Accepted Manuscript

The Microbiome in Dermatology

Shenara Musthaq, Anna Mazuy, Jeannette Jakus

PII: S0738-081X(18)30048-8
DOI: doi:10.1016/j.clindermatol.2018.03.012
Reference: CID 7233
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The Microbiome in Dermatology

Shenara Musthaq BA1, Anna Mazuy MD2, Jeannette Jakus MD, MBA1

1
Department of Dermatology, SUNY Downstate Medical Center, 450 Clarkson Avenue,

#46, Brooklyn, NY11203, USA

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2
Early Clinical Evaluation Department , Galderma - Nestlé Skin Health R&D, Les

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Templiers, 2400 route des Colles, Sophia Antipolis, 06410 Biot, FRANCE

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Corresponding Author:
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Jeannette Jakus, MD, MBA
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SUNY Downstate Medical Center

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Department of Dermatology
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450 Clarkson Avenue, #46

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Brooklyn, NY 11203

Phone: (718) 270-1229

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E-mail: Jeannette.Jakus@downstate.edu
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Abstract

The skin supports a delicate ecosystem of microbial elements. Although the skin
typically acts as a barrier, these microbes interact with the internal bodily environment
and imbalances from the “healthy” state that have been linked to several dermatologic
diseases. Understanding the changes in microbial flora in disease states allows for the
potential to treat by restoring equilibrium. With the rising popularity of holistic and
natural consumerism, pre-biotics, pro-biotics, symbiotic, and other therapies are under
study to find alternative treatments to these skin disorders through manipulation or

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supplementation of the microbiome.

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What is the microbiome?

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The skin is the human body’s largest barrier to the external world, exhibiting
physical and chemical defenses for protection against pathogens. Paradoxically, upon this
barrier, the body maintains a dynamic and symbiotic relationship with a vast ecosystem

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of bacteria, viruses, fungi, mites, and archaea– the skin microbiome. The skin microbiota
can be defined as all the microbial cells of a region or the body, while the microbiome
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includes the cells and their genetic material.

“Microbiome” was only coined as a term in 2001, although its study has been
ongoing since the 1680’s.1 Scientists have long questioned the nature of the relationship
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between humans and these microorganisms: What is their purpose? How do they
colonize? How do they affect disease course? The advent of next-generation DNA
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sequencing has allowed for the isolation and identification of the constituents of
microbiome to a degree which was previously impossible with culture techniques alone.
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Through sequencing of the 16S rRNA small-subunit gene in bacteria, the 18S rRNA and
Intervening Internal Transcribed Spacer region in fungi, and dsDNA in viruses, the great
breadth of diversity in organisms has been better elucidated. 2-5
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In the bacterial kingdom, 850 distinct microbial operational taxonomic units from
36 phyla were observed from a sampling of various sites.2 In the fungal kingdom, 80
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genera were found on the plantar heel alone.3 The types of microorganisms found vary
between topographic regions of the body, which are typically categorized as dry, moist,
or sebaceous. Inter-individual difference in skin microbiota have also been associated
with differences in host factors such as age, diet, gender, geographic region, and climate.
2, 3, 6

As a part of this symbiotic relationship, the body provides a diverse habitat for
colonization, while the microorganisms and their genetic material contribute to immune
defense and regulation. Competition between or within microbial species can
inadvertently provide beneficial effects for the human host. For example, Staphylococcus
epidermidis, the most common clinical isolate of cutaneous microbiota, has evolved
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successfully to inhabit the human body through sensing the human innate immune system
and in response, up-regulating protective virulence factor proteases against endogenous
anti-microbial peptides. In addition, bacteria produce peptide toxins and free fatty acids
that deter other potentially pathogenic organisms, such as S. aureus and group A
Streptococcus (S. pyogenes) from inhabiting the skin. 7-9 Corynebacterium jeikeium,
another common innocuous bacterium, produces bacteriocin-like antimicrobial
compounds and scavenges for nutrients, which prevents colonization by other competing
species. C. jeikeium also produces superoxide dismutase, which protects the bacteria from

