42 Lugdunin represents a bactericidal
activity acting against various important pathogens, including
methicillin-resistant S. aureus, vancomycin-resistant Enterococcus
faecalis, Listeria monocytogenes, Streptococcus pneumoniae, and
Pseudomonas aeruginosa. Although peptide bacteriocins such as
lugdunin are rather ineffective alternatives to systemic antibiotics
due to their immunogenicity, they may represent potential antibi-
otic agents for topical applications. In this case, either the pure
bacteriocin or a probiotic strain producing the compound could
be applied to the skin.
Similar to the human gut, the skin microbiota is thought to be
involved in the development and regulation of the innate and
adaptive immune system and maintenance of skin homeosta-
sis.43,44 Lipoteichoic acids of S. epidermidis prevented skin injury-
based inflammation by inhibition of inflammatory cytokines
release from keratinocytes as well as TLR2-based immune-
66
responses elicited by injured skin cells.45 So far, skin bacteria were
believed to cause rather than to reduce skin inflammation. Also,
S. epidermidis was shown to enhance skin defense mechanisms
against infection by enhancing gene expression of antimicrobial
peptides, such as hBDs.46 Finally, it was shown that S. epidermidis
can tune the function of resident skin T-lymphocytes and
thereby contribute to protective immunity against skin patho-
gens. Monoassociation of the skin of previously germ-free mice
with S. epidermidis restored the production of IL-17A in skin T-
cells and thereby protective immunity against infection.26 Clearly,
skin commensals such as S. epidermidis are important drivers and
amplifiers of human skin immunity44 and a good example that
the human body comprises additional niches to the intestinal
tract, were immunosurveillance systems are locally fine-tuned by
a commensal microbiota.47
The skin microbiota in skin disorders and diseases
Many human skin disorders and diseases have been linked with
changes in skin microbiota composition and/or functionality.
However, in most cases it is still not clear whether these changes
are the cause or the consequence of the underlying disease. Never-
theless, such changes are expected to have diagnostic, preventive,
and potentially therapeutic implications.
In the case of acne vulgaris, P. acnes is regarded as the primary
disease-associated bacterium. Importantly, the major trigger of
acne is not the presence of P. acnes itself, but hormone-induced
increased sebum production, providing P. acnes with optimal liv-
ing conditions in an anaerobic and lipid-rich environment.
Genome analyses of P. acnes revealed a variety of virulence factors
probably involved in the pathobiology of acne, e.g., hyaluroni-
dases, lipases, and proteases.48 In a recent study49 comparing the
skin of acne patients with healthy individuals, it was shown that
the relative abundances of P. acnes species were similar, but on
the strain-level the population structures were significantly differ-
ent in the two cohorts. Certain strains were highly associated
with acne, and other strains were enriched in healthy skin. The
authors also identified potential genetic determinants of various
P. acnes strains in association with acne or health, which could
become future targets for therapeutic interventions. For instance,
particularly disease-associated strains contained sequences encod-
ing CRISPRs (Clustered Regularly Interspaced Short Palin-
dromic Repeats), which have been shown to confer protection
against viruses, phages, and plasmids.
Higher frequencies of Firmicutes and lower frequencies of Acti-
nobacteria, in particular of propionibacteria, were detected in pso-
riatic lesions compared to normal skin stretches of patients and
of skin from healthy individuals.50 An analysis of triplet samples
from diseased, unaffected, and healthy skin showed that psoriasis
induced physiological changes both at the lesion site and the sys-
temic level.51 Lesions were characterized by a reduced microbial
species diversity. Psoriasis patients were characterized by higher
combined relative abundances of the major skin genera Coryne-
bacterium, Propionibacterium, Staphylococcus, and Streptococcus,
while genera such as Cupriavidus, Methylobacterium, and Schlege-
lella were significantly less abundant.
VOLUME 102 NUMBER 1 | JULY 2017 | www.cpt-journal.com
 Atopic dermatitis (AD) is characterized by increased bacterial
colonization with S. aureus.52,53 Interestingly, the induction of
hBD-2 and hBD-3 usually seen in inflammatory lesions of acne
and psoriasis is not observed in AD lesion.15,16,54 Since both pep-
tides show potent antimicrobial activity against S. aureus,17 a lack
of appropriate induction of hBD2 and hBD3 expression might
contribute to increased levels of S. aureus, and thus pathology of
AD. At present, the mechanistic defects leading to insufficient
induction of hBD-2 and hBD-3 have not been elucidated.
