Available online at www.sciencedirect.
com
ScienceDirect
Mechanisms for control of skin immune function by the
microbiome
Teruaki Nakatsuji, Joyce Y Cheng and Richard L Gallo
The skin represents the largest area for direct contact between
microbes and host immunocytes and is a site for constant
communication between the host and this diverse and essential
microbial community. Coagulase-negative staphylococci are
an abundant bacterial genus on the human skin and are
regulated through various mechanisms that include the
epidermal barrier environment and innate and adaptive immune
systems within the epidermis and dermis. In turn, some species
and strains of these bacteria produce beneficial products that
augment host immunity by exerting specifically targeted
antimicrobial, anti-inflammatory, or anti-neoplastic activity
while also promoting broad innate and adaptive immune
responses. The use of selected skin commensals as a
therapeutic has shown promise in recent human clinical trials.
This emerging concept of bacteriotherapy is defining
mechanisms of action and validating the dependence on the
microbiome for maintenance of immune homeostasis.
Address
Department of Dermatology, University of California, San Diego, United
States
Corresponding author: Gallo, Richard L (rgallo@health.ucsd.edu)
Current Opinion in Immunology 2021, 72:324–330
This review comes from a themed issue on Allergy and
hypersensitivity
Edited by Toshiaki Kawakami and Ulrich Blank
For a complete overview see the Issue and the Editorial
Available online 16th September 2021
https://doi.org/10.1016/j.coi.2021.09.001
0952-7915/ã 2021 The Authors. Published by Elsevier Ltd. This is an
open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
Human skin provides a unique milieu for
host–microbe interactions
Mammalian skin possesses intrinsic defenses against
infection by microbial pathogens. Both skin resident cells
and commensal bacteria participate in a variety of protec-
tive innate and adaptive immune mechanisms. Antimi-
crobial peptides (AMPs) form an important part of this
defense. They are produced by various cells in the
epidermis and dermis, including keratinocytes, sebo-
cytes, and immunocytes such as neutrophils, mast cells,
monocytes, T-cells, and dermal adipocytes [1]. AMPs
Current Opinion in Immunology 2021, 72:324–330
typically provide semi-specific and highly potent defense
against a broad range of microbes by disrupting mem-
branes. Thus, control of the expression and post-tran-
scriptional activation of these peptides and proteins is a
primary innate host defense mechanism for directly sup-
pressing microbial growth [1,2]. AMP expression
increases when the skin detects danger signals or inflam-
matory cues in response to wounding or infection, and this
is mediated by both classical and unique signaling path-
ways that include pattern recognition receptors, cyto-
kines, vitamins, hormones, and neuropeptides [1,3–6].
Activation of AMP activity is essential for control of
bacterial growth on the skin in case of epithelial barrier
damage.
Despite intrinsic expression of AMPs by diverse cells in the
skin, an abundant and diverse population of microbial
organisms colonizes the epithelial surfaces of mammals.
This community of bacteria, fungi, protozoa, and viruses
has been called the ‘microbiome’. Emerging evidence over
the last 15 years has suggested that the microbiome con-
tributes crucially not only to human health and a well-
functioning immune system but also to the pathogenesis of
diverse diseases including atopic dermatitis (AD), inflam-
matory bowel disease, obesity, and cancer [7,8]. These
associations have driven the hypothesis that our body is
in continuous communication across epithelial barriers
with microbial ecosystems that influence both local and
systemic homeostasis within our bodies. The following will
review evidence that supports this hypothesis.
It is a common misconception that human skin is a flat
surface and impermeable barrier for microbes. In reality,
it contains complex anatomical structures, including
grooves, hair follicles, sebaceous glands, and eccrine
sweat glands with specific physiological functions to
maintain a dynamic environmental interface. Follicular
glands provide a rich source of triglycerides and fatty acids
for microbial growth. Indeed, a larger quantity of
microbes reside within hair follicles and eccrine glands
than on the epidermal surface of human skin [9]. When
the various anatomical structures of the skin are taken
together, the total surface area of this interface is vast,
comparable to or larger than that of the intestine, but
without a thick mucous layer separating microbes from
the epithelial surface [10]. This physical structure and
concentration of microbes within protected follicles
implicates the skin as a major site for potential host–
microbe interactions. In particular, follicular epithelial
surfaces represent an important interface for immune
www.sciencedirect.com
 The skin microbiome as an element of immune system Nakatsuji, Cheng and Gallo 325
system interaction with microbes. Sebaceous and eccrine
glands also actively regulate the growth of resident bac-
teria through production of AMPs and antimicrobial lipids
to prevent unwanted bacterial overgrowth [11,12]. These
facts suggest that mammalian skin is uniquely suited to
harbor, control, and protect a microbial ecosystem.
Elements of the microbial community residing on the
human skin surface routinely penetrate the epidermal