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superoxide radicals, and may concurrently prevent oxidative damage to surrounding skin
tissue. 7

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Other bacterial effects may alter the function of the immune system through

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activating signaling pathways within cells. Lipotechoic acids (LTA), which are products
of staphylococcal species, have been shown to down-regulate inflammation through
keratinocyte activation of the Toll-like receptor (TLR) pathway 2 that then inhibits the

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TLR3 pathway, an initiator of the inflammatory response in the skin. 10-12

Due to a complex interplay between the body and its habiting microflora, changes
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or imbalances in either endogenous or exogenous factors, such as modern diet and
hygiene practices, are under review for their role in dermatologic disorders. 13 In the skin,
dysbiosis has been most studied for its implication in psoriasis, atopic dermatitis, acne,
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and rosacea, and a lesser number of studies have focused on such conditions as
seborrheic dermatitis, body odor, and wound healing.
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The relevance of skin microbiome in alternative and complementary medicine lies

in the poorly defined regulatory categorization of products and therapeutics aimed at
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altering, destroying, and/or restoring these commensurate organisms. Therapeutic

modalities targeting the microbiome typically fall into one of four categories:
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1. Prebiotics
2. Probiotics
3. Bacteriophages
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4. Transplantation

These categories are commonly included in functional foods or natural and

complementary medicinal treatment groups, as they are “naturally derived.” A recent
review of probiotics across the globe 14 points out that due to the broad role of probiotics
in both preventative and curative therapy, their regulatory categorization remains unclear.
For example, Canadian probiotics are considered natural health products, while in the
USA, they can fall into several categories including dietary supplements, drugs, medical
food, live biotherapeutic agents, and biologic agents, depending on the product claim and
use. 14 As global demand for these products continues to grow, the need for standardized
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regulatory categorization will be a necessary step towards the development of this

industry.

The Microbiome

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Healthy Skin

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Cultivation of the microbiome begins at birth and changes dynamically over time.

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Differences in modes of delivery are reflected in the composition of microorganisms
found on newborns. Vaginal microorganisms, such as Lactobacullis, Prevotella, and
Sneathia, dominate the skin flora of naturally delivered infants, while those delivered by

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caesarean section contain Staphylococcus, Corynebacterium, and Propionibacterium,
which resemble the composition of adult skin.15 The relationship between host and
commensal bacteria is established early in the post-natal period through education of
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regulatory T cells, which play a major role in maintaining immune homeostasis in
peripheral tissue. Within the first weeks of life, there is a wave of regulatory T-cells that
arrive at the epithelial barriers and develop tolerance to the microbes that reside there.
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The long term effects of the mix of microbes acquired at birth have been best
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studied in relation to the gut microbiome whereby Cesaerean delivery is associated with a
higher risk of developing autoimmune or inflammatory disorders such as Celiac disease,
Type 1 diabetes, and asthma.
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There are four dominant phyla of bacteria that are conserved between adult
individuals:
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1. Actinobacteria
2. Proteobacteria
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3. Firmicutes
4. Bacteroidetes

The variability of the microbiome comes from lesser-represented bacterial species.

Within a single individual, skin location is the main determinant of diversity between
bacterial communities. The skin contains three major ecologic environments: dry (ex.
forearm), moist (ex. axilla) and sebaceous (ex. scalp). Species diversity within each local
area, referred to as “alpha diversity”, is greatest in dry environments and least in
sebaceous. The types of organisms found in each site are suited thrive in that
environment: Staphylococcus and Corynebacterium colonize in moist areas that are
occluded, as they prefer high humidity habitats; while Propionibacterium, lipophilic
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bacteria, tends to colonize sebaceous areas. 12, 17, 18 The differences in site-specific
colonization are highly conserved between individuals.

Temporal changes in the microbiome are also observed, although maintain less
importance in diversity than site location. In a 4-6 month study, dry environments were
found to have the greatest change in composition, while moist environments were
typically stable. 4, 17 Composition can also vary greatly during different life stages; for
example, during puberty there is an increased level of lipophilic bacteria levels due to an
increase in sebum production in comparison to the adult state described above. 6 Inter-

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individual differences are due to secondary factors and can be attributed to environment,

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occupation, diet or hygiene habits. 6, 17

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When defining healthy skin, proportions of bacteria are an important factor;
however, as the microbiome is a living ecosystem engaging with the cutaneous immune
system, it is the nature of these interactions between host and bacteria that ultimately

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define the health of an individual.

