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

 Changing our microbiome: probiotics in dermatology, Y. Yu et al. 3

organisms or promoting immune tolerance, which can reduce Hence, modulation of the microbiome may be a promising
the severity of inflammatory diseases.11,12 new preventative and therapeutic strategy in AD.
Topical probiotics represent a direct method to alter the The utility of oral probiotics for the treatment and preven-
skin microbiome and immune response in various diseases.8,9 tion of AD has been explored through several large cohort and
Although currently few in number, several clinical trials have randomized controlled studies. In a recent meta-analysis
already demonstrated favourable results with topical probiotic including 1070 children, significant reductions were observed
use (Table S1; see Supporting Information). 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
The gut microbiome and oral probiotics for skin disease
meta-analyses support the use of oral probiotics for the treat-
The mechanisms by which the gut microbiome induces and ment of AD29 and even for prevention, suggesting that Lacto-
prevents disease states have many applications to the skin. Dis- bacillus alone and Lactobacillus with Bifidobacterium bifidum are
turbances in the normal gut microbiome promote chronic protective against development of AD, with odds ratios of 0
7
inflammation, which can lead to neoplasia.13,14 Commensals and 0
62, respectively.30 Additionally, daily oral supplementa-
in the gut independently regulate and reduce gastrointestinal tion with a mixture of Bifidobacterium and Lactobacillus casei strains
inflammation.13 Thus, by restoring a healthy gut microbiome, for 12 weeks in patients with moderate AD led to a 19
2-
commensal microbes can protect against malignancy by acting point greater mean reduction in SCORAD compared with con-
as antioxidants, inducing tumour suppressor genes,15 priming trol patients.31 However, some effects may be strain or species
the immune system against cancer cells, or reducing inflam- specific, as probiotics with Lactobacillus rhamnosus and Lactobacillus
mation via regulatory T cells.16–18 paracasei have yielded mixed results.32–36
Gut microbes also have the ability to influence systemic Thus far, few studies have utilized live bacteria in topical
inflammation, oxidative stress, glycaemic control and tissue probiotics for treatment of AD. Nakatusji et al. recently
lipid content.2 A disturbed gut microbiome has been demonstrated that topical application of commensal skin bac-
described in patients with inflammatory skin diseases such as teria protects against pathogens.37 When coagulase-negative
the bowel-associated dermatosis–arthritis syndrome2,19 and staphylococci were applied to the skin of patients with AD, S.
rosacea,20 for which restoration of the normal gut microflora aureus colonization decreased due to selective killing by highly
has resulted in complete disease remission. Thus, modulation potent antimicrobial peptides secreted by the commensal,
of the intestinal microflora via oral probiotics can indirectly coagulase-negative staphylococci.37 Early data show that this
influence skin diseases (Table S1; see Supporting Information). type of intervention not only suppresses S. aureus, but is also
Such therapy is most well studied in AD. associated with clinical improvement and decreased local
inflammation.38 Other skin commensal species have been
investigated, including the Gram-negative species Roseomonas
Atopic dermatitis
mucosa, application of which was associated with significant
The combination of epidermal barrier dysfunction and decreases in pruritus, SCORAD and steroid usage in adults and
immune dysregulation in AD favours pathogenic bacterial col- paediatric patients, without adverse events or complications.39
onization. AD skin harbours increased Staphylococcus aureus abun- Several topical probiotic studies have also explored the util-
dance with overall decreased microbial diversity.21–24 A recent ity of gut commensals, with favourable results. Application of
investigation confirmed lower diversity in both lesional and Lactobacillus johnsonii to AD lesions twice daily for 3 weeks led to
nonlesional skin of patients with AD, suggesting a globally reduction in S. aureus load, which correlated with decrease in
affected skin microbiome in AD.25 Microbial diversity is also SCORAD.40 Another study revealed that a 2-week topical
inversely correlated with disease severity. Dramatic reductions administration of Streptococcus thermophilus cream in patients with
in the skin microbial diversity are observed in more severe AD led to a significant improvement in erythema, scaling and
disease and during AD flares, whereas treatment of AD lesional pruritus.41 Furthermore, a topical cream containing lysate of
skin leads to rediversification.21,24,25 Specifically, staphylococ- Vitreoscilla filiformis, a Gram-negative bacterium found in thermal
cal species increase during AD flares, including Staphylococcus epi- spring water, also led to clinical improvement in patients with
dermis, which may serve as a compensatory mechanism to AD.42 Although research on probiotics for AD remains in its
control S. aureus.21,22,24 Indeed, an investigation of AD flares early stages, many trials thus far have shown benefits.
showed that S. aureus dominated in patients with more severe
disease, while S. epidermidis was more abundant in patients with
Acne vulgaris
less severe disease.26 Furthermore, the intestinal environment
may also impact the pathogenesis of AD. Infants with IgE- Acne vulgaris is associated with Cutibacterium acnes, recently
associated eczema have a reduced proportion of bifidobacterial renamed from Propionibacterium acnes. Disruption of the gut
species and low microflora diversity early in life.19 Early microbiome has also been implicated in acne pathogenesis via
intestinal colonization with Escherichia coli at 2 months of age the gut–skin axis,2 suggesting the potential utility of oral pro-
may even confer long-term health benefits, as it was associated biotics. One study showed that consumption of Lactobacillus aci-
with decreased incidence of AD by the age of 6 years.27 dophilus, Lactobacillus delbrueckii bulgaricus and B. bifidum was as