barrier and enter dermal compartments [9], suggesting
that bacteria in the dermis directly interact with various
dermal cell types and influence their phenotypes. Skin
penetration by bacteria is dependent upon proteolytic
mechanisms and is independent from translocation by
CD11c+ phagocytic immune cells [13]. Indeed, the com-
position and richness of the microbial community in the
dermal compartment differ from those in the superficial
epidermal layer [14], indicating that only selected bacte-
ria can translocate across the epithelial barrier. Bacterial
penetration is highly regulated by epidermal barrier ele-
ments, including the AMP cathelicidin and filaggrin
barrier protein [13]. Skin-resident innate lymphoid cells
(ILCs) isolated from the epidermis, dermis, or subcutis
demonstrate layer-specific transcriptomic profiles [15],
indicating they receive unique signals from the microbial
community in different anatomical layers of the skin.
Therefore, the epithelial barrier regulates host–microbe
interactions not only by selecting for bacterial survival but
also by controlling the movement of commensal bacteria.
The microbiome is a master manipulator of
cutaneous immunity
The mechanisms by which certain microbes evade detec-
tion by the cutaneous immune system during skin colo-
nization are of great interest. Regulatory T cells are
essential for establishing and maintaining immune
homeostasis in epithelial tissues. Skin colonization by
Staphylococcus epidermidis during the neonatal period
may establish immune tolerance through accumulation
of commensal-specific regulatory T cells after second
exposure to the same species in later life [16]. In contrast,
exposure to a-toxin produced by S. aureus prevents this
immune tolerance to commensals and activates the alar-
min pathway instead, resulting in breakdown of inflam-
matory homeostasis and enhancing immune response to
commensals [17]. Moreover, short-chain free fatty acids
(SCFAs), fermentation products of sebum by skin com-
mensal bacteria Corynebacterium acnes, can also actively
control immune tolerance to commensals through inhibi-
tion of histone deacetylase activity [18,19]. Thus, com-
mensals likely influence immune tolerance through mul-
tiple mechanisms to maintain inflammatory homeostasis.
Although many microbes on the skin are potential oppor-
tunitic pathogens or do not influence the host immune
system, some selected species or strains of bacteria appear
to have a mutualistic and beneficial relationship with the
www.sciencedirect.com
skin immune system (Figure 1). For example, S. epider-
midis produces a uniquely structured lipoteichoic acid
that blocks overactivation of pro-inflammatory signaling
triggered by damage-associated molecular pattern recog-
nition after tissue damage [20,21]. In this relationship,
the host benefits from controlled wound repair, while the
commensals are protected from excessive acute inflam-
mation. A lipopeptide produced by S. epidermidis defends
the host from pathogen infection by enhancing AMP
production in human keratinocytes and mast cells, boost-
ing the innate immune system [22–24].
Colonization with S. epidermidis has been shown to
enhance CD8+ skin-resident T cell functions via activa-
tion of IL-1 signaling [25]. This in turn promotes upre-
gulation of AMP production in keratinocytes, limiting
pathogen invasion [26]. S. epidermidis-specific CD8+ T-
cells express genes associated with immunoregulatory
and tissue repair signatures [27]. Furthermore, it has been
demonstrated in mice that early life exposure to ribofla-
vin-synthesizing commensals, including S. epidermidis,
promotes development of skin-residing mucosal-associ-
ated invariant T cells in adult life [28]. These events in
development of specific types of T-cells are integral to
controlling tissue repair and homeostasis.
S. epidermidis also facilitates wound healing independent
of T-cell-mediated mechanisms through the activation of
neutrophils to express the chemokine CXCL10 [29].
CXCL10 forms a complex with DNA from commensals,
which activates type I interferon-producing plasmacytoid
dendritic cells and accelerates wound closure. Further-
more, selected strains of S. epidermidis produce 6-N-
hydroxyaminopurine, a unique nucleobase analog, with
the capacity to inhibit DNA replication in cancer cells.
Topical application of the S. epidermidis strain protects
mouse skin from neoplasia induced by mutagen sensiti-
zation and ultraviolet B exposure [30].
Given the body of evidence suggesting that the commu-
nity of symbiotic bacteria influences and is necessary to
maintain health, the hologenome theory was introduced
to better explain host–microbiome homeostasis [31,32].
In this theory, a holobiont (a host and all of its associated
symbiotic microbes) should be considered as a single unit
in the process of evolution, even though the genomes of
host and symbionts have separate origins.
The microbiome provides additional layers of
antimicrobial barrier on human skin
In general, bacterial populations inhabiting the same
ecological niche compete with each other for nutrients
and other resources using strategies including production
of antibiotics, secretion of digestive enzymes, and quo-
rum sensing. Recent studies have demonstrated that this
ecological concept also applies within human-associated
microbial communities such as the gut and skin
Current Opinion in Immunology 2021, 72:324–330
326 Allergy and hypersensitivity