Psoriasis
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Psoriasis affects 1-3% of the population. It is characterized by epidermal hyper-
proliferation, hyperkeratosis, dermal inflammation, and angiogenesis resulting in
thickened, scaly plaques. The exact etiology is unknown; however, genetics, age, co-
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morbidities, trauma, and environmental factors have been linked to the disease. The
pathophysiology suggests an inappropriate activation of the cutaneous immune system
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against a perceived pathogen. 19, 20

Studies elucidating the connection between the skin microbiome and psoriasis
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have been conducted, showing an imbalance from the typical distribution of

microbacteria. In a sampling from four body sites, all the major taxa were present in a
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comparison of healthy skin to skin of a psoriasis patient, but with differences in relative
abundance. At all taxonomic levels, a decrease in diversity was found when comparing
skin samples from healthy controls to samples of unaffected skin from a psoriasis patient,
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and to a psoriatic lesion. 15, 21Priopionibacterium, and Actinobacteria species had a lower
representation in psoriatic lesions than in normal control skin; while Firmicutes,
Proteobacteria, Acidobacteria, Schlegelella Streptococcaeae, Rhodobacteracaea,
Campylobacteraceae and Moraxcellaceae species were overrepresented. 8, 22, 23

Differences in the composition of cutaneous flora could be associated with the

strong induction of cathelidins and human beta defensins -- antimicrobial peptides
secreted by keratinocytes in psoriasis. This disease is also known to decrease the risk of
cutaneous infection indicating that changes in immunological physiology could be
shifting the skin microflora through selective stress. 21, 22 Decreased prevalence of
common commensal bacteria such as P. acnes, which has recently been linked to
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inhibition of tumor growth and of the Th2-mediated allergy response through activation
of the Th1-type cytokine immune response, could be affecting the local cutaneous
immune system allowing immunological over-activation. 24-26 The microflora found in
lesions from patients of varying severities of psoriasis were similar in composition and
yielded no statistically significant differences, suggesting that progression of disease is
not linked to microflora composition. 21

Atopic Dermatitis

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Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disorder with an

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onset in childhood and links to asthma and allergic rhinitis and conjunctivitis.
AD is considered the first step of the so-called atopic march.27 The

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pathophysiology of AD is as complex as its clinical phenotype and includes altered
barrier function, a robust Th2 response to environmental antigens, as well as deficiencies
in the innate immune system.29 Recent studies revealed the genetic origin of AD is

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related to skin barrier function abnormalities such as loss of the role of filaggrin. Loss of
function mutations for the filaggrin gene (FLG) are found in 10%–30% of Caucasian
patients with AD.28
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A role for skin microbiome in AD has been well documented 29. The important
interplay between organisms and humans in AD is no better demonstrated than through
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the “hygiene hypothesis”. First proposed in 1989, this theory suggests that modern day
hygiene practices have led to a reduced exposure to bacteria and other organisms early in
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life leading to altered immune tolerance.30 It is thought that a child’s early skin
microbiome positively influences immune system development away from allergic over-
sensitization; however, poor development or changes in the balance of the microbiome
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and the host’s cutaneous immune response have been shown to predispose children to a
whole host of immune conditions such as atopic dermatitis and may lead to frequent
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secondary skin infections.31, 32

Differences in skin microbiome composition may explain the predilection for AD

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to occur in its characteristic locations in the antecubital and popliteal folds. 37 Once the
disease is established, it remains largely unclear whether subsequent changes seen in the
skin microbiome are due to shifts in the balance of the immune response or occur
secondarily due to barrier permeability changes.10 The role of the intestinal microbiota in
the pathogenesis of AD has recently been investigated but remains uncertain.33

AD flairs have long been associated with colonization and frequent infections by
the pathogen S. aureus. 31, 34 In AD, an altered skin microbiome may increases
susceptibility to Staphylococcus aureus colonization and creates an increase in otherwise
commensal Staphylococcus epidermidis colonization.35, 36 After adequate therapy, the
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healthy skin microbiome has been shown to regenerate.31 Presently, consensus is that
microorganisms have a secondary role in AD, but only little is understood about their
contribution to its pathogenesis.

