BJD

R EV IE W AR TI C LE British Journal of Dermatology

Changing our microbiome: probiotics in dermatology

Y. Yu iD ,1 S. Dunaway,1 J. Champer,2 J. Kim3 and A. Alikhan4
1
Department of Dermatology, University of Cincinnati, Cincinnati, OH, U.S.A.
2
Department of Computational Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, U.S.A.
3
Division of Dermatology and Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, U.S.A.
4
Sutter Medical Foundation, Sacramento, CA, U.S.A.

Summary

Correspondence Background Commensal bacteria are a major factor in human health and disease
Yang Yu and Ali Alikhan. pathogenesis. Interest has recently expanded beyond the gastrointestinal microbiome
E-mails: yangyu@ucla.edu; alikhama@sutter- to include the skin microbiome and its impact on various skin diseases.
health.org
Objectives Here we present current data reviewing the role of the microbiome in
Accepted for publication dermatology, considering both the gut and skin microflora. Our objective was to
26 April 2019 evaluate whether the clinical data support the utility of oral and topical probiotics
for certain dermatological diseases.
Funding sources Methods The PubMed and ClinicalTrials.gov databases were searched for basic
None. science, translational research and clinical studies that investigated differences in
the cutaneous microbiome and the impact of probiotics in patients with atopic
Conflicts of interest
Y.Y., J.C., and J.K. have filed for a patent related
dermatitis, acne vulgaris, psoriasis, chronic wounds, seborrhoeic dermatitis and
to the use of topical probiotics for acne. The other cutaneous neoplasms.
authors declare no conflicts of interest. Results Few clinical trials exist that explore the utility of probiotics for the preven-
tion and treatment of dermatological diseases, with the exception of atopic der-
DOI 10.1111/bjd.18088 matitis. Most studies investigated oral probiotic interventions, and of those
utilizing topical probiotics, few included skin commensals. In general, the avail-
able clinical trials yielded positive results with improvement of the skin condi-
tions after probiotic intervention.
Conclusions Oral and topical probiotics appear to be effective for the treatment
of certain inflammatory skin diseases and demonstrate a promising role in
wound healing and skin cancer. However, more studies are needed to confirm
these results.

What’s already known about this topic?

• The microbiome plays a role in human health and disease pathogenesis.
• Probiotics can manipulate the host microbiome and may confer health benefits for
patients.
• Research to date has already begun to explore the utility of oral and topical probi-
otics for certain dermatological diseases.

What does this study add?

• This review presents basic science and clinical trial data to support the role of the
gut and skin microbiome in dermatology.
• Current data are reviewed on the use of probiotics in the prevention and treatment
of skin diseases, including atopic dermatitis, acne vulgaris, psoriasis, seborrhoeic
dermatitis, chronic wounds and cutaneous neoplasms.
• Future probiotic interventions are proposed.

© 2019 British Association of Dermatologists British Journal of Dermatology (2019) 1

2 Changing our microbiome: probiotics in dermatology, Y. Yu et al.

Commensal bacteria play important roles in the maintenance
of a healthy immune system. Disturbances in the microbiome
allow for opportunistic species and pathogenic bacteria to col-
onize and thereby cause disease. The microbiome of the gas-
trointestinal system in relation to disease has been extensively
studied, including its impact on the skin.1,2 Although fewer in
number than gastrointestinal bacteria, the bacteria residing on
our skin have similar functions in immune regulation and dis-
ease pathogenesis.3
With our growing understanding of the microbiome’s role
in disease,4 treatments to modulate the immune system using
microbes are a promising new avenue of research. One of the
most direct ways to accomplish this is via the use of probi-
otics,5 which consist of live microorganisms that, when
administered in adequate amounts, may confer a health bene-
fit to the host.6 Here we review the role of the microbiome in
human health with a focus on how both oral and topical pro-
biotics may be of use in the prevention and treatment of skin
disease.
Methods
A literature search was conducted using the PubMed and Clin-
icalTrials.gov databases for relevant studies with the keywords
‘microbiome’, ‘microbiota’, ‘commensal’, ‘bacteria’, ‘probi-
otic’, ‘topical’, ‘skin’ and ‘dermatology’. All search terms were
used in various combinations and studies were screened for
relevance based on their abstracts. Basic science, in vitro
research, animal model studies and clinical trials were
included for both oral and topical probiotic interventions.
Studies written in a language other than English were not con-
sidered. We focused on diseases for which studies existed that
had investigated the differences in the cutaneous microbiome
and the impact of probiotics in their relevant patient popula-
tions. Among the search results, such studies existed for the
following: atopic dermatitis (AD), acne vulgaris, psoriasis,
seborrhoeic dermatitis, chronic wounds and wound healing,
and skin carcinogenesis.
The skin microbiome and topical probiotics
Humans harbour over 1000 species of bacteria on the skin,
each adapted to a particular microenvironment.7 Most skin
bacteria are commensals that generally do not harm their
hosts7 and contribute to a diverse microbiome, which can
prevent or aid in the resolution of disease (Fig. 1).8–10 Com-
mensal bacteria can accomplish this by passively occupying a
similar ecological niche to that of a pathogenic microbe, thus
impeding its colonization of the skin. Additionally, a com-
mensal may actively compete against pathogenic bacteria by
secreting antimicrobial factors. Commensals may also modu-
late the immune system, directing it to attack disease-causing