Figure 1

Current Opinion in Immunology

Beneficial actions of coagulase-negative staphylococci in the skin microbiome.

Gram positive bacteria are the dominant organisms that colonize human skin and Coagulase negative Staphylococci are the major class of these
microbes that can establish themselves in the commensal skin community. Of these diverse species, some have a mutualistic beneficial
interactions with the immune system through a variety of strain-specific mechanisms. 6-HAP, 6-N-hydroxyaminopurine; LTA, lipoteichoic acid;
DAMP, damage-associated molecular pattern; CoNS, coagulase-negative staphylococcus; AMP, antimicrobial peptide; MAIT cells, mucosal-
associated invariant T cells; pDC, plasmacytoid dendritic cell.

microbiome [33,34]. In cooperation with the host immune
system, these antagonistic interactions determine the
composition of a functional antimicrobial barrier.
Coagulase-negative staphylococcus (CoNS) is an abun-
dant culturable member of the human skin microbiome
[35]. Bacteriocins, a class of prokaryotic antimicrobials
produced by some strains of CoNS, serve as an important
antimicrobial barrier on the skin surface that comple-
ments the expression of AMPs by the host. For example,
lantibiotics and phenol-soluble modulins (PSMs) pro-
duced by CoNS limit survival of pathogenic bacteria
on the skin surface [34,36,37]. Importantly, these pro-
karyotic AMPs are found abundantly on normal skin and
can synergize with host AMPs including cathelicidin and
b-defensin-2 against pathogenic bacteria, which further
enhances antimicrobial defense [34,36–38]. Prokaryotic
AMPs selectively exhibit bactericidal activity against skin
pathogens, such as S. aureus (S. aureus), Group A Strepto-
coccus, and Escherichia coli, but are not typically active
against commensal organisms such as S. epidermidis. This
selectivity may be important to maintaining healthy and
diverse microbial ecosystems.
the epithelial barrier and promote inflammation [39]. The
presence of S. aureus strains with functional agr quorum
sensing systems is associated with AD disease; in contrast,
S. aureus strains with loss-of-function mutations in the agr
gene are more prevalent in non-AD subjects [40], impli-
cating S. aureus quorum sensing in the pathogenesis of
AD. Various CoNS strains within the human skin micro-
biome produce a unique cyclic peptide known as the
autoinducing peptide (AIP), which blocks quorum sens-
ing system in a wide range of S. aureus strains [41].
Recent observations suggest that certain strains of S.
epidermidis abundantly produce cysteine proteases under
the control of quorum sensing, which exacerbates skin
inflammation in AD, while AIP produced by a S. hominis
strain can inhibit quorum sensing by S. epidermidis [42]. S.
aureus and S. epidermidis protease production under con-
trol of the agr system have also been recently shown to
closely associate with exacerbations of disease in the
monogenetic human disorder Netherton’s syndrome,
and this too can be inhibited by AIPs from CoNS resident
on human skin [43]. Thus, interspecies antagonism by
AIPs produced by beneficial commensal strains can
reduce the detrimental effects of pathogenic bacteria.