Observations that skin microbial communities change during AD flare and

recovery periods has sparked interest in the ability of skin commensal organisms to
promote recovery. Recent studies show a strong association between worsening disease
severity and lower skin bacterial diversity.97 Traditional AD treatment with anti-

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inflammatory and antimicrobial medications, even if intermittent, has been linked to
greater microbial diversity, specifically increases in the populations of Streptococcus,

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Corynebacterium, and Propionibacterium.31 Other explanations include promotion of
microbes that control S. aureus predominance or a general reduction of skin microbes

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followed by a prompt re-colonization with a community of broader diversity.10 Among
the traditional therapies,the effect of narrowband UV-therapy shows an increase in
microbial diversity.38

Rosacea
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Rosacea is a chronic inflammatory condition of the blood vessels and
pilosebaceous units of the face that commonly presents with flushing, blushing and
sensitive skin. 39 The role of the microbiome in the pathogenesis of rosacea has been
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connected to Helicobacter pylori, Staphylococcus epidermidis, Chlamydia pneumonia,

Bacillus olenorium and Demodex mite; however, none of these have conclusively
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demonstrated cause. 40 The composition of the microbiome is postulated to be more

important than a specific microorganism population. Rosacea patients exhibit abnormal
overexpression of TLR2 in the epidermis providing an explanation for enhanced
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inflammatory responses. TLR2 expression also leads to abnormal production of

cathelicidin antimicrobial peptides and increased expression and activity of serine
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protease kallikrein, which are two hallmarks of the disease.41, 42 Changes in microbiome
composition may play a role in this overexpression, but it is not known whether these
changes are the product or the cause.
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Demodex follicularum is a commensal mite found in nearly all humans. The mites
colonize the body extensively but have a predilection for sebaceous areas as they can use
sebum as a food source. Demodex follicularum are found in rosacea patients with the
papulopustular subtype at a population density of more than 5x that of a healthy patient.
Demodex mites are implicated in other skin lesions. The mechanism inducing reaction is
thought to be that the chitinous exoskeleton and mite waste products are perceived as
foreign bodies causing an innate immune system reaction or delayed type
hypersensitivity. Specific to rosacea, the Demodex mite acts as a vector for the bacteria,
Bacillus olenorium. It has been hypothesized that the mites cause the distention of the
follicles, allowing for the bacteria to be introduced to the innate immune system through
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the pilosebaceous unit and a subsequent mononuclear cell proliferation and induction of
neutrophils follows.40, 43 Other recent data elucidate a relationship between small
intestinal bacterial overgrowth (SIBO), which is more prevalent in rosacea patients than
the general population, and the symptoms of rosacea. 41, 44

Acne

Acne vulgaris is a chronic inflammatory disease of the pilosebaceous units and occurs in
sebaceous areas of the face, neck, chest and back. Acne typically affects adolescents and

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is correlated with a surge in androgens. Androgens influence cellular differentiation,

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proliferation, lipogenesis and comedogenesis in sebocytes and keratinocytes, which
primes or initiates acne development.46 In adolescence and adulthood, sebaceous areas

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are colonized primarily by the lipophilic Propionibacterium.12, 45Propionibacterium
hydrolyzes triglycerides in sebum to produce free fatty acids, which acidify and weaken
the skin.12 While the connection between Propionibacterium acnes and acne vulgaris has