© 2019 British Association of Dermatologists 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%

Psoriasis
lesion reduction after 12 weeks and fewer side-effects.43 A
combination of this oral probiotic and minocycline had even It has been proposed that alteration of the skin microbiome
greater effectiveness.43 Another study showed a 30% reduction may trigger activation of the Th17 pathway in psoriasis.61,62
in inflammatory lesions after daily consumption of L. bulgaricus Several studies have demonstrated differences between the
and S. thermophilus for 12 weeks.44 Sebum content and free fatty cutaneous microbial communities of psoriatic skin compared
acid concentration also decreased by 50% or more in the skin with unaffected skin, such as a trend towards decreased
of patients taking this oral probiotic.44 A recent study revealed microbial diversity.63–65 Actinobacteria is significantly under-
that patients receiving oral L. rhamnosus SP1 for 12 weeks represented in psoriatic lesions compared with healthy
exhibited significant improvement of their back acne com- skin.64,65 Staphylococcus aureus and Streptococcus pyogenes are also
pared with placebo, which was accompanied by normalized minimally present to absent in psoriatic lesions.64,65 However,
skin expression of insulin signalling genes.45 much is still unknown given the limited number of studies
Recently, several studies found that certain phylotypes (IA-2 with different sampling techniques.
with plasmid factor, IB-1, I-C) of C. acnes were more com- To date, studies investigating the role of probiotics in psori-
monly associated with acne, while others (II-ribotype 6, III) asis are lacking, although there is some evidence that probi-
were exclusively associated with healthy skin.46–50 Therefore, otics may exert beneficial immunoregulatory effects by
these phylotypes may be a factor in the pathogenesis of acne. reducing inflammation.66,67 In patients with psoriasis, oral
An in vitro study revealed that acne-associated phylotypes administration of Bifidobacterium infantis for 8 weeks led to signif-
induce high T helper cell (Th)1 and Th17 responses, while icantly decreased levels of inflammatory C-reactive protein and
healthy skin-associated phylotypes induce relatively low Th1 tumour necrosis factor-a, although it is unclear whether this
and Th17 responses, but a high interleukin (IL)-10 anti- was accompanied by clinical improvements.67 However, in a
inflammatory response.51 This suggests that the healthy skin- mouse model of psoriasis, oral administration of Lactobacillus
associated C. acnes phylotypes may be of use in a topical probi- pentosus GMNL-77 reduced tumour necrosis factor-a and IL-
otic treatment or preventative regimen, designed to replace 23–IL-17 axis cytokines, which was associated with decreased
acne-associated and other potentially opportunistic phylo- erythematous scaling lesions.66 More research exploring the
types.46,51,52 Such a targeted strategy utilizing the same species role of the microbiome and its modulation as a therapy in
of bacteria that share an ecological niche may be a more effec- psoriasis would be complementary to the many ongoing
tive approach than using other skin or especially gut commen- immunological treatment studies.
sals, by allowing faster and longer-lasting improvements to
the skin microbiota.
Seborrhoeic dermatitis
Unfortunately, the limited number of topical probiotic stud-
ies for acne have utilized gut or other nonskin bacteria. A lyo- Seborrhoeic dermatitis is thought to be an inflammatory
philized powder containing enterocins from Enterococcus faecalis response to free fatty acids produced by the fungus Malassezia
SL-5 has already been studied in patients with acne, decreasing furfur, a normal resident of the skin.68,69 While improvement
inflammatory lesions by 60% compared with the control after of disease has been associated with a decrease in yeast burden,
8 weeks.53 A new phase IIb/III study has demonstrated that absolute levels of Malassezia do not correlate with disease sever-
application of Nitrosomonas eutropha, twice daily for 12 weeks, ity.70,71 Decreased bacterial diversity is a better predictor of
led to a 2-point reduction in Investigator’s Global Assessment disease severity.72–74 For this reason, several investigators have
of acne severity compared with control and a trend in the evaluated the use of probiotics for treatment of seborrhoeic
reduction of the number of inflammatory lesions.54 However, dermatitis. Topical application of V. filiformis decreased ery-
as these species do not naturally occur on the skin, a contin- thema, scaling and pruritus in a double-blinded study of 60
ued protective effect after discontinuing the treatment is unli- patients.75 Vitreoscilla filiformis lysate increased IL-10 production
kely compared with utilization of a skin microbe. In contrast, by dendritic cells and increased regulatory T-cell activity.76
twice-weekly application of a topical gel containing S. epider- Patients receiving oral L. paracasei experienced significant symp-
midis changes the host skin microbiome and leads to robust tomatic relief, accompanied by improvements in scalp dan-
colonization.55 Thus, utilization of a skin commensal like druff, erythema and seborrhoea.77 Similarly to Vitreoscilla,
S. epidermidis may be more suitable than N. eutropha, particularly as L. paracasei induced a switch to a normal immune state by
S. epidermidis has been shown to inhibit C. acnes growth in vitro.56 producing IL-10 and transforming growth factor-b,78 lending
Topical probiotics may also include C. acnes bacteriophages, support to the utility of both topical and oral probiotics in
which are viruses that can lyse host bacteria. Two studies showed seborrhoeic dermatitis.
that some C. acnes bacteriophages lyse only acne-associated and
uncorrelated (potentially pathogenic) phylotypes, but are often
Wound healing
ineffective against phylotypes associated with healthy skin.57–60
This potential combination of healthy-skin-associated C. acnes Disruption of the cutaneous microbiome and prolonged
together with bacteriophages that target other C. acnes could inflammation after injury result in delayed wound healing.79
potentially allow for highly specific strain replacement (Fig. 2). Probiotics may promote the healing process by modulating

