Phan S, Lee J, Huynh C, Hassan O, Lio P.

Topical Prebiotics and Microbiome

Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in
Atopic Dermatitis. Journal of Integrative Dermatology. Published online July 11, 2023.

Review Article

Topical Prebiotics and Microbiome Metabolites: A Systematic

Review of the Effects of Altering the Skin Microbiome in Atopic
Dermatitis
Sheshanna Phan, BS1, Jenna Lee, BS2, Christy Huynh, BS3, Omron Hassan, DO4, Peter Lio, MD5
1College of Osteopathic Medicine, Touro University Nevada, Henderson, NV; Northwestern University Feinberg School of Medicine, Chicago, IL,
2Rowan School of Osteopathic Medicine, Stratford, New Jersey; University of Illinois at Chicago, Chicago, IL, 3 College of Osteopathic Medicine, Touro
University Nevada, Henderson, NV, 4 Freeman Hospital, Joplin, MO, 5 Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Keywords: systematic review, atopic dermatitis, skin microbiome, prebiotics, postbiotics, metabolomics

Journal of Integrative Dermatology

Relevance
Skin microbiome dysbiosis plays a large role in the pathogenesis of atopic dermatitis
(AD). The metabolic pathways of the skin microbiome provide a potential target for AD
treatment by altering microbial diversity and decreasing inflammation.

Objective
This systematic review synthesizes findings of the current literature, which investigate
topical prebiotics and metabolites of the skin microbiome’s influence on AD.

Methods
Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines, a search was performed on PubMed, Embase, and Web of Science
databases from earliest records to March 2022. After screening based on predetermined
inclusion criteria, outcomes were extracted, and risk of bias assessments were performed
on the included studies.

Results
The search yielded 1,124 publications. Five studies published were found to fit the
inclusion criteria. Four studies investigated the efficacy of a topical prebiotic in treating
AD, and three indicated improvement of AD severity with topical prebiotic use. The sole
study on metabolites suggest that a tryptophan metabolite may decrease AD severity.
The most significant risks of bias were found in the selection process, determination of
treatment efficacy, and statistical analyses.

Conclusion
Current literature suggests that topical prebiotics hold promise in AD as they may
beneficially modify the skin microbiome, which can lead to improvements in AD.
Metabolites of the skin microbiome demonstrated anti-inflammatory effects that may
provide a novel target for AD treatment. However, further investigation with improved
and standardized protocols are required to validate the efficacy of topical prebiotics and
the initial results on metabolites of the skin microbiome.