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long been acknowledged, further knowledge of the skin and follicular microbiome may
challenge the importance of this relationship.
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As Propionibacterium is a commensal organism in healthy patients, its presence
alone cannot fully explain the pathogenesis of acne. One study comparing the strain level
composition of Propionibacterium acnes and other common bacteria in acne patients to
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healthy patients, found similar species in both patient groups – Propionibacterium acnes,
Staphylococcus epidermidis, Propionibacterium humerusii and Propionibacterium
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granulosum. In addition, the most abundant strains of Propionibacterium acnes were

comparable in population in both groups; however, the strains of lesser populace were
unique to either acne patients or healthy patients. Two strains classified as Ribotype (RT)
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4 and RT5 were unique only to acne patients and both carried similar genetic elements,
and are now thought to play a role in the pathogenesis of the disease. 47
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Sebum can change composition or lipid types in response to endogenous and

exogenous stressors such as diet and UV exposure. Acne patients have increased sebum
production, as well as higher amounts of squalene peroxide and decreased vitamin E
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within the sebum composition. 48 As stated before, sebaceous areas are very low in
diversity and it can be postulated that changes in sebum production or its composition can
help foster the growth of different strains of Propionibacterium acnes.

Other Conditions

The role of microbiome in body odor, and specifically in regard to axillary odor,
dates back to the pivotal study by Leyden et al. in 1981 in which traditional culture-based
microbiological studies identified Staphylococcus (S. aureus, S. epidermis, S.
saprophyticus), Propionobacteria and Corynebacterium as the main resident bacteria of
the axilla. 49 Of these, Corynebacterium has since been implicated as the most likely
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contributor to odor, as studies have elucidated the interaction between these microbiota
and secretions of the axillary eccrine, apocrine and sebaceous glands.50-52

The most recent and comprehensive review to date further defines the relationship
between axillary microbiota and the biotransformation of natural human secretions to
produce medium chain volatile fatty acids (VFA’s) and thioalcohols – the most likely
causal molecules responsible for axillary odor.51 Small-scale studies of the effects of
deodorants and antiperspirants on axillary bacterial communities show that the use of
these products significantly alters the axillary microbiome; however, the consequence of

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these changes is unclear.53, 54 It is conceivable that with the advent of high-throughput

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sequencing leading to the discovery and identification of even more resident axillary
species, researchers will gain a better understanding of the mechanisms behind body odor

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leading to better-targeted therapies.

Dandruff, or seborrheic dermatitis, is one of the most common skin conditions

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afflicting modern day humans. This chronic hyper-proliferative inflammatory condition
typically results a red and flaky appearance of the scalp and/or sebaceous areas of the
face and sometimes chest. While the etiology of this condition remains to be poorly
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understood, it has long been associated with the Malassezia yeasts. Recent investigations
comparing the microbiota of healthy subjects to those with dandruff reveal a higher
diversity of bacterial and fungal microbiota in those with dandruff, establishing a
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broadened etiologic role of microbiota in this condition. This shift was also interestingly
present in non-lesional sites suggesting a more systemic pathogenesis than was
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previously suspected. 55

Pre-, Pro- and Synbiotics

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In the early 1900’s, a Russian zoologist and Nobel prize winner Ilya Ilyich
Mechnikov (1845-1916) made an astute observation of Bulgarian peasants – he
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attributed their longevity to the consumption of lactic acid-producing bacteria found in

yogurt. This observation would become the founding basis for the use of probiotics in
health and medicine.
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Probiotics are defined by the Food and Agriculture Organization of the United
Nations and the World Health Organization as “live microorganisms which when
administered in adequate amounts, confer a health benefit on the host.” 56 Today, the
most commonly available and therefore most studied probiotic strains are lactobacillus
and bifidobacteria. These can be found in a whole host of products ranging from
fermented milk products to pills to powders to topical preparations.

The concept of prebiotics began to take ground in the 1980’s with early reports
and observations of the bifidogenic properties of inulin, oligofructose,
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fructooligosaccharides (FOS) and galactose and xylose-containing oligosaccharides. 57

The term “prebiotic” was then officially coined by Glenn Gibson in 1995 as “a non-
digestible food ingredient that beneficially affects the host by selectively stimulating the
growth and/or activity of one or a limited number of bacteria in the colon and thus
improves health.” 57 The most commonly available prebiotic compounds are inulin-type
fructans (ITF) and galacto-oligosaccharides (GOS); typically plant or food-derived
molecules, they have been shown to selectively promote the growth of lactic acid-
producing bacteria and bifidobacteria in the gut leading to similar benefits to those seen

