Skin microbiome in acne vulgaris, skin aging, and rosacea: An evidence-based review

Abstract

The goal of this systematic review was to explore emerging perspectives on the role of skin microbiota in acne vulgaris, skin aging, and rosacea. We searched the literature for published clinical trials, randomized controlled trials, cross-sectional studies, and cohort studies, both experimental and observational, whose primary main purpose was to ascertain the associations between the skin microbiome and chronic skin disease, acne vulgaris, rosacea, and skin aging, using the Embase and PubMed databases. Fifty-one relevant published articles were identified for systematic review (up to December 2021). The possible roles of the skin microbiome in these skin diseases were explored to shed light on its development and to identify potential therapeutic targets for treatment. However, the mechanisms of microbial interaction in these diseases are still under-studied. The results of this evidence-based review suggest that it may be possible to develop individualized therapies targeting the pathogenic strains within the skin microbiome involved in these diseases. This alternative therapeutic approach, involving modifications of the microbiome, may form the basis of the next generation of treatment, known collectively as “ecobiological” anti-inflammatory therapies.

Full text

© 2022 Dermatologica Sinica | Published by Wolters Kluwer ‑ Medknow 129
Abstract
Review Article
introduCtion
Acne vulgaris is a chronic and relapsing inammatory skin
disease, mainly caused by Cutibacterium acnes. C. acnes
overgrowth might increase lipid production and has long
been proposed to be the only microorganism that leads to
acne vulgaris inammation. An increasingly body of evidence
shows not only C. acnes but also Staphylococcus epidermidis,
and a diverse skin microbiome play important roles in the
development of acne.
Rosacea is a dicult-to-treat skin disease with uncertain
mechanisms and can be categorized into essential-telangiectasia
form, papular-pustular form, rhinophyma, or ocular rosacea
in phenotype. In addition, the recent literature showed that
Demodex spp. is a possible microorganism that can trigger
either flare-up or remission of rosacea. Moreover, some
other skin microorganisms, in addition to Demodex, play
an important role in controlling the chronic inammation of
rosacea.
The aforementioned ndings imply that certain prebiotics
or probiotics could be applied to treat skin disease and
The goal of this systematic review was to explore emerging perspectives on the role of skin microbiota in acne vulgaris, skin aging, and
rosacea. We searched the literature for published clinical trials, randomized controlled trials, cross-sectional studies, and cohort studies, both
experimental and observational, whose primary main purpose was to ascertain the associations between the skin microbiome and chronic skin
disease, acne vulgaris, rosacea, and skin aging, using the Embase and PubMed databases. Fifty-one relevant published articles were identied
for systematic review (up to December 2021). The possible roles of the skin microbiome in these skin diseases were explored to shed light on
its development and to identify potential therapeutic targets for treatment. However, the mechanisms of microbial interaction in these diseases
are still under-studied. The results of this evidence-based review suggest that it may be possible to develop individualized therapies targeting
the pathogenic strains within the skin microbiome involved in these diseases. This alternative therapeutic approach, involving modications
of the microbiome, may form the basis of the next generation of treatment, known collectively as “ecobiological” anti-inammatory therapies.
Key words: Acne vulgaris, rosacea, skin aging, skin microbiome
Address for correspondence: Prof. Yi-Ju Chen,
Department of Dermatology, Taichung Veterans General Hospital, No. 1650,
Section 4, Taiwan Blvd., Taichung 407, Taiwan.
College of Medicine, National Chung Hsing University, Taichung, Taiwan.
E-mail: yjchenmd@vghtc.gov.tw
Access this article online
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Website:
www.dermsinica.org
DOI:
10.4103/ds.ds_28_22
How to cite this article: Weng YC, Chen YJ. Skin microbiome in acne
vulgaris, skin aging, and rosacea: An evidence-based review. Dermatol
Sin 2022;40:129-42.
Skin microbiome in acne vulgaris, skin aging, and rosacea:
An evidence-based review
Yu-Ching Weng1,2, Yi-Ju Chen1,3*
1Department of Dermatology, Taichung Veterans General Hospital, Taichung, Taiwan, 2Graduate Institute of Clinical Medicine, National Yang Ming Chiao Tung
University, College of Medicine, Taipei, Taiwan, 3College of Medicine, National Chung Hsing University, Taichung, Taiwan
Contents lists available at ScienceDirect
Dermatologica Sinica
journal homepage: www.dermsinica.org
Submitted: 19-Nov-2021 Revised: 03-May-2022 Accepted: 17-May-2022 Published: 14-Sep-2022
This is an open access journal, and arcles are distributed under the terms of the Creave
Commons Aribuon-NonCommercial-ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non-commercially, as long as appropriate credit
is given and the new creaons are licensed under the idencal terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
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Weng and Chen: Skin microbiome of acne vulgaris, skin aging, and rosacea
130 Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
provide a whole new approach to treatment, involving
novel modalities, such as vaccine or phages, which have the
potential to overtly tackle these challenging skin diseases
and conditions.
It has also been proposed that the skin microbiota plays a role in
the process of skin aging. Dierences in the skin microbiome in
dierent age groups have been demonstrated in many studies.
However, further research is needed to clarify the relationship
between aging and the skin microbiome.
In this evidence-based review, recent insights into various
aspects of the skin microbiota and the interactions with the
immune system would be discussed. Our goal was to undertake
a comprehensive review of all relevant studies in the literature,
which included studies on the relationships between the skin
microbiome and acne vulgaris, rosacea, and skin aging, and
to provide medical providers with an overview of current
perspectives on treatment. A detailed understanding of these
topics is important for further development of new therapeutic
approaches involving targeting of the skin microbiome.