Fig 1. Mechanisms of disease inhibition by commensal bacteria. Commensal bacteria may occupy a similar ecological niche to that of pathogenic
microbes, directly impeding their colonization. Commensals may also either directly secrete antimicrobial factors such as bacteriocins, phenol-
soluble modulins, propionic acid and antimicrobial peptides (AMPs) or indirectly prime the immune system to attack disease-causing microbes.
Commensal bacteria can also promote immune tolerance, reducing inflammation and severity of disease. Th, T helper cell; Treg, regulatory T cell.

British Journal of Dermatology (2019) © 2019 British Association of Dermatologists


organisms or promoting immune tolerance, which can reduce
the severity of inflammatory diseases.11,12
Topical probiotics represent a direct method to alter the
skin microbiome and immune response in various diseases.8,9
Although currently few in number, several clinical trials have
already demonstrated favourable results with topical probiotic
use (Table S1; see Supporting Information).
The gut microbiome and oral probiotics for skin disease
The mechanisms by which the gut microbiome induces and
prevents disease states have many applications to the skin. Dis-
turbances in the normal gut microbiome promote chronic
inflammation, which can lead to neoplasia.13,14 Commensals
in the gut independently regulate and reduce gastrointestinal
inflammation.13 Thus, by restoring a healthy gut microbiome,
commensal microbes can protect against malignancy by acting
as antioxidants, inducing tumour suppressor genes,15 priming
the immune system against cancer cells, or reducing inflam-
mation via regulatory T cells.16–18
Gut microbes also have the ability to influence systemic
inflammation, oxidative stress, glycaemic control and tissue
lipid content.2 A disturbed gut microbiome has been
described in patients with inflammatory skin diseases such as
the bowel-associated dermatosis–arthritis syndrome2,19 and
rosacea,20 for which restoration of the normal gut microflora
has resulted in complete disease remission. Thus, modulation
of the intestinal microflora via oral probiotics can indirectly
influence skin diseases (Table S1; see Supporting Information).
Such therapy is most well studied in AD.
Atopic dermatitis
The combination of epidermal barrier dysfunction and
immune dysregulation in AD favours pathogenic bacterial col-
onization. AD skin harbours increased Staphylococcus aureus abun-
dance with overall decreased microbial diversity.21–24 A recent
investigation confirmed lower diversity in both lesional and
nonlesional skin of patients with AD, suggesting a globally
affected skin microbiome in AD.25 Microbial diversity is also
inversely correlated with disease severity. Dramatic reductions
in the skin microbial diversity are observed in more severe
disease and during AD flares, whereas treatment of AD lesional
skin leads to rediversification.21,24,25 Specifically, staphylococ-
cal species increase during AD flares, including Staphylococcus epi-
dermis, which may serve as a compensatory mechanism to
control S. aureus.21,22,24 Indeed, an investigation of AD flares
showed that S. aureus dominated in patients with more severe
disease, while S. epidermidis was more abundant in patients with
less severe disease.26 Furthermore, the intestinal environment
may also impact the pathogenesis of AD. Infants with IgE-
associated eczema have a reduced proportion of bifidobacterial
species and low microflora diversity early in life.19 Early
intestinal colonization with Escherichia coli at 2 months of age
may even confer long-term health benefits, as it was associated
with decreased incidence of AD by the age of 6 years.27
© 2019 British Association of Dermatologists
Changing our microbiome: probiotics in dermatology, Y. Yu et al. 3
Hence, modulation of the microbiome may be a promising
new preventative and therapeutic strategy in AD.
The utility of oral probiotics for the treatment and preven-
tion of AD has been explored through several large cohort and
randomized controlled studies. In a recent meta-analysis
including 1070 children, significant reductions were observed
in Scoring Atopic Dermatitis (SCORAD) values for patients
receiving oral probiotics with Lactobacillus fermentum, Lactobacillus
salivarius and a mixture of different strains.28 Results from older
meta-analyses support the use of oral probiotics for the treat-
ment of AD29 and even for prevention, suggesting that Lacto-
bacillus alone and Lactobacillus with Bifidobacterium bifidum are