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by direct ingestion of these bacteria. The improved delivery, safety and affordability of

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these products make prebiotics an attractive complementary or alternative option to

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probiotics. Synbiotics, the combination of both pre- and probiotics, have been shown to
confer a synergistic effect on the gut microbiota. 58

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The reported benefits of oral pre- and probiotics on health are many, with most
data coming from the gastroenterology literature. Through the restoration of healthy gut
flora, oral pre- and probiotics have been shown to positively influence the immune
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system both locally in the gut and systemically. Restoration of the flora also repairs the
gut mucosal barrier to improve the symptoms of certain gastrointestinal conditions such
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as acute gastroenteritis, irritable bowel syndrome, necrotizing enterocolitis, inflammatory

bowel disease and constipation. 58-61 Early pre-clinical studies suggest that probiotics may
even have a role in the prevention of colon cancer. 62-65
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In dermatology, the use of pre-, pro- and synbiotics has been suggested in several
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conditions including AD, acne, rosacea and wound healing. Though little has been
reported, readers can find a detailed approach to manipulating the gut microbiome in
psoriasis by Haines Ely elsewhere in this issue. Pre- and probiotics are also increasingly
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being promoted for cosmetic use and in skin maintenance and health although scientific
data on these uses is mostly lacking.
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Atopic Dermatitis

Most of our data on the use of pre-, pro- and synbiotics in dermatology comes
from studies conducted in AD. Pre-, pro- and synbiotics have been shown to alter the
immune system through modulation of the Th1/Th2 axis and up-regulation of T
regulatory (Treg) lymphocytes in the gut. An additional effect on the gut barrier is
suspected to alter exposure to potential allergens, which may be responsible for the
inflammatory cascade implicated in allergic conditions including AD.
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A search of the literature on the use of pre-, pro- and synbiotics in the treatment
and prevention of AD has yielded 13 English language meta-analyses and countless other
reviews and contributions. 66-78 The most recent meta-analysis has focused specifically on
the use of synbiotics (the simultaneous use of pre- and probiotics) in the primary
prevention and treatment of AD. This report included 6 treatment studies and 2
prevention studies in the final analysis and found that despite the significant
heterogenicity, there was enough evidence to support the use of synbiotics in children
ages 1 year and older. Pooled weighted mean differences (WMD) in change in SCORAD

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(“Scoring AD” severity score) for this group was -7.37; 95%CI, -14.66 to -0.07; P=0.048.
The evidence was also significant in studies in which mixed strains of probiotic bacteria

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were used (WMD, -7.32; 95% CI, -13.98 to -0.66; P=0.03).

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Another recent meta-analysis reviewing the treatment effects of both pro- and
synbiotics in AD found strikingly similar results.67 25 randomized controlled trials in the
final analysis, demonstrating an overall difference in SCORAD value of -4.51 [95% CI, -

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6.78, -2.24; P<0.001] but with high heterogenicity [I2=87%]; therefore, yielding uncertain
clinical significance. In the primary analysis, however, there were statistically significant
reductions in the mean differences of SCORAD values in children ages 1-18 [WMD -
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5.74, 95% CI -7.27 to -4.20, P<0.001, I2=28%] and in adults 18 years and older [WMD -
8.26, 95% CI -13.28 to -3.25, P=0.001, I2=57%] when using probiotics versus a placebo.
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This was not seen in infants less than 1 year of age. Subgroup analyses also found
significantly greater effects on the reduction in SCORAD when using synbiotics versus
probiotics alone, using mixtures of bacteria versus single species, when duration of
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treatment was greater than 8 weeks and when treating moderate and severe AD versus
mild atopics. Nine of the twenty-five trials reported adverse events, mostly related to
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gastrointestinal symptoms in both the treated and placebo groups. No serious adverse
events were reported rendering the use of pre- and synbiotics to be relatively safe.
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Findings from an earlier meta-analyses of pre-, pro- and synbiotics were less
favorable, showing little or no evidence to support the use of probiotics for the treatment
of AD.71
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16 studies were evaluated in the final meta-analysis, looking at the effect of