MAtEriAls And MEthods
We searched the Embase and PubMed databases from 2012 to
2021 using the keywords “skin microbiome,” “acne vulgaris,”
or “skin aging,” or “rosacea” and included all controlled
studies on the skin microbiome and chronic skin inammatory
diseases. Article selection was conducted by two reviewers
who examined each of the titles and abstracts independently
to assess their suitability for inclusion. Regarding the
inclusion and exclusion criteria, we searched the literature for
published clinical trials, randomized controlled trials (RCTs),
and cohort studies, both experimental and observational,
whose primary main purpose was to ascertain the association
of the skin microbiome and chronic skin diseases and
conditions, such as acne vulgaris, skin aging, and rosacea.
All of the reviewed articles were required to include explicit
statements of search methods, inclusions, data synthesis, and
exclusions. The primary outcomes of interest for inclusion in
the review were associations between the skin microbiome
and skin disease. Decisions regarding study quality and
eligibility were done by two reviewers, and any disagreement
between them was resolved by discussion of the authors’
team. We used the following Oxford scales to evaluate the
strength of evidence of searched published studies: 1a refers
to a systematic review or meta-analysis of RCTs which with
narrow condence interval; 1b indicates an individual RCT
with a narrow condence interval; 2a is a systematic review
of cohort studies; 2b denotes a low-quality RCT or individual
cohort study; 3a refers to a systematic review of several
case–control studies; 3b indicates the individual case–control
study; 4 donates a case series or individual case–control
study/low-quality cohort.
RCTs were considered to be high-level of evidence, whereas
the levels of evidence of serial cross-sectional, ecological, and
cross-sectional designs were considered to be lower.
rEsults
Fifty-one relevant published clinical trials, RCTs, and cohort
studies, both observational and experimental, fullling the
inclusion criteria were identied. With respect to the quality
of studies included in the review, the published clinical trials,
RCTs, and cohort studies, both observational and experimental,
were published between 2012 and 2021; after excluding
duplicate publications, we summarized 51 publications on
the associations between skin microbiome and acne vulgaris,
rosacea, or skin aging. All (100%) of the selected publications
were prospective studies, 2% were RCTs, and the rest were
cross-sectional studies, ex vivo studies, cohort studies, and
before–after studies [Figure 1].
Publication bias was not addressed for any of the included
articles. Some of the studies had some methodological
limitations. Methods used to reduce bias in the data extraction
were specied in most of the studies that were included.
Because of the heterogeneity of the ndings and the study
design, data are listed as narrative summaries.
All 29 articles showed that the skin microbiota had
associations with acne vulgaris, as depicted in Table 1.[1-29] All
13 articles shown in Table 2 found that the skin microbiome
was related to changes in skin aging.[30-42] All nine articles
on rosacea showed that the skin microbiome was related to
the disease, as shown in Table 3.[5,43-50] Two RCTs showed
that the skin microbiome was closely linked to acne vulgaris.
Two RCTs showed that the skin microbiome had a close
relationship with skin aging. The before–after studies on
the skin microbiome showed that it plays a signicant role
in acne vulgaris, skin aging, and rosacea. Comprehensive
comparisons of the three diseases and the skin microbiome
are shown in Table 4.
Acne
Data were primarily obtained from case series, before–after
studies, and RCTs of the skin microbiome and acne vulgaris.
Dreno et al.[3] found an overabundance of Firmicutes and
Proteobacteria and reduced colonization of Actinobacteria
in acne patients. Staphylococcus spp. showed high abundance
on the surfaces of comedones, pustules, and papules than
on nonlesional skin, and its proportions increased with
acne severity in a cohort study (n = 26, 26 acne patients,
P = 0.004 and P = 0.003, respectively). On day 28 following
the application of Eaclar® Duo+ or erythromycin 4%, the
number of Actinobacteria decreased with erythromycin
4%, while Eaclar® Duo+ decreased both the number of
Staphylococci spp. and Actinobacteria spp. Coughlin et al.[10]
showed that the main bacterium in the skin microbiome
of adults with acne vulgaris was C. acnes, whereas there
were more Streptococcus bacteria in pediatric populations,
based on the results of a randomized control trial (n = 16, 8
healthy controls and 8 acne patients, P < 0.01). The number
of bacterial phylogenetic diversity and bacterial species
decreased after treatment with topical agent along with
tretinoin and benzoyl peroxide (P < 0.01). Other studies
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Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
Table 1: Literature review of studies on acne vulgaris and microbiota
Author Year Study type Case number Treatment/intervention Analysis method
of microbiome
Routes of
sampling
Results Level of
evidence
Li et al.[1] 2019 Cross-sectional
study
9 healthy controls
67 acne patients
- 16s rRNA genes