Rosacea and seborrheic dermatitis are skin diseases linked with
Demodex mites and Malassezia fungi and an immunological and
microbial dysbiosis of the skin ecosystem.3 In the case of rosacea,
microbiota-associated changes on the skin and in the small intes-
tine have been observed simultaneously.55 Seborrheic dermatitis,
particularly of the scalp (dandruff), affects 50% of the global
population and is mainly caused by M. restricta and M. globosa
producing high levels of irritant fatty acids, such as oleic acid, Figure 2 The three major concepts to manipulate the human skin micro-
causing skin hyperproliferation and scaling. In unaffected per- biota in order to improve human health and well-being. The use of topically
sons, these organisms are harmless commensals of the skin and applied antibiotics is effective in reducing the overall bacterial load of the
scalp microbiota. The factors that allow these normally harmless skin, but does not allow for a differentiation between beneficial (green)
commensals to switch to a pathogenic state are still not fully and adverse/pathogenic (red) bacteria. In contrast, pre- and probiotic
strategies aim at increasing the number of beneficial bacteria and reduc-
understood. Recent evidence shows the increased production of ing the number of adverse/pathogenic ones. Skin microbiota transplanta-
specific phospholipases on affected skin sites in dandruff and sig- tion is a very new strategy and is based on the transfer of beneficial
naling molecules such as malassezin in seborrheic dermatitis.56 microorganisms or communities from healthy to diseased and microbiolog-
In addition to dandruff, also other, rather cosmetic, skin prob- ically imbalanced skin. All picture elements were obtained from pixabay.
lems such as impure skin, sensitive skin, or body odor are linked com and are distributed under a Creative Commons CC0 license. The cen-
tral skin element was changed from a picture created by Don Bliss,
with the skin microbiota. Strong body odor (bromidrosis) is a National Cancer Institute, Rockville, MD, USA.
pathological phenomenon, triggers a person’s attractiveness for
mosquitoes, and might thus play a role in the transmission of uncouple mutualistic host–microbe relationships. Recently, orally
infectious diseases such as malaria.57 The human armpit repre-
administered vancomycin was shown to influence the amount
sents one of the most densely colonized habitats of the human
and composition of bacteria on the skin of mice, with negative
skin. Its composition is gender-specific58 and characterized by an
consequences for wound healing.65 Thus, alternative therapies
asymmetric (left vs. right) activity.59 Members of the resident
that make use of the mutualistic interactions between the skin
microbiota metabolize odorless sweat to malodorous compounds
microbiota and its host are increasingly investigated.64,66–68
using hydrolytic enzyme activities, such as aminoacylase and cys-
The prebiotic concept was transferred from nutrition to the
tathionin-b-lyase.10 While it was long believed that mainly cory-
field of skin care products about 15 years ago.69,70 For example,
nebacteria produce body odor, recent cultivation-independent
application of a cosmetic product containing 0.5% of a mixture
studies58 suggest that also other groups are involved, such as anae-
of pine, black current, and ginseng to human skin twice per day
rococci60 and staphylococci.61,62
for 3 weeks was effective in inhibiting the growth of P. acnes,
MANIPULATION OF THE HUMAN SKIN MICROBIOTA whereas commensals such as S. epidermidis were not affected.70
Strategies to manipulate the skin microbiota for therapeutic rea- Farnesol and xylitol were used to balance the skin microbiota of
sons can be divided into three categories (Figure 2): antimicro- patients with atopic dermatitis, by removing and preventing the
bial (antibiotic) therapy, application of pre- or probiotics, or adhesion of biofilm-producing S. aureus species.71 An extract
transplantation of entire microbial consortia to diseased skin. from avocado, consisting mainly of mannoheptulose and persei-
While antibiotic treatment aims at an elimination of specific tol, affected the adherence of M. furfur to keratinocytes, and
(pathogenic) microorganisms, the goal of the application of pro- induced the production of hBD2,72 possibly due to structural
biotics or microbiota transplantation is an increase of selected, similarities of its main components to cell wall constituents of
potentially beneficial microorganisms.63,64 yeasts. Future developments in this field have to balance a stimu-
The overall beneficial effect of antibiotics against severe micro- lated antimicrobial defense system vs. an immunological overreac-
bial skin infections is unquestionable. While their aim is to tion. This issue was addressed in a study on the induction of
reduce or completely eradicate specific pathogens, they often also defensins in keratinocytes by plant extracts.73 Only some of the
reduce or eliminate other, sometimes beneficial, members of the tested extracts, e.g., arnica, betel, black elder, and mugwort,
microbiota. Moreover, these effects, and specifically the use of enhanced expression of defensins without inducing proinflamma-
broad-spectrum antibiotics, may have pervasive and long-lasting tory cytokines, such as IL-8, IL-1a, or MIP-3a, rendering them
consequences for the microbial ecosystem of the skin that potential cosmetic or skin therapeutic ingredients.