probiotics administered pre- and/or post-natally in the prevention of AD. 65 Despite
substantial heterogenicity [I2=67.04%], the authors found that the administration of
probiotics can protect against AD occurrence [OR=0.64, CI=0.56-0.74, P<0.001] but
only when administered both pre- and post-natally [OR=0.61, CI=0.52-0.71, P<0.001].
This finding was corroborated in a 2013 meta-analysis performed 67 and again in a
detailed review. Additional findings from these longer term studies include possible
benefits in AD prevention beyond age 2.
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In a similar meta-analysis. 68 a more homogenous group of 18 publications

[I2=24.0%] were found to support the early use of probiotics in the prevention of AD. In
this report, however, there was no significant difference in outcomes based on timing of
probiotic use, whether it was given pre- or post-natally or to the mother and/or child. In
an analysis of 14 studies, 76 the researchers found that pro- and synbiotics may reduce the
incidence of AD in children less than 2 years of age. While this report did not show a
significant effect with prebiotics alone, a Cochrane review 74 did find a significant
reduction in the incidence of AD in infants whose feedings were supplemented with

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prebiotics.

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The benefit of using of pre-, pro- and synbiotics in the prevention and treatment

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of AD remains controversial. Limitations of the many studies and analyses published
include significant heterogeneity in study design, making interpretation of these data

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difficult and inconclusive. In general, the strongest evidence seems to suggest that pre-,
pro-, and synbiotics may have a role in the prevention of AD when administered both
prenatally and then after birth. There may be some benefit in treatment for using pre-,
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pro- and synbiotics in children and adults but not infants.

Acne
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While little data exist on the clinical use of pre- and probiotics in the treatment of
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acne, the theory behind their use in this condition is quite compelling. The main rationale
for the use of pre- and probiotics in acne stems partly from the gut-brain-skin axis theory
that suggests a link between the gut microflora, mental health, and inflammatory
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conditions of the skin.79 Other suggested mechanisms by which acne may be improved
through use of probiotics include through modulation of systemic insulin-like growth
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factor release, through selective reduction of Proprionibacterium acnes by specific

bacterial species, such as staphylococcus, through synergy of use with oral antimicrobials
such as minocycline and through modulation and optimization of skin barrier function
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and ceramide production. 80-83 The successful use of probiotics in the treatment of acne
has been limited to just a few published reports and reviews.81, 82

Rosacea

The etiopathogensis of rosacea is multifactorial and has recently included

dysbiosis and small intestinal bacterial overgrowth (SIBO). In one long term follow-up
study, 64.5% of rosacea patients with SIBO treated with a single 10-day course of
rifaximin showed sustained remission of disease up to 3 years. 84 This impressive
response to the eradiation of gut bacterial overgrowth in patients with rosacea may
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warrant future use of pre-, pro- and synbiotics as a new and effective alternative to
antimicrobials. This idea was also supported recently in a single case report of a rare form
of scalp and ocular rosacea that was treated successfully with a combination of
doxycycline and probiotic therapy.85

Wound Healing

While published studies on the use of probiotics in human cutaneous wound

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healing is limited, preclinical data on their use are promising. A recent meta-analysis of
animal studies included six studies (five topical and one oral route) to conclude that the

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administration of probiotics was effective in accelerating the early stages of cutaneous

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wound healing.86 In this review, sterile kefir extracts, containing filtered supernatants of
kefir culture fermentation, proved to be more effective than bacteria and yeast.

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Cosmetics

The anti-aging benefits of probiotics have been touted since the very earliest days
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of Elie Métchnikoff (1845-1916) and the yogurt-consuming Bulgarians. More detail
Increasing public knowledge of and demand for “natural” remedies has given rise to a
flourishing market of microbiome-based cosmetic products. Companies large and small
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are racing to promote the benefits of their technologies, many of them with similar
promises of restoring and maintaining the “natural skin microbiome” to improve skin
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barrier integrity and promote healthier and better skin quality and texture. As is common
with over the counter products, little science has been published to support these claims;
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however, it has been well-established that probiotics have antioxidant properties that may
be of benefit in reducing UV damage, and promoting skin hydration and dermal
thickening. Recently, a team from Korea were able to successfully demonstrate that
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consumption of Bacillus licheniformis, a probiotic isolated from traditional Korean food

products, could enhance longevity of the nematode Caenorhabditis elegans (C. elegans).
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87-89
This animal model is one of the first to demonstrate the anti-aging benefits of
probiotics, but whether or not it can be transferred to humans has yet to be demonstrated.