sequencing
Skin swab Grade 4 acne has a signicantly dierent skin
microbiome
Grade 4 acne has an increased alpha diversity and
also increased colonization of four Gram-negative
bacteria (Bacteroides, Faecalibacterium,
Klebsiella, and Odoribacter)
Grade 4 acne has signicant dysbiosis
3b
Fitz-Gibbon
et al.[2]
2013 Cross-sectional
study
52 healthy controls
49 acne patients
- 16s rRNA genes
sequencing
Skin
microcomedone
by strips
Dierent strains of P. acnes are associated with
acne or health patients
Virulence properties of C. acne is due to acquired
DNA sequences and bacterial immune elements
3b
Dreno et al.[3] 2017 Cohort study 26 acne patients 28 days of application
of erythromycin 4% or a
dermocosmetic
16s rRNA genes
sequencing
Skin swab Staphylococcus spp. were abundant on the surface
of comedones, pustules, and papules than on
nonlesional skin
The dermocosmetic decreased the number of
Staphylococcus spp. and Actinobacteria and after
28 days
2b
Kang et al.[4] 2015 Cohort study 20 healthy controls
13 acne patients
Intramuscular injection of
Vitamin B12 (1 mL of 1000
µg/mL hydroxocobalamin)
Topical acne therapies:
Tazarotene, tretinoin, salicylic
acid, and benzoyl peroxide
16S, 23S, and 5S
rRNA sequencing
Skin swab Vitamin B12 supplementation leads to acne
development
Vitamin B12 inuences the metabolite-mediated
interactions between the skin microbiome and the
and modulates the transcriptional activities of the
skin bacteria
2b
Thompson
et al.[5]
2021 Case-control
study
8 healthy controls
8 acne patients
- 16s rRNA genes
sequencing
Skin swab C. acnes is abundant in rosacea, especially
inammatory papules and pustules, which
was more similar to that of acne than that of
noninammatory rosacea lesions
S. marcescens and C. acnes were enriched in
patients with rosacea compared to acne
3b
Ahluwalia
et al.[6]
2019 Cohort study 51 acne patients Benzoyl peroxide 4% wash
for 6-8 weeks
16s rRNA genes
sequencing
Skin swab Microbiome diversity is changed with age and the
number of acne lesions
C. acnes is more abundant on forehead and nose,
as opposed to chin and cheeks
Alpha diversity of the skin microbiota was similar
between preadolescent before and after treatment
with benzoyl peroxide
2b
Barnard
et al.[7]
2016 Cross-sectional
study
34 healthy controls
38 acne patients
- 16s rRNA genes
sequencing
Skin swab C. acnes strains were more diverse in acne
patients with enriched virulence-associated factors
3b
Contd...
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132 Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
Table 1: Contd...
Author Year Study type Case number Treatment/intervention Analysis method
of microbiome
Routes of
sampling
Results Level of
evidence
Park et al.[8] 2020 Cohort study 20 acne patients Oral doxycycline, 100 mg,
twice daily for 6 weeks
16s rRNA genes
sequencing
Skin swab C. acnes was the main species followed by
S. epidermidis
Antibiotic treatment reduced the clinical grades of
acne in all subjects and
Antibiotics administration was associated with an
increase in alpha diversity
2b
Kelhälä
et al.[9]
2018 Cohort study 34 healthy controls
38 acne patients
Isotretinoin at starting dose of
0.4-0.6 mg/kg/day
Lymcycline at a starting dose
of 300 mg twice daily
16s rRNA genes
sequencing
Skin swab C. acnes is the most common bacteria in untreated
acne skin, sebaceous areas of healthy, and back
Both treatments reduced the clinical grades of
acne and the abundance of Cutibacterium spp.
After acne treatment, the diversity of the
microbiota on the back and cheek was
signicantly increased
2b
Coughlin
et al.[10]
2017 Randomized
controlled trial
8 healthy controls
8 acne patients
Topical therapy with benzoyl
peroxide 5% gel or cream or
tretinoin 0.025% cream for
8-10 weeks
16s rRNA genes
sequencing
Skin swab After treatment with benzoyl peroxide and
tretinoin, the phylogenetic diversity and the
number of bacterial species decreased
1b
Hall et al.[11] 2018 Cross-sectional
study
20 acne patients - 16s rRNA genes
sequencing
Skin swab,
pore strips, and
cyanoacrylate glue
follicular biopsy
The viral composition of the skin surface is unique
C. acnes bacteria, bacteriophages, and ribotypes
were identied equally by all sampling methods
3b
Chien et al.[12] 2019 Cohort study 4 acne patients Oral minocycline, 100 mg,
twice daily for 4 weeks
16s rRNA genes
sequencing
Skin swab Antibiotic treatment was associated with reduction
in the level of C. acnes
Antibiotic administration was associated with an
initial decrease of bacterial diversity followed by
recovery
2b
Khmaladze
et al.[13]
2019 Ex vivo study Full-thickness
native skin from
plastic surgery waste
material
L. reuteri DSM 17938 lysate - Full-thickness
skin tissue
Topically use of L. reuteri DSM 17938 lysate can
have anti-inammatory eect by reducing IL-6
and IL-8 in UVB-stressed native skin epidermal
explants
Live L. reuteri DSM 17938 has a positive eect
on AQP3, the lysate up-regulates laminin A/B, and
KLK5 gene expression
X
Bek-Thomsen
et al.[14]
2014 Cross-sectional
study
18 healthy controls
20 acne patients
- Spectrometry
proteome analysis
Sebaceous
follicular casts and
cyanoacrylate-gel
biopsies
Surface-exposed dermatan sulphate adhesins,
uncharacterized lipase, CAMP factors were the
most abundant proteins of C. acne
3b
Contd...
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Table 1: Contd...