INTRODUCTION distribution of the skin microbiome, specifically decreased

Atopic dermatitis (AD) is the most common chronic inflam-
matory skin disorder worldwide.1 Its pathogenesis is mul-
tifactorial,2,3 and different AD treatments purport to focus
on one or more of the pathogenic mechanisms. The most
common treatment target is the disordered immune system
and resulting inflammation,2 but there is an emerging body
of research suggesting that the skin microbiome can be ma-
nipulated for AD treatment.
A growing body of literature has reinforced the relation-
ship between AD severity and alterations in the species
biodiversity with predominance of Staphylococcus aureus (S.
aureus) in AD.1,4‑7 Whether these microorganisms are colo-
nizers, true pathogens, or more nuanced pathobionts is still
not fully understood. Some studies suggest that AD skin
is permissive to S. aureus colonization and more suscepti-
ble to S. aureus virulence.1,5 In turn, S. aureus disrupts the
epidermal barrier and induces Th2 response, both patho-
genic mechanisms implicated in AD,5 but not all microbes
have detrimental effects on the skin. Some coagulase-neg-
ative Staphylococcus species, which are deficient in lesional
AD skin, produce antimicrobial peptides against S. aureus.8,
 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...
9 Other studies have found that specific bacteria such as
Roseomonas mucosa,10 Vitreoscilla filiformis,11 Lactobacillus
johnsonii NCC 533,12 and Streptococcus thermophilus13 ap-
pear to reduce inflammation and may decrease AD severity
as well.
Metabolic pathways provide another potential target in
altering the skin microbiome for AD treatment. Metage-
nomic studies suggest that alterations in the skin micro-
biome’s metabolism may influence AD severity.14,15 Pre-
biotics are substrates in the metabolic pathway that can
selectively increase or limit the population of beneficial
and detrimental microbes, respectively.16 Postbiotics are
the metabolites produced by the microbiome that can in-
fluence microbial diversity and inflammation.14,15,17 Many
studies demonstrate the positive effect of oral prebiotics
and postbiotics on the gut microbiome in a variety of condi-
tions and found potential benefit towards AD,17‑20 but few
studies have investigated the effect of topical prebiotics on
the skin microbiome of AD patients.
While the literature suggests that the skin microbiome
plays an important role in the pathogenesis of AD, there
have not yet been larger studies analyzing the effects of al-
tering the metabolic pathways of the skin microbiome in
the setting of AD. This systematic review aims to assess
the current literature investigating the effects of prebiotics
and metabolites of the skin microbiome on AD. The present
study also evaluates the current literature’s quality to help
guide investigators in designing and effectively conducting
future studies such that protocols are optimized to reduce
bias.
MATERIALS AND METHODS
The selection process is outlined in Figure 1. This sys-
tematic review was conducted in accordance with PRISMA
guidelines. Articles were retrieved from PubMed, Embase,
and Web of Science database from the earliest records to
March 2022 using the search formula: (“atopic dermatitis”
OR eczema) AND ((metabolite* OR metabolom* OR
metabonom* OR “metabolic profile” OR “fatty acid
metabol*” OR ceramide* OR “fatty acid” OR sphingo* OR
prebiotic) AND (“skin microbiome*” OR “skin flora”)) OR
((prebiotic OR oat OR glucan OR oligosaccharide) AND
(topical OR emollient OR moisturizer OR lotion OR cream
OR ointment)).
SCREENING
Initial screening was conducted using Rayyan. Duplicates
were deleted, and two independent reviewers assessed each
article’s title and abstract to exclude articles that were re-
views or published abstracts, not in English, not published
in a peer-reviewed journal, did not use human subjects, not
on AD, and not investigating metabolites of the skin mi-
crobiome or topical prebiotics. In the case of disagreement,
a third reviewer made the decision to include or exclude a
publication after reviewing the study.
Subsequently, two independent reviewers screened the
remaining publications by evaluating the entire article. In
Journal of Integrative Dermatology
the case of disagreement, a third reviewer made the deci-
sion to include or exclude a publication after reviewing the
study. Studies were included if they met the following in-
clusion criteria: not a review or published abstract, pub-
lished in a peer-reviewed journal, published in English,
subjects with atopic dermatitis, and investigated the effect
of metabolites of the skin microbiome or prebiotics on
atopic dermatitis. An exclusion criterion based on type of
study was not included due to the lack of research in this
field.
QUALITY ASSESSMENT
Two independent reviewers assessed the quality of each
publication using the appropriate quality assessment tool.
Randomized controlled trials (RCT), quasi-experimental
studies, and case-control studies were assessed with the re-
spective Joanna Briggs Institute (JBI) critical appraisal tool.
To determine the risk of bias in an animal study, the SYR-
CLE’s risk of bias tool was used (Hooijmans). Reviewers
judged if the publication had a low, moderate, or high risk
of bias based on the criteria of each tool. In the event that
there was a discrepancy in score between the two reviewers,
a third reviewer made the final judgment for that publica-
tion.
OUTCOME MEASUREMENTS
For the purpose of this study, treatment outcome was de-
fined as any statistically significant change in AD severity
reported by the authors. Treatment was considered clini-
cally relevant if the mean change in SCORAD was 8.7 or
higher.21 Adverse effects were identified and recorded.
RESULTS
The initial search resulted in 1,124 studies. During the ini-
tial screening, 112 duplicate studies were removed, and 906
studies were excluded. The remaining 106 studies were as-
sessed based on the full article, and 100 articles were ex-
cluded because they did not meet the inclusion criteria.
Five articles were included in this systematic review.
SUMMARY OF STUDY DESIGN
Four out of the five studies were clinical trials investigating
the effect of topical prebiotic application on atopic der-
matitis (Table 1). Of these studies, 50% (2/4) were double-
blinded22,23 and 50% (2/4) were open-label.24,25 Only one
study included a control.22 All four studies used SCORAD as
the primary evaluation method of AD severity.
Table 2 summarizes the study design for trials investi-
gating the utility of topical prebiotics. Exclusion criteria
included: severe AD,24,25 psychological disease,24 immun-
odeficiencies,22 pregnancy,22 and simultaneous AD treat-
ment.24,25 Two studies allowed concomitant treatment.24,
25 Antao et al (2017) allowed topical corticosteroid use, but
Rigoni et al (2018) was more stringent and did not allow
any simultaneous topical or systemic treatment except for
2
 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...