Phage Therapy

Global concerns over increasing antibiotic resistance have led to a revival of

interest in phage therapy. Bacteriophages (phages) are viruses that infect bacterial cells
and are capable of rapid reproduction, DNA transfer, and cell lysis. Phages are highly
specific to bacterial species and often to only a few strains within a species.90 Due to
these qualities, they are postulated to be a useful tool in altering or re-establishing the
microbiome equilibrium or providing better access for antimicrobials in the treatment of
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bacterial-based dermatologic diseases. Once inside the host, phages can hone to specific
sites, unlike traditional antimicrobials, and replicate to the necessary amount based on the
bacterial population.

The study of phaapy, which started predominantly in Georgia, Russia, France, and
Poland, has been in practice since the early 1900’s for treatment of infectious diseases,
such as dysentery, shigellosis, and typhoid, and the treatment of wounds; however, it is
since fallen out of favor due to the advent and success of antimicrobials and lack of

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proper clinical trials. Once again, it is regarded as an experimental procedure. 91-94

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Although not typically thought of as probiotics, phages do fall under the purview

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of a “live microorganism” which confers an advantage to the host. There are many
approaches to phage therapy being explored – direct utilization of the phage
lytic/lysogenic cycle, use of phage enzymatic products to attack pathogens, use of phages

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to disrupt bacterial biofilms, and utilizing their ability to integrate into the genome to
introduce antibiotic sensitive genes which would lessen antibiotic resistance.91, 95 Studies
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of in vitro models in the context of acne have shown promising results. Cocktails of lytic
phages isolated from Propionibacteria acnes bacterium have been able to clear zones
from bacterial lawns.96
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When specific strains of P. acnes are studied to be more contributory to the

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manifestations of acne, phage cocktails can be made to infect these specific strains,
leaving other “healthy” bacteria to grow preferentially. Phage therapy is also being
investigated for treating ulcers, burns, and skin infections There have been positive in
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vivo results, in which phage and antibiotic loaded creams and bandages can be externally
applied to the affected skin. Additionally, an important potential use is in prophylaxis of
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wound care against bacterial infection, which is currently in practice in Georgia today. 91,
92
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Potential limitations of phage therapy are many fold due to a lack of confirmatory
stuides. Concerns lay in the realm of bioavailability and elimination rates. Development
of antibodies against the phages is a possibility, although the production of antibodies is
much slower than the rate of action of the phages. In addition, it is unclear how effective
phages would be in treating intracellular pathogens.93 As with all therapies, inevitably
there will be levels of treatment resistance. One potential mechanism of resistance is
“pseudolysogeny,” in which the phage genome does not integrate into the bacterial
genome and does not cause lysis. 96

Conclusions
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As the available technology improves for microbial isolation and sequencing, so

does the potential for deeper understanding of the pathogenesis of dermatologic disorders
and the potential for therapeutic manipulation of the microbiome. Developing a better
understanding of healthy skin and the mechanisms that change during a disease course
will elucidate how the composition of the microbiome in problematic areas needs to be
altered and what pre-, pro- or synbiotic therapies can be used to achieve normal
composition. In addition, as in the example of wound healing, or perhaps in preventative
use against oxidative damage and UV protection, the microbiome can be altered to utilize

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the advantageous aspects of certain microbes. As the intestinal microbiome has also been
implicated in some disorders, in addition to the role of the skin microbiome, there are

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more modes of delivery of the pre-, pro- and synbiotic and bacteriophages possible.
Progression of knowledge in this field opens up a wide range of complementary and

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alternative medicinal options to dermatologic disorders.

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