Author Year Study type Case number Treatment/intervention Analysis method
of microbiome
Routes of
sampling
Results Level of
evidence
Shi et al.[15] 2021 Cross-sectional
study
16 healthy controls
5 acne patients
- 16s rRNA genes
sequencing
Skin swab Lachnospiraceae, Clostridiales, Moraxellaceae,
Prevotella, and L. garvieae were the most
abundant species found in acne patients
Achromobacter, Stenotrophomonas,
Porphyromonas, Prevotella, and Pseudomonas
were the most abundant species in healthy
controls
3b
Ryan-Kewley
et al.[16]
2017 Cohort study 56 acne patients Isotretinoin (1 mg/kg/day) for
20 weeks
16s rRNA genes
sequencing
Skin swab Oral isotretinoin shows ecacy in the treatment
of moderate-to-severe acne, and this nding
correlates with reductions in the number of
resistant strains of C. acnes on the skin
2b
Kim et al.[17] 2021 Cross-sectional
study
17 healthy controls
16 acne patients
- 16s rRNA genes
sequencing
Skin swab The patients with acne had higher abundance of
Staphylococcus spp. compared to Cutibacterium
spp.
C. acnes was identied to have opposed
interactions with Malassezia globosa and
Staphylococcus
3b
Wilantho
et al.[18]
2017 Cross-sectional
study
40 healthy Thai
male
- B-RISA and
16s rRNA genes
sequencing
Skin swab Diversities were found between the young adults
and elderly adults, followed by that between
normal controls and acne young adults
Abundance of C. acnes and S. epidermidis were
found in young adults
3b
Somboonna
et al.[19]
2017 Cross-sectional
study
10 teenage. hea (19-
24 years), 10
teenage. acn (19-
24 years), and 10
elderly. hea (51-
57 years)
- 16s rRNA genes
sequencing
Skin swab The majority of skin microbiota are
Gemmatimonadetes, Planctomycetes, and
Nitrospirae in the teenage.hea
Firmicutes are more abundant in elderly.hea and
teenage.acn skin
3b
Karoglan
et al.[20]
2019 Cohort study 14 acne patients Application of
nonacne-causing strains,
active induction (5% benzoyl
peroxide gel, 7 days), and
interventional C. acnes strains
treatment (5 weeks)
16s rRNA genes
sequencing
Skin swab After treatment, reduction of noninamed lesions
and pH of skin were found, and the number of
comedone counts improved in inammatory
lesions
2b
Thompson
et al.[21]
2020 Cohort study 8 healthy controls
8 acne patients;
baseline acne
severity ranged from
RAGS grade 3~5
Minocycline 100 mg twice
daily for 4 weeks
16s rRNA genes
sequencing
Skin swab, stool
samples
Derangements in the skin and gut microbiota can
be induced by minocycline use
The results showed that minocycline has the
potential for more than antimicrobial treatments
for acne
2b
Contd...
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Table 1: Contd...
Author Year Study type Case number Treatment/intervention Analysis method
of microbiome
Routes of
sampling
Results Level of
evidence
Loss et al.[22] 2021 Cross-sectional
study
13 acne patients - 16s rRNA genes
sequencing
Punch biopsy
specimens
In comedones, biolm was frequently detected;
in inammatory papules and uninvolved skin,
biolm was less detected
The highest mean alpha diversity is the
comedones type of acne
The higher abundance of Staphylococcus spp. was
found in comedones compared with normal skin
4
Bek-Thomsen
et al.[23]
2008 Cross-sectional
study
5 healthy controls
3 acne patients
- 16s rRNA genes
sequencing
Cyanoacrylate
biopsy
Follicles were exclusively colonized by C. acnes
in healthy controls
Acne is not related to those currently uncultured
bacteria
3b
Onwuliri
et al.[24]
2021 Observational
cohort study
25 adult volunteers L. pentosus KCA1 cream 16s rRNA genes
sequencing
Skin swab L. pentosus KCA1 cream application decreased
the relative abundance of Corynebacterium spp. in
both males and females
Some Malodor species decreased after treatment
in males
2b
Akaza et al.
[25]
2016 Cross-sectional
study
15 acne patients - 16s rRNA genes
sequencing
Skin swab,
follicular content
In follicles, there were abundance of
Staphylococcus spp., Propionibacterium spp., and
Malassezia spp. than in normal skin
The number of Malassezia spp. was related
to follicular contents and the number of
inammatory acne
Other cutaneous resident microbiota are also
related to acne, such as Malassezia spp.