Figure 1. Flowchart depicting selection process of publications for this systematic review, number of publications
(n)

oral antihistamines.25 Seité et al (2017) only included pa- TREATMENT EFFECT ON AD

tients with mild to moderate AD defined as SCORAD < 40
PREBIOTICS
at the initial visit and excluded seven subjects if they im-
proved less than 25% in the 15 days from screening to ini-
Different modalities of treatment were studied including
tial study visit.23
emollients,23‑25 baths,22 and body washes.24 One study in-
The total number of subjects in each study ranged from
vestigated the use of a prebiotic face cream and prebiotic
22-60. Two studies enrolled subjects from a wide range of
body wash in comparison to a prebiotic body cream alone.24
ages, including both children and adults,23,25 but one study
The most commonly used prebiotics were alpha-glucan
focused on children from 3-36 months old.24 One study did
oligosaccharide24,25 and inulin,22,24 which were included in
not report the age of their subjects.22
50% (2/4) of the studies. Other prebiotics studied include
The final included study was a translational study. Gel-
maltodextrin,22 apple pectin,22 mannose,23 and thermal
patch and swab were used to collect skin samples from
spring water.23
19 subjects with AD and 19 controls and analyzed for the
Out of the four studies, 75% (3/4) of the studies found
concentration of indole-3-aldehyde (IAId), which is pro-
a statistically significant decrease in AD severity and re-
duced by the skin microbiome after metabolizing trypto-
ported decreased dermatitis symptoms such as erythema
phan (Trp). To study the effects of topical IAId application,
and lichenification,22,24,25 and 33% (2/3) of the studies
a mouse model for AD was used, and MC903 was painted on
found a clinically relevant decrease in AD severity. Al-
mouse ears for 14 days to induce an AD-like dermatitis be-
though Seité et al (2017) reported a decrease in AD severity
fore treatment with IAId.26
with topical prebiotic treatment, it was not statistically sig-
nificant compared to treatment with placebo. However, the
authors noted that the SCORAD variation (calculated as

Journal of Integrative Dermatology 3

 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...

Table 1. Summary of patient demographics and treatment efficacy of topical prebiotics

Clinically
relevant
Number decrease
of Treatment Treatment in AD
Author Subjects Age Treatment Prebiotics Regimen Length severity1
Noll et 22 NR Synbiotic Maltodextrin, 10 mins 14 days Y
al. bath (n = 7) inulin, apple daily
(2021) Prebiotic pectin
bath (n = 8)
Placebo bath
(n = 7)
Rigoni 26 1.5-45 Prebiotic Alpha-glucan- 2-3 times 8 weeks N
et al. years emollient oligosaccharide daily
(2018)
Antao 60 3-36 Prebiotic face Alpha-glucan- Cream: 2 56 days Y
et al. months cream and oligosaccharide times
(2017) prebiotic and inulin daily
body wash (n Wash:
= 30) daily
Prebiotic
body cream (n
= 30)
Seité 60 6 Prebiotic Mannose and 2 times 28 days N
et al. months-63 emollient (n = thermal spring daily
(2017) years 26) water
Placebo
emollient (n =
27)

Atopic dermatitis (AD), double-blinded (DB), no (N), not reported (NR), open label (OL), yes (Y)
1 Decrease in AD severity is considered clinically relevant if it is statistically significant (p < 0.05) and mean difference in SCORAD is 8.7

Table 2. Summary of study design for topical prebiotic trials

Study Permitted AD Outcome Statistical

Author Design Exclusion Criteria Treatments Measures Analysis
Noll et DB Age < 5 years, pregnancy, immunodeficiency, None SCORAD, ITT
al. ongoing antibiotic treatment 10-point PRO
(2021) for quality of life
Rigoni OL Age < 1 year, SCORAD ≥ 40, known allergy Oral SCORAD, ITT
et al. to ≥ 1 tested component, simultaneous antihistamines adjusted IGA
(2018) administration of topical or systemic
medications
Antao OL SCORAD ≥ 35, psychological disease, Topical SCORAD; PP
et al. simultaneous use of cosmetic creams corticosteroids 5-point scale for
(2017) xerosis,
erythema, and
edema
Seité DB SCORAD ≥ 40, SCORAD improved by < 25% None SCORAD PP
et al. between screening and initial visit (15 days)
(2017)