protective against development of AD, with odds ratios of 0
7
and 0
62, respectively.30 Additionally, daily oral supplementa-
tion with a mixture of Bifidobacterium and Lactobacillus casei strains
for 12 weeks in patients with moderate AD led to a 19
2-
point greater mean reduction in SCORAD compared with con-
trol patients.31 However, some effects may be strain or species
specific, as probiotics with Lactobacillus rhamnosus and Lactobacillus
paracasei have yielded mixed results.32–36
Thus far, few studies have utilized live bacteria in topical
probiotics for treatment of AD. Nakatusji et al. recently
demonstrated that topical application of commensal skin bac-
teria protects against pathogens.37 When coagulase-negative
staphylococci were applied to the skin of patients with AD, S.
aureus colonization decreased due to selective killing by highly
potent antimicrobial peptides secreted by the commensal,
coagulase-negative staphylococci.37 Early data show that this
type of intervention not only suppresses S. aureus, but is also
associated with clinical improvement and decreased local
inflammation.38 Other skin commensal species have been
investigated, including the Gram-negative species Roseomonas
mucosa, application of which was associated with significant
decreases in pruritus, SCORAD and steroid usage in adults and
paediatric patients, without adverse events or complications.39
Several topical probiotic studies have also explored the util-
ity of gut commensals, with favourable results. Application of
Lactobacillus johnsonii to AD lesions twice daily for 3 weeks led to
reduction in S. aureus load, which correlated with decrease in
SCORAD.40 Another study revealed that a 2-week topical
administration of Streptococcus thermophilus cream in patients with
AD led to a significant improvement in erythema, scaling and
pruritus.41 Furthermore, a topical cream containing lysate of
Vitreoscilla filiformis, a Gram-negative bacterium found in thermal
spring water, also led to clinical improvement in patients with
AD.42 Although research on probiotics for AD remains in its
early stages, many trials thus far have shown benefits.
Acne vulgaris
Acne vulgaris is associated with Cutibacterium acnes, recently
renamed from Propionibacterium acnes. Disruption of the gut
microbiome has also been implicated in acne pathogenesis via
the gut–skin axis,2 suggesting the potential utility of oral pro-
biotics. One study showed that consumption of Lactobacillus aci-
dophilus, Lactobacillus delbrueckii bulgaricus and B. bifidum was as
British Journal of Dermatology (2019)
4 Changing our microbiome: probiotics in dermatology, Y. Yu et al.
effective as minocycline in the treatment of acne, with 67%
lesion reduction after 12 weeks and fewer side-effects.43 A
combination of this oral probiotic and minocycline had even
greater effectiveness.43 Another study showed a 30% reduction
in inflammatory lesions after daily consumption of L. bulgaricus
and S. thermophilus for 12 weeks.44 Sebum content and free fatty
acid concentration also decreased by 50% or more in the skin
of patients taking this oral probiotic.44 A recent study revealed
that patients receiving oral L. rhamnosus SP1 for 12 weeks
exhibited significant improvement of their back acne com-
pared with placebo, which was accompanied by normalized
skin expression of insulin signalling genes.45
Recently, several studies found that certain phylotypes (IA-2
with plasmid factor, IB-1, I-C) of C. acnes were more com-
monly associated with acne, while others (II-ribotype 6, III)
were exclusively associated with healthy skin.46–50 Therefore,
these phylotypes may be a factor in the pathogenesis of acne.
An in vitro study revealed that acne-associated phylotypes
induce high T helper cell (Th)1 and Th17 responses, while
healthy skin-associated phylotypes induce relatively low Th1
and Th17 responses, but a high interleukin (IL)-10 anti-
inflammatory response.51 This suggests that the healthy skin-
associated C. acnes phylotypes may be of use in a topical probi-
otic treatment or preventative regimen, designed to replace
acne-associated and other potentially opportunistic phylo-
types.46,51,52 Such a targeted strategy utilizing the same species
of bacteria that share an ecological niche may be a more effec-
tive approach than using other skin or especially gut commen-
sals, by allowing faster and longer-lasting improvements to
the skin microbiota.
Unfortunately, the limited number of topical probiotic stud-