4
Perin et al.[26] 2019 Observational
cohort study
4 healthy controls Collection and transfer of skin
microbiota from the forearm
to the back unidirectionally
16s rRNA genes
sequencing
Skin swab The technique of unenriched transfer of whole
cutaneous microbiome is still challenging but
worthy
2b
Dagnelie
et al.[27]
2018 Case-control
study
12 healthy controls
24 acne patients
- Multi- and
single-locus
sequence-type
determination and
sequencing
Skin swab In patients with severe acne, the population of
C. acnes were similar on the face and back
The severity of acne on the back is related with
loss of diversity, and the predominant C. acne
strain is phylotype IA1
The dysbiosis of C. acnes subgroups on the skin
may trigger inammation
3b
Lomholt
et al.[28]
2017 Case-control
study
11 healthy controls
12 acne patients
- MLST Cyanoacrylate
biopsy
The antibiotic-resistant C. acne clone ST3 and
clonal complex CC18 are associated with acne
3b
Wang et al.[29] 2016 Not human
study
Mouse ears 20 g/L sucrose 16s rRNA genes
sequencing
- Sucrose can selectively induced the fermentation
of S. epidermidis, which may be the potential
target treatment to acne
X
C. acne: Cutibacterium acne, S. epidermidis: Staphylococcus epidermidis, C. acnes: Cutibacterium acnes, P. acnes: Propionibacterium acnes, L. pentosus: Lactobacillus pentosus, L. reuteri: Lactobacillus
reuteri, S. marcescens: Serratia marcescens, L. garvieae: Lactococcus garvieae, rRNA: Ribosomal ribonucleic acid, GEA scale: Global Acne Severity Scale, MLST: Multi-locus sequence typing,
IL: Interleukin, AQP3: Aqua-Orin 3, KLK5: Kallikrein 5, UVB: Ultraviolet B, CAMP: Christie-Atkins-Munch-Peterson, RISA: Ribosomal intergenic spacer analysis, RAGS: Revised acne grading system,
DSM: Deutsche sammlung von mikroorganismen, hea: Healthy group, acn: Acne group
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Table 2: Microbiota alteration in skin aging
Author Year Study type Case number Treatment/
intervention
Analysis method of
microbiome
Routes of
sampling
Results Level of
evidences
Li et al.[30] 2020 Cross-sectional
study
80 individuals of varying
ages
- 16s rRNA genes
sequencing
ITS sequencing for
fungus
Skin swab The composition of skin microbiota in the
children group was signicantly dierent to the
other age groups
Many pathways showed that skin microbiota
may play an important role in aging, due to the
interaction with our immune system and metabolism
and biosynthesis of age-related substances
3b
Kim et al.[31] 2019 Cross-sectional
study
73 healthy Chinese
women in two age groups
(25-35 years; 56-63 years)
- 16s rRNA genes
sequencing
Skin swab Age-related skin microbiome have been found
to inuence some functional pathway to prevent
skin aging
3b
Hillebrand
et al.[32]
2021 Cross-sectional
study
2-year period (2017-2019)
in 115 healthy
- 16s rRNA genes
sequencing
Skin swab The diversity and composition of skin
microbiome in healthy people are relatively stable
through years
3b
Meunier
et al.[33]
2019 Not human
study
Skin stem cell Orobanche rapum
extract
-Stem cell Skin microbiota can protect stem cells by
maintaining their clone-forming capacity and
resisting UV through by caspases inhibition
Skin microbiota can renew the skin surface by
microbiota analysis
X
Jugé et al.[34] 2018 Case-control
study
34 healthy Western
European women: 17
younger (21-31 years) and
17 older individuals (54-
69 years)
- 16s rRNA genes
sequencing
Skin swab Older people have a higher alpha diversity on the
skin surface with compared to younger ones
A high interpersonal variation was also noticed
within older individuals
In older skin, skin microbiome composition
changes with a decrease in Actinobacteria and
Cutibacterium and an increase in Proteobacteria
and Corynebacterium
3b
Dimitriu
et al.[35]
2019 Cross-sectional
study
495 North American
subjects (ages, 9-78 years)
- 16s rRNA genes
sequencing
Skin swab and
oral epithelium
Corynebacterium spp. is the one that showed
reproducible associations between skin aging,
chronological age, and members by microbiota
analysis
Skin microbiome composition can also be shaped
by some other factors, such as lifestyle and host
selection
3b
Suzuki
et al.[36]
2020 Cross-sectional
study
36 healthy subjects
(young-age subjects: 9
men/9 women, age range:
20-35 years; elderly age
subjects: 9 men/9 women,
age range: 60-70 years)
- 16s rRNA genes
sequencing
Skin swab In the young subjects, the meibum microbiome
showed a high α-diversity and resembled that of
the conjunctival sac
In the elderly subjects, the meibum showed
a lower α-diversity, and the microbiome
composition of the conjunctival sac changed to
similar with that of the eyelid
About the skin microbiome of eyelid skin,
C. acnes was dominant in the young subjects,
but Corynebacterium spp. or Neisseriaceae was
dominant in the elderly subjects
3b
Contd...
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Table 2: Contd...
Author Year Study type Case number Treatment/
intervention
Analysis method of
microbiome
Routes of
sampling
Results Level of
evidences
Kim et al.[37] 2021 Cohort study 52 healthy Korean women Streptococcus-secreted
spermidine
16s rRNA genes
sequencing,
whole-genome
shotgun metagenomic
analysis
Skin sterilized
tape
Through metagenomic analysis,
Streptococcus-secreted spermidine plays an
important role in the recovery of skin barrier
function and skin structure by upregulation of
lipid and collagen synthesis in aged skin cells
2b
Lee et al.[38] 2021 Interventional
study
Caco-2 cells
HS68 cells
L. plantarum HY7714 16s rRNA genes
sequencing
- HY7714 EPS improved hydration capacity in
HS68 cells and UVB-induced cytotoxicity and
by downregulating production of reactive oxygen
species and metalloproteinases
HY7714 EPS is a molecule that can have
therapeutic role against UVB-induced skin
diseases and also can have antiaging eect in skin
2b
Kim et al.[39] 2020 Cross-sectional
study
73 Korean women
were sorted into one
of three age groups:
10-29 years (n=24),
30-49 years (n=21), and
50-79 years (n=28)
- 16s rRNA genes
sequencing
Skin swab Several bacteria contribute to maintaining
skin health by dominant occupation, such as
Staphylococcus, Streptococcus, Corynebacterium,
and Cutibacterium. Above situation was aected by
increasing age, especially on hand and forehead skin
On forehead skin, α-diversity increased
signicantly with age
Due to skin dysbiosis, older people may be
susceptible to age-related pathogenic invasions
3b
Zhai et al.[40] 2018 Cross-sectional
study
50 volunteers divided
into children, adolescents,
young adults, middle-aged
adults, and the elderly
- 16s rRNA genes
sequencing
Skin swab Skin sites, age, and sex can inuenced the skin
microbiome
The elderly adults had higher bacterial diversity
and the skin-site dierence decreased with aging
Males had a higher species richness in certain
skin sites and age groups
3b
Wu et al.[41] 2020 Cross-sectional
study
65 Sardinians from three
age groups were recruited
- 16s rRNA genes
sequencing
Skin swab, oral
samples, and
fecal samples
The purpose of this paper is to perform ITS1 gene
amplicon sequencing and 16S rRNA gene of skin
microbioime from dierent body habitats
3b
Li et al.[42] 2014 Case-control
study
Axillary fossa of 37
healthy human adults
in two age groups (old
people and young adults)
- 16s rRNA genes
sequencing
Skin swab The total bacteria, such as S. epidermidis,
Corynebacterium spp., and Staphylococcus spp.,
were further listed by quantitative PCR
Species diversity proles is no signicant
dierent between those age groups
Quantitative PCR and sequencing showed that the
composition of skin bacteria diered by age
The number of total bacteria and
Corynebacterium spp. was reduced in younger
subjects, whereas the quantity number of S.