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 102 NUMBER 1 | JULY 2017 67

 The topical application of beneficial bacteria as probiotics (as
living or inactivated whole cells) represents a second strategy to
(re)balance the skin microbiota. In an early study,74 the use of
food-grade propionibacteria was proposed for cosmetic products,
since cutaneous isolates might be correlated with skin infections.
The selected strains revealed an antimicrobial activity against sev-
eral skin pathogens, such as M. furfur, C. albicans, and S. aureus,
attributed to the secretion of organic acids and/or competition
for attachment sites on keratin.
In a pilot study on keratoconjunctivitis, a reduction of symp-
toms and of the molecular markers ICAM-1 and TLR-4, both
proteins of the innate immune system, were observed after admin-
istration of eyedrops containing inactivated Lactobacillus acidophi-
lus cells for 2–4 weeks.75 Besides lactic acid bacteria, biomass of
Vitreoscilla filiformis represents another probiotic ingredient in cos-
metic products. It was shown to modulate a mitochondrial super-
oxide dismutase in skin cells, thereby conferring antioxidative
protection.76 Biomass of the same organism lead to a stimulation
of mRNA expression coding for antimicrobial peptides hBD2 and
S100A7 in a reconstructed epidermis model. Furthermore, involve-
ment of the TLR2/protein kinase C zeta-transduction pathway
was supposed.77 Finally, the effects of orally ingested probiotics on
the skin were described: In a double-blinded, placebo-controlled
trial, ingestion of Lactococcus lactis strains improved selected skin
and body properties in women, such skin elasticity.78
In contrast to the intestinal tract, where fecal transplantation
has become an increasingly accepted therapeutic option, the
transplantation of (selected members of) a healthy skin micro-
biota to diseased skin tissue with an unbalanced microbiota is still
at a very experimental stage. Very recently, cultivable Gram-
negative bacteria taken from healthy volunteers but not from
patients with AD were shown to be associated with enhanced
barrier function, innate immunity activation, and control of S.
aureus in in vitro and in vivo models of AD.63
OUTLOOK: TRENDS AND CHALLENGES
The microbiota of the human skin clearly plays a significant role
for human health and well-being. Future research in this field will
therefore (continue) to focus on the definition of a “normal”
(healthy) state of skin microbiota composition and functioning and
its shaping by environmental and host factors. The interplay of the
three domains of life and of viruses among each other and with
host physiology and immune system is another important topic,
not only on the human skin, but also regarding interactions with
the microbiota of other body compartments, e.g., the human intes-
tinal tract. In order to better discriminate cause and effect, a deeper
and more mechanistic (functional) understanding of the role of the
skin microbiota in skin diseases and cosmetic skin disorders is
needed. Increased understanding in this area will aid the definition
of microbiological biomarkers for an early and reliable diagnosis of
skin diseases as well as the development of alternative therapeutic
strategies (prebiotic, probiotic, transplantation) and products which
respect and utilize mutualistic host–microbe relationships.
Additional Supporting Information may be found in the online version of
this article.
68
CONFLICT OF INTEREST
R.S. is employed by Henkel AG & Co, KGaA, a company which produces
skin cosmetics. M.E. has previously worked for Henkel and is still
involved in microbiology projects funded by the company.
C 2017 American Society for Clinical Pharmacology and Therapeutics
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