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

 Changing our microbiome: probiotics in dermatology, Y. Yu et al. 5

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. established biofilms.86 Staphylococcus caprae is able to exert
A recent meta-analysis of animal studies concluded that topical antimicrobial activity against methicillin-resistant S. aureus and
probiotics with Lactobacillus brevis, Lactobacillus plantarum and L. fer- inhibit S. aureus colonization in a mouse model.87 Staphylococcus
mentum led to reduced inflammation and acceleration of wound epidermidis produces antimicrobial compounds that selectively
contraction.80 Several human studies also demonstrated the target S. aureus and S. pyogenes, while also suppressing skin
benefits of these bacteria in chronic ulcers. Topical probiotics inflammation via lipoteichoic acid.10,12,88 Two studies have
containing L. plantarum reduced bacterial load and induced heal- also shown that C. acnes inhibited the growth of S. aureus in an
ing of diabetic ulcers through the regulation of IL-8 and open wound mouse model89 via production of propionic
recruitment of phagocytic cells and fibroblasts.81 Similarly, acid.90
application of L. plantarum for 30 days led to > 90% area reduc-
tion of chronic leg ulcers in nondiabetic patients.81 Oral pro-
Skin cancer
biotics containing Lactobacillus species were also effective in
treating chronic diabetic ulcers, resulting in decreased ulcer Disturbances in the skin microbiome exist in several cutaneous
size and decreased levels of inflammatory markers.82 neoplasms and have been implicated in the promotion of car-
Probiotic studies have also shown enhancement of wound cinogenesis. One example is the link between S. aureus infec-
healing in burn patients83,84 and in the prevention and treat- tion and cutaneous T-cell lymphoma disease severity, through
ment of skin infections. A topical probiotic containing L. plan- the potential role of a staphylococcal superantigen in carcino-
tarum reduced Pseudomonas aeruginosa skin infections in a mouse genesis.91–94
model of burn wounds.85 In humans, L. plantarum, when In contrast, a healthy microbiome may suppress carcinogen-
applied to second- and third-degree burns, was as effective as esis through its regulation of the immune system and control
silver sulfadiazine in reducing the risk of infection and bacte- of inflammation by activating antineoplastic or immuno-
rial load, while promoting granulation tissue and wound heal- surveillance pathways.3,95 For example, oral intake of lipotei-
ing.84 Skin commensals are also excellent candidates in a choic acid from lactobacilli was associated with less ultraviolet
topical probiotic, with likely superior resilience given their damage and a reduced risk of skin cancer.96 Recently, strains
inherent adaptation to the skin environment. For example, Pro- of S. epidermidis were found to produce a nucleobase molecule
pioniferax innocua, a skin commensal, has been found to degrade that selectively inhibited tumour proliferation, and application

© 2019 British Association of Dermatologists 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 9 Krutmann J. Pre- and probiotics for human skin. Clin Plast Surg
tumours in mice.97 A healthy microbiome can also potentially 2012; 39:59–64.
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their role as host guardians. Benef Microbes 2014; 5:201–15.
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11 Lai Y, Cogen AL, Radek KA et al. Activation of TLR2 by a small
therapy or platinum chemotherapy regimens for tumours had molecule produced by Staphylococcus epidermidis increases antimicro-
superior effectiveness in mice with healthy gut microbiomes bial defense against bacterial skin infections. J Invest Dermatol 2010;
compared with germ-free or antibiotic-treated mice.98 It is 130:2211–21.
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Additional Supporting Information may be found in the online
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