epidermidis and Staphylococcus spp. showed no
statistical dierences
The skin ora undergo qualitative and
quantitative changes with age
3b
C. acnes: Cutibacterium acnes, S. epidermidis: Staphylococcus epidermidis, L. plantarum: Lactobacillus plantarum, rRNA: Ribosomal ribonucleic acid, AQP3: Aquaporin 3, ITS: Internal transcribed spacer,
UVB: Ultraviolet B, UV: Ultraviolet, EPS: Exopolysaccharides, PCR: Polymerase chain reaction
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Weng and Chen: Skin microbiome of acne vulgaris, skin aging, and rosacea
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Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
Table 3: Microbiota alteration in rosacea
Author Year Study type Case number Treatment/
intervention
Analysis Routes of
sampling
Results Level of
evidences
Thompson
et al.[5]
2021 Case-control
study
19 healthy controls
19 rosacea patients
- 16s rRNA
genes
Skin swab C. acnes is abundant in rosacea, especially inammatory
papules and pustules, which was more similar to that of acne
than that of noninammatory rosacea lesions
S. marcescens and C. acnes were enriched in patients with
rosacea compared to acne
3b
Rainer
et al.[43]
2020 Case-control
study
19 healthy controls
19 rosacea patients
- 16s rRNA
genes
Skin swab R. mucosa is depleted in the skin microbiota of
erythematotelangiectatic rosacea
C. kroppenstedtii, C. ureolyticus, and the oral ora
P. intermedia were rich in papulopustular rosacea
C. kroppenstedtii was highly abundant in patients with a
combination of papulopustular and erythematotelangiectatic rosacea
C. kroppenstedtii was related to more extensive rosacea, which
aects both the cheeks and nose
3b
Woo et al.[44] 2020 Cohort study 12 rosacea patients Oral doxycycline,
100 mg, twice
daily for 6 weeks
16s rRNA
genes
Skin swab In all subjects, antibiotic treatment can reduce the grades
of clinical rosacea and antibiotic treatment can increase
W. confusa was also found
Bacterial diversity was not signicantly altered after antibiotics
treatment
2b
Yuan et al.[45] 2020 Cross-sectional
study
25 rosacea patients - 16s rRNA
genes
Skin swab In lesional skin, a lower skin conductivity was detected due to
a higher transepidermal water loss than in nonlesional areas
The skin conductivity due to dierence of transepidermal water
loss was noticed in lesional and nonlesional skin of rosacea
3b
Murillo
et al.[46]
2014 Case-control
study
57 healthy controls
15 erythematotelangiectatic
rosacea
15 papulopustular rosacea
- 16s rRNA
genes
Standardized
skin surface
biopsies
In analysis, 36 out of 86 species were identied as
Demodex-specic microbiota
In the papulopustular rosacea, the proportions of Firmicutes
and Proteobacteria increased whereas the proportion
Actinobacteria decreased
3b
Zhou et al.[47] 2021 Case-control
study
20 SLE patients
20 healthy controls
20 rosacea patient
- 16s rRNA
genes
Skin swab When we use the rash region of SLE as standard, the richness
and diversity were increased in healthy controls but decreased
in rash region of rosacea and nonrash region of SLE
Skin microbial composition changed in dierent taxonomic
levels between those four groups
3b
Forton and De
Maertelaer[48]
2021 Case-control
study
200 healthy controls
844 rosacea patients
- Microscope
of surface
skin biopsy
Skin tissue Demodex spp. increased with age in men and decreased with
age in women by standardized skin surface biopsies
S. epidermidis was frequently isolated when associated
bacterial infection was suspected
The pathogenesis of rosacea is closely related to the
interactions between the sebaceous gland size and function,
mites, and the subtle variations of immune status
There were some potential factors that may inuence
the proliferation of Demodex, such as hypothyroidism,
contagiosity, pregnancy, corticosteroid administration, genetic
background, and S. epidermidis
3b
Contd...
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Weng and Chen: Skin microbiome of acne vulgaris, skin aging, and rosacea
138 Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
Table 3: Contd...