ies for acne have utilized gut or other nonskin bacteria. A lyo-
philized powder containing enterocins from Enterococcus faecalis
SL-5 has already been studied in patients with acne, decreasing
inflammatory lesions by 60% compared with the control after
8 weeks.53 A new phase IIb/III study has demonstrated that
application of Nitrosomonas eutropha, twice daily for 12 weeks,
led to a 2-point reduction in Investigator’s Global Assessment
of acne severity compared with control and a trend in the
reduction of the number of inflammatory lesions.54 However,
as these species do not naturally occur on the skin, a contin-
ued protective effect after discontinuing the treatment is unli-
kely compared with utilization of a skin microbe. In contrast,
twice-weekly application of a topical gel containing S. epider-
midis changes the host skin microbiome and leads to robust
colonization.55 Thus, utilization of a skin commensal like
S. epidermidis may be more suitable than N. eutropha, particularly as
S. epidermidis has been shown to inhibit C. acnes growth in vitro.56
Topical probiotics may also include C. acnes bacteriophages,
which are viruses that can lyse host bacteria. Two studies showed
that some C. acnes bacteriophages lyse only acne-associated and
uncorrelated (potentially pathogenic) phylotypes, but are often
ineffective against phylotypes associated with healthy skin.57–60
This potential combination of healthy-skin-associated C. acnes
together with bacteriophages that target other C. acnes could
potentially allow for highly specific strain replacement (Fig. 2).
British Journal of Dermatology (2019)
Psoriasis
It has been proposed that alteration of the skin microbiome
may trigger activation of the Th17 pathway in psoriasis.61,62
Several studies have demonstrated differences between the
cutaneous microbial communities of psoriatic skin compared
with unaffected skin, such as a trend towards decreased
microbial diversity.63–65 Actinobacteria is significantly under-
represented in psoriatic lesions compared with healthy
skin.64,65 Staphylococcus aureus and Streptococcus pyogenes are also
minimally present to absent in psoriatic lesions.64,65 However,
much is still unknown given the limited number of studies
with different sampling techniques.
To date, studies investigating the role of probiotics in psori-
asis are lacking, although there is some evidence that probi-
otics may exert beneficial immunoregulatory effects by
reducing inflammation.66,67 In patients with psoriasis, oral
administration of Bifidobacterium infantis for 8 weeks led to signif-
icantly decreased levels of inflammatory C-reactive protein and
tumour necrosis factor-a, although it is unclear whether this
was accompanied by clinical improvements.67 However, in a
mouse model of psoriasis, oral administration of Lactobacillus
pentosus GMNL-77 reduced tumour necrosis factor-a and IL-
23–IL-17 axis cytokines, which was associated with decreased
erythematous scaling lesions.66 More research exploring the
role of the microbiome and its modulation as a therapy in
psoriasis would be complementary to the many ongoing
immunological treatment studies.
Seborrhoeic dermatitis
Seborrhoeic dermatitis is thought to be an inflammatory
response to free fatty acids produced by the fungus Malassezia
furfur, a normal resident of the skin.68,69 While improvement
of disease has been associated with a decrease in yeast burden,
absolute levels of Malassezia do not correlate with disease sever-
ity.70,71 Decreased bacterial diversity is a better predictor of
disease severity.72–74 For this reason, several investigators have
evaluated the use of probiotics for treatment of seborrhoeic
dermatitis. Topical application of V. filiformis decreased ery-
thema, scaling and pruritus in a double-blinded study of 60
patients.75 Vitreoscilla filiformis lysate increased IL-10 production
by dendritic cells and increased regulatory T-cell activity.76
Patients receiving oral L. paracasei experienced significant symp-
tomatic relief, accompanied by improvements in scalp dan-
druff, erythema and seborrhoea.77 Similarly to Vitreoscilla,
L. paracasei induced a switch to a normal immune state by
producing IL-10 and transforming growth factor-b,78 lending
support to the utility of both topical and oral probiotics in
seborrhoeic dermatitis.
Wound healing
Disruption of the cutaneous microbiome and prolonged
inflammation after injury result in delayed wound healing.79
Probiotics may promote the healing process by modulating
© 2019 British Association of Dermatologists