Quorum sensing is a form of communication that allows
bacterial cells to share information about population
density and regulate gene expression accordingly. S.
aureus relies on quorum sensing to secrete selective toxins
and proteases such as PSMs and d-hemolysin that damage
Targeting dysbiosis in atopic dermatitis offers
novel therapeutic approaches
Because the cutaneous immune system actively regulates
the microbial community, dysregulation of AMP expres-
sion on the skin can lead to an imbalance in the microbial

Current Opinion in Immunology 2021, 72:324–330 www.sciencedirect.com

 The skin microbiome as an element of immune system Nakatsuji, Cheng and Gallo 327

community known as ‘dysbiosis’. In many cases, dysbiosis
can trigger the development of skin disorders through the
detrimental effects of overgrown pathogens as well as
commensals. In addition, dysbiosis disrupts symbiotic
interactions with beneficial bacteria within the micro-
biome, disequilibrating cutaneous homeostasis. Com-
bined, the abnormal skin immune environment of inflam-
matory skin diseases promotes dysbiosis that is
manifested as both an increase in pathogenic microbes
and a decrease in beneficial organisms. This dysbiosis in
turn drives further exacerbation of the host inflammatory
response with resulting establishment of chronic disease
(Figure 2).
In patients with AD, expression of AMPs such as cathe-
licidin and b-defensins on the skin is decreased by over-
expression of Th2 cytokines, including IL-4, IL-13 and
TSLP, in comparison with other inflammatory conditions,
such as psoriasis and cutaneous wounds [36,37]. Although
AMP production in AD skin is greater than that in non-
inflamed healthy skin, it is not enough to suppress growth
of S. aureus. With its relative paucity of AMPs, AD skin is
more susceptible to colonization and infection by patho-
gens like S. aureus and herpes virus [44,45]. In addition,
AMP dysregulation in AD weakens selective pressure on
skin microbiota, altering the microbial composition of AD
skin compared with normal skin [46]. Strains of commen-
sal CoNS such as S. epidermidis, S. hominis, S. warneri, or S.
capitis, which produce bacteriocins that selectively kill S.
aureus, are much rarer on AD skin than on healthy skin
[34]. A lower frequency of commensal CoNS strains on
the skin has been observed to correlate with S. aureus
colonization and contributes to the overgrowth of detri-
mental pathogens [34].
Normalization of the skin microbiome offers a promising
therapeutic avenue for restoring homeostasis in the man-
agement of inflammatory skin diseases such as AD. One
approach to this has been by targeting defective host
immune systems that cause the skin dysbiosis. Because of
the action of 1,25-hydroxyvitamin D to induce the human
AMP gene CAMP, oral vitamin D supplementation has
been evaluated as a method to increase skin cathelicidin
production and improve disease severity in AD patients
[47,48], though further studies are needed to determine
whether this increase functionally protects against skin
infections. Cross-sectional observational studies have
noted a correlation between serum 25-hydroxyvitamin
D deficiency, increased skin colonization by S. aureus, and
increased disease severity in AD patients [49,50]. Another
approach has been to consider an old remedy for AD and
other skin diseases, topical coal tar. Activation of the aryl
hydrocarbon receptor by coal tar is postulated to induce
expression of keratinocyte-derived AMPs. Topical coal
tar treatment has been shown to decrease staphylococcus
abundance in AD patients compared with vehicle and

Figure 2

Current Opinion in Immunology

Dysbiosis fuels the chronic disease cycle.

Barrier dysfunction on the skin surface may promote dysbiosis with overgrowth of pathogenic bacterial species and/or a decrease in beneficial
commensal strains. The dysbiosis in the skin microbiome can expand defects in the physical barrier and stimulate inflammation that then further
promotes inflammation and additional injury (red arrows). Bacteriotherapy using rationally designed or selected beneficial commensals could
directly and indirectly restore beneficial interactions between host and microbes (green lines). Solid green lines represent relationships supported
by human clinical studies and broken lines represent relationships validated only in preclinical investigations. Such bacteriotherapy could be
expected to be useful for a wide range of disease states associated with dysbiosis.