Author Year Study type Case number Treatment/
intervention
Analysis Routes of
sampling
Results Level of
evidences
Gutiérrez
et al.[49]
2021 Cross-sectional
study
680 rosacea patients - Microscope
of surface
skin biopsy
Standardized
skin surface
biopsies
There were dierent species of Demodex, D. folliculorum was
found in 89.1% of rosacea, while D. brevis was found in the
10.9% of rosacea
Rosacea is more prevalent in subjects exposed to generally
dust-rich environments and who worked indoors
Other environmental factors, such as environmental pollution,
or sun exposure may also aect the mites
3b
Kotakeyama
et al.[50]
2021 Cross-sectional
study
276 healthy Japanese
women
- 16s rRNA
genes
HCA
Skin swab Strong relationships were found between sebum-rich skin and
skin microbiome and the pH
According to the outcomes of HCA, the age-related skin in
female may have risk based on the change of microbiome
3b
C. acnes: Cutibacterium acnes, S. marcescens: Serratia marcescens, R. mucosa: Roseomonas mucosa, C. kroppenstedtii: Corynebacterium kroppenstedtii, C. ureolyticus: Campylobacter ureolyticus,
P. intermedia: Prevotella intermedia, W. confuse: Weissella confuse, S. epidermidis: Staphylococcus epidermidis, D. folliculorum: Demodex folliculorum, D. brevis: Demodex brevis, rRNA: Ribosomal
ribonucleic acid, SLE: Systemic lupus erythematosus, HCA: Hierarchical clustering analysis
revealed that the microbiome diversity was high in nonlesional
skin and treated areas.[1-29]
Recent data have shown that the interactions between C. acnes
and S. epidermidis are vital for skin homeostasis. C. acnes
growth and induced skin inammation can be inhibited by
S. epidermidis. S. epidermidis controls the proliferation
of C. acnes by releasing succinic acid and fermentation of
glycerol. The mechanism of the anti-inammatory eects
of S. epidermidis is to inhibit the production of Toll-like
receptor (TLR)-2. TLR-2 can then suppress the tissue level
of interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha,
which is induced by C. acne through the inammation of
keratinocyte.[1,18] The most abundant fungus of skin microbiota
in acne patients is Malassezia spp. The lipase, which can
stimulate proinammatory cytokine in Malassezia spp. is
more active than that in C. acnes, as shown in Figure 2.[25,51]
Current acne treatment may aect skin microbiota. Isotretinoin
and oral/topical antibiotics for acne treatment are capable of
increasing bacterial diversity after treatment (P < 0.005).[16]
Probiotics and prebiotics supplementation has been reported to
aect both skin and intestinal microbiome. Lactobacilli spp. and
Bidobacteria spp. have been used as probiotics to treat chronic
inammatory skin diseases.[13] Short-chain fatty acids, a product
of the glycerol fermentation by S. epidermidis, can suppress
the growth of C. acnes. Sucrose, a fermentation initiator, is
able to increase the fermentation activity of S. epidermidis
and further leads to a signicant decrease in the growth of
C. acnes (P < 0.001).[29] Further research is warranted to develop
therapies that target pathogenic strains to teat acne. Probiotic,
prebiotics, and phage therapy can be used to combat the
bacteria. In addition, vaccines could be developed to reduce the
infections caused by C. acnes and one such anti-inammatory
treatment approach is termed “ecobiological.”[52]
Skin aging
Skin aging can be characterized by the appearance of wrinkles,
pigmentary irregularities, and laxity. Both intrinsic and
extrinsic factors can inuence or deteriorate the process of skin
Figure 1: Flow diagram of literature screening and screening process.
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Weng and Chen: Skin microbiome of acne vulgaris, skin aging, and rosacea
139
Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
aging.[30,31] Physiological changes and skin structure changes in
the elderly are caused, at least in part, by age-related factors,
e.g., changes in immunosenescence, cellular metabolism, and
altered hormone conditions. The changes in skin structure
are also inuenced by environmental and lifestyle factors,
including pollution, cumulative UV exposure, and smoking.
These physiological changes alter the composition of the
skin microbiome, especially sebum production, which may
decrease considerably.[52] In several areas of skin, such as
the cheek, forehead, and forearm, an age-associated decline
in Cutibacterium spp. colonization was found, probably
related to the decrease activity of sebaceous glands in old
age, but Prevotella, Rothia, and Veillonella had become
overrepresented. Aging signicantly aects the proportion
of archaea in the skin microbiome, which is more abundant
in old age as a consequence of the reduced moisture and
lower sebum levels.[53] Further purication of metabolites of
specic antiaging microorganisms is used in the development
of cosmetic medical products. Regulators of skin microbiome
homeostasis in dierent age groups could be developed as
targets in new treatments of age-related skin diseases.[52]
Several studies revealed that microbiome diversity was higher
in areas without skin aging nonlesional than in areas with
skin aging.[32,34,36,39,40,42] Jugé et al.[34] revealed an increase of
Proteobacteria and Corynebacterium and a lower colonization
of Actinobacteria and Propionibacterium in old skin in a
case–control study of European women (n = 68, 34 healthy
controls, 17 younger and 17 older individuals, P < 0.05). In
addition, similar ndings across dierent age groups were
found in Korean and Chinese women.[39,40] Li et al.[42] used
nested polymerase chain reaction-denaturing gradient gel
electrophoresis to prove that the skin microbiome undergoes
both qualitative and quantitative changes related to aging in
a case–control study (n = 80, 80 individuals of varying ages,
P < 0.01). The resident skin microbiome include not only
bacteria but also fungi and archaea, which the interaction
between each other will produce dierent skin outcome.[54,55]
Further, Wu et al.[41] found that not only bacteria but also fungi
on the skin were signicantly dierent in each age group in
a cross-sectional study (n = 65, three age groups, P < 0.001).