Fig 2. Topical probiotic combination therapy for strain-specific replacement. A novel topical probiotic formulation containing health-promoting,
commensal bacterial combined with bacteriophages that target only the pathogenic microbes could potentially allow for highly specific strain
replacement.
the inflammatory response and limiting pathogen colonization.
A recent meta-analysis of animal studies concluded that topical
probiotics with Lactobacillus brevis, Lactobacillus plantarum and L. fer-
mentum led to reduced inflammation and acceleration of wound
contraction.80 Several human studies also demonstrated the
benefits of these bacteria in chronic ulcers. Topical probiotics
containing L. plantarum reduced bacterial load and induced heal-
ing of diabetic ulcers through the regulation of IL-8 and
recruitment of phagocytic cells and fibroblasts.81 Similarly,
application of L. plantarum for 30 days led to > 90% area reduc-
tion of chronic leg ulcers in nondiabetic patients.81 Oral pro-
biotics containing Lactobacillus species were also effective in
treating chronic diabetic ulcers, resulting in decreased ulcer
size and decreased levels of inflammatory markers.82
Probiotic studies have also shown enhancement of wound
healing in burn patients83,84 and in the prevention and treat-
ment of skin infections. A topical probiotic containing L. plan-
tarum reduced Pseudomonas aeruginosa skin infections in a mouse
model of burn wounds.85 In humans, L. plantarum, when
applied to second- and third-degree burns, was as effective as
silver sulfadiazine in reducing the risk of infection and bacte-
rial load, while promoting granulation tissue and wound heal-
ing.84 Skin commensals are also excellent candidates in a
topical probiotic, with likely superior resilience given their
inherent adaptation to the skin environment. For example, Pro-
pioniferax innocua, a skin commensal, has been found to degrade
© 2019 British Association of Dermatologists
Changing our microbiome: probiotics in dermatology, Y. Yu et al. 5
established biofilms.86 Staphylococcus caprae is able to exert
antimicrobial activity against methicillin-resistant S. aureus and
inhibit S. aureus colonization in a mouse model.87 Staphylococcus
epidermidis produces antimicrobial compounds that selectively
target S. aureus and S. pyogenes, while also suppressing skin
inflammation via lipoteichoic acid.10,12,88 Two studies have
also shown that C. acnes inhibited the growth of S. aureus in an
open wound mouse model89 via production of propionic
acid.90
Skin cancer
Disturbances in the skin microbiome exist in several cutaneous
neoplasms and have been implicated in the promotion of car-
cinogenesis. One example is the link between S. aureus infec-
tion and cutaneous T-cell lymphoma disease severity, through
the potential role of a staphylococcal superantigen in carcino-
genesis.91–94
In contrast, a healthy microbiome may suppress carcinogen-
esis through its regulation of the immune system and control
of inflammation by activating antineoplastic or immuno-
surveillance pathways.3,95 For example, oral intake of lipotei-
choic acid from lactobacilli was associated with less ultraviolet
damage and a reduced risk of skin cancer.96 Recently, strains
of S. epidermidis were found to produce a nucleobase molecule
that selectively inhibited tumour proliferation, and application
British Journal of Dermatology (2019)
6 Changing our microbiome: probiotics in dermatology, Y. Yu et al.
of these strains reduced the incidence of ultraviolet-induced
tumours in mice.97 A healthy microbiome can also potentially
impact cancer response to therapy by modulating the tumour
microenvironment. In one study, oligonucleotide immuno-
therapy or platinum chemotherapy regimens for tumours had
superior effectiveness in mice with healthy gut microbiomes
compared with germ-free or antibiotic-treated mice.98 It is
therefore conceivable that the use of probiotics may be
beneficial for reducing the risk of or even during the treat-
ment of cutaneous neoplasms.
Conclusions
In summary, the microbiome plays an important role in der-
matology and serves as a potential target for treatment. Probi-
otics to promote a healthy microbiome may positively
contribute by reducing inflammation, creating an optimal bal-
ance of immune activation, and preventing colonization by
pathogenic bacteria. While rapid increases in the medical use
of probiotics have confirmed their excellent safety profile,
long-term safety data are limited. Of concern, reports also link
probiotics to infections and other severe side-effects in
immunocompromised individuals.99 Thus, more basic research
and epidemiological studies are needed to characterize further
the microbiome as a risk factor and in the treatment of dis-
ease.100 Clinical trials of oral and topical probiotics with larger
samples and greater power are necessary to characterize the
safety, as well as the particular species combinations, doses
and treatment durations that are most effective. Future probi-
otic trials utilizing combination therapy with either phage or
initial antibiotic treatment could yield interesting results to
support a microbiome replacement strategy.
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Supporting Information
Additional Supporting Information may be found in the online
version of this article at the publisher’s website:
Table S1 Summary of probiotic intervention studies in
humans.
© 2019 British Association of Dermatologists