www.sciencedirect.com Current Opinion in Immunology 2021, 72:324–330

328 Allergy and hypersensitivity
shifted the microbial composition toward that of healthy
controls [51]. Modern, targeted biologic therapy has also
shown promise. Excess production of Th2 cytokines is a
key element in the pathophysiology of AD and sup-
presses host AMP functions to control S. aureus survival.
Dupilumab, a fully human antibody against IL-4 receptor
a, inhibits both IL-4 and IL-13 signaling and should
theoretically enable more normal AMP function. This
hypothesis was supported in a randomized, double-blind,
placebo-controlled trial, that showed sixteen weeks of
treatment with dupilumab increased microbial diversity
and decreased S. aureus abundance [52].
Future perspectives on development of
bacteriotherapies using beneficial
commensals
The relative deficiency of CoNS with antimicrobial activ-
ity on AD skin, combined with their multiple antagonistic
defense mechanisms against pathogenic S. aureus, present
novel therapeutic opportunities for the use of protective
CoNS in the management of S. aureus colonization in AD
(Figure 2). As discussed previously, multiple beneficial
functions from the skin commensal microbial community
could be used therapeutically. Recently, our group con-
ducted the first multi-center, double-blind, vehicle-con-
trolled, phase 1 clinical trial of bacteriotherapy in adult
patients with AD using a rationally selected strain of S.
hominis (ShA9) that was isolated from a healthy individual
[53]. This strain is present in healthy populations, but
not on individuals with AD [34]. ShA9 was chosen
because it produces two lantibiotics and an AIP that
selectively target S. aureus and deleterious strains of S.
epidermidis. Bacteriotherapy with ShA9 did not cause
serious adverse events, successfully inhibited S. aureus
survival, and blocked quorum sensing by S. aureus on the
lesional skin of AD patients. These multiple protective
effects were associated with improvement in clinical AD
symptoms [53]. In other work, an open-label bacter-
iotherapy trial of Roseomonas mucosa, a Gram-negative
bacteria with anti-S. aureus activity, decreased S. aureus
colonization, and improved severity of AD compared to
baseline, though vehicle effect was not determined
[54,55]. In addition, topical application of a lysate of
Vitreoscilla filiformis has shown therapeutic efficacy in
treating AD in humans [56]. The therapeutic mechanism
may be through the induction of regulatory T-cells [57],
though functions of this cell type in AD are still contro-
versial. Overall, large-scale, longer-term, blinded, and
randomized trials are needed to fully understand the
therapeutic potential of bacteriotherapy with beneficial
commensal microbe strains.
In pre-clinical trials using various murine models, it has
been demonstrated that the topical application of S.
epidermidis results a wide variety of beneficial actions to
the host, including anti-inflammatory activity, promotion
of wound healing, and suppression of UV-B-induced skin
Current Opinion in Immunology 2021, 72:324–330
tumors (Figure 1). Translation of these additional find-
ings to treat a wide range of human skin disorders is
currently underway.
Conclusion
The preponderance of current experimental and clinical
studies have shown that selected species or strains within
the skin microbial community can work together with the
cutaneous immune system to maintain local and systemic
defense against pathogenic bacteria. The skin micro-
biome is therefore correctly considered an important
component of the human holobiont system. Dysbiosis
in the colonized microbial community can promote
inflammatory disease that further disrupts immune
homeostasis and may lead to the development of skin
disorders. Pharmaceutical antibiotics are widely used to
temporarily suppress overgrowth of pathogenic bacteria,
but the non-selective action of these antibiotics also kills
beneficial microbes and should be reserved for infections,
an invasive stage beyond bacterial colonization. More
selected, rational, and targeted use of bacteriotherapy
for the control and regulation of immune functions is a
promising next step in human therapeutics.
Conflict of interest statement
R.L.G. is a co-founder, scientific advisor, consultant and
has equity in MatriSys Biosciences and is a consultant,
receives income and has equity in Sente. T.N. and R.L.G
are co-inventors of technology described in this report
that has been disclosed to the University of California San
Diego.
Acknowledgements
RLG is supported by N.I.H. grantsR37AI052453,R01AR074302,
andR01AI153185. TN and RLG are supported by NIH grants
R01AR076082 andU01AI52038.
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