As skin aging, Cutibacterium spp. decreased colonization over
skin.[41] Even the presence of Cutibacterium spp. decreased
with aging, it is well established that Cutibacterium spp. is
still one of the most prevalent bacteria in aged skin. However,
the current literature shows that the skin microbiome may
partly explain the pathogenesis of skin aging, and thus, further
study is needed to elucidate the relationship between the skin
microbiome and skin aging.
Rosacea
It is generally accepted that Demodex-specic microorganisms
play a major role in rosacea.
In the papulopustular rosacea, the proportions of Firmicutes
and Proteobacteria are higher, whereas they were found to be
lower in Actinobacteria. Nonetheless, bacterial diversity was
not signicantly altered by antibiotic treatments.[5,43-49] The
role of cutaneous microbiota in rosacea has been elucidated
in recent studies.[47-49] In a cross-sectional study (n = 680
rosacea patients), Gutiérrez et al. noted that rosacea was
more prevalent in subjects exposed to generally dust-rich
environments and who worked indoors (25.0% condence
Figure 2: New views on the pathophysiology of acne vulgaris, modified from O’Neill and Gallo.[51] NF-kB: Nuclear factor kappa-light-chain-enhancer of
activated B cells, TLR2: Toll-like receptor 2, LTA: Lipoteichoic acid, CAMP: Christie-Atkins-Munch-Peterson, FFAs: Free fatty acids, SCFAs: Shor t-chain
fatty acids, ROS: Reactive oxygen species, MAPK: Mitogen-activated protein kinases, TRAF6: Tumor necrosis factor receptor-associated factor 6,
TNF-α: Tumor necrosis factor α, MyD88: Myeloid differentiation primary response 88, IL-1α: Interleukin 1α, IL-1β: Interleukin 1β, IL-6: Interleukin 6.
Table 4: Comprehensive comparisons of acne vulgaris,
skin aging, and rosacea in the relative abundance of skin
microbiota
Acne vulgaris Skin aging Rosacea
Increased
abundance
Firmicutes spp.
Proteobacteria spp.
Actinobacteria spp.
Staphylococcus spp.
Streptococcus spp.
Prevotella
spp.
Rothia spp.
Veillonella
spp.
Demodex spp.
Firmicutes spp.
Proteobacteria spp.
S. epidermidis
C. acnes
B. oleronius
Decreased
abundance
S. epidermidis Cutibacterium
spp.
Actinobacteria spp.
S. epidermidis: Staphylococcus epidermidis, C. acnes: Cutibacterium
acnes, B. oleronius: Bacillus oleronius
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Weng and Chen: Skin microbiome of acne vulgaris, skin aging, and rosacea
140 Dermatologica Sinica ¦ Volume 40 ¦ Issue 3 ¦ July-September 2022
interval 16.1–33.91). Other environmental factors, such as
environmental pollution, or sun exposure may also aect mites
prevalence in skin.[49] Forton et al. reported that the relative
prevalence of Demodex spp. increased with age, especially in
men (P = 0.001) but not in women (P = 0.004) in a large-scale
case–control study (n = 1044, 200 healthy controls and 844
rosacea patients).[48]
The skin microbiome is important for proper immune
function within the skin. Several microorganisms including
S. epidermidis, Demodex folliculorum, C. acnes, and Bacillus
oleronius have been studied in the light of their potential
roles in the pathogenesis of rosacea.[56] These microorganisms
induce activation of the immune system via TLR-2, causing
signicantly greater expression of cathelicidin. This can result
in abnormal downstream effects, including vasodilation,
angiogenesis, extracellular matrix deposition, and leukocyte
chemotaxis. Research eorts are underway to understand the
roles of timolol, a nonselective beta-adrenergic antagonist,
and some human monoclonal antibodies which can reduce the
eect of calcitonin gene-related peptide receptor. In addition,
the gastrointestinal microbiome may also play roles in the
propagation of rosacea. All of the abovementioned ndings
may be useful in discovering targets of treatment for chronic
inammatory skin disease, such as anti-inammatory agents,
vasoconstrictive agents, and antimicrobial agents.[56] The whole
new potential pathophysiology of skin microbiome in rosacea
is shown in Figure 3.[57,58] Innate immunity can be upregulated
and activated by Demodex spp. in rosacea patients. In addition,
skin commensal bacteria, such as B. oleronius, will induce
the expressions of proinammatory cytokines, leukocytes
chemotaxis, and vasodilatation. Moreover, leukocytes
aggregation will produce more severe skin inammation.[57,58]
ConClusion
The ndings of this evidence review on the roles of the skin
microbiota in acne vulgaris, skin aging, and rosacea suggest
that the skin microbiota and its interactions with the skin could
have potential in the development of targeting pathogenic
strains for the treatment of chronic inammatory skin diseases.
Alternative modalities involving modications of the skin and
gut microbiota may form the next generation of treatment for
skin diseases.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. Yi-Ju Chen, an associate editor at Dermatologica Sinica,
had no role in the peer review process of or decision to publish
this article. The other author declared no conicts of interest
in writing this paper.
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