Double blind (DB), intention to treat (ITT), open label (OL), per protocol (PP), SCORing Atopic Dermatitis (SCORAD)

SCORAD at study end minus SCORAD at first visit) between ness and less inflammatory infiltrates, suggesting that IAId
the treatment and placebo group was significant.23 decreased the inflammatory process associated with AD.26

METABOLITES OF THE SKIN MICROBIOME ADVERSE EFFECTS

Yu et al (2019) found a higher concentration of IAId in
Out of 168 total subjects across four studies, only one sub-
the skin samples of controls and non-lesional skin samples
ject discontinued the use of a face cream because of an
of subjects with AD. In their mouse model, mice treated
unpleasantly strong fragrance.24 Otherwise, none of the
with topical IAId had less visible erythema and scale, and
studies reported an adverse effect, and Rigoni et al (2018)
histopathology demonstrated decreased epidermal thick-

Journal of Integrative Dermatology 4

 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...
Figure 2. Risk of bias in each included study presented as percentages
actually reported that 77% (20/26) and 33% (6/26) of sub-
jects rated the prebiotic emollient as very good and good,
respectively.25
RISK OF BIAS
The studies demonstrated varying levels of bias (Figure 2).
One study was judged to not have high risk of bias in any
criteria but did have moderate bias in two criteria.22 All
other studies had high risk of bias in 8% (1/12) to 25% (5/
20) of the graded criteria in their respective quality assess-
ment tools.24
Table 3 summarizes the risk of bias for each criterion.
The JBI checklist for RCT was used to assess two publi-
cations.22,23 Both demonstrated moderate risk of selection
bias in randomization and allocation concealment. Of the
two publications, one also had high risk of attrition bias be-
cause they chose to analyze patients because they did not
include every randomized subject in their analysis.23
The JBI checklist for quasi-experimental studies was
used to assess two publications.24,25 Both lacked a control
group and were open label. Furthermore, one study demon-
strated moderate risk of selection bias in the baseline char-
acteristics of their subjects.
Yu et al (2019) required evaluation based on both the JBI
checklist for case-control and SYRCLE’s risk of bias tool be-
cause their publication included multiple study designs.26
There was moderate risk of selection bias in subject re-
cruitment, but they appropriately matched subjects in both
groups. In the animal study, there was high risk of se-
lection bias in randomization and allocation concealment,
high risk of performance bias, and some moderate risk of
attrition and reporting bias.
Journal of Integrative Dermatology
DISCUSSION
Historically, there has been a debate concerning whether
AD follows an “outside-in” hypothesis or “inside-out” hy-
pothesis.27 That is to say, whether immune dysregulation
causes skin barrier dysfunction or that skin barrier dysfunc-
tion is primary with resultant secondary inflammation. Re-
gardless of which aspect may come first, it is now abun-
dantly clear that AD is characterized by both intrinsic and
extrinsic factors, and that the skin microbiome is intimately
entwined with these processes. An emerging area of re-
search focuses on the metabolic pathways of the skin mi-
crobiome and demonstrates potential treatment avenues.
THERAPEUTIC POTENTIAL FOR TREATMENT
ALTERNATIVES
PREBIOTICS
All studies found that AD severity decreased with topical
prebiotic treatment, but the difference between the treat-
ment and placebo group at endpoint was not clinically
meaningful in two studies.23,25 Rigoni et al (2018) reported
a statistically significant change in SCORAD, and Seite et
al (2017) found a significant SCORAD variation between
the two groups such that the calculated decrease in SCO-
RAD from initial to final treatment was significantly dif-
ferent between patients using topical prebiotics and those
on placebo. These results suggest that topical prebiotics
+ emollients may provide more clinical improvement than
emollients alone.23
Although all four studies suggest some therapeutic ben-
efit from topical prebiotic use, the results may not be gen-
eralizable to the entire population of AD patients because
5
 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...
three out of four studies included only patients with mild to
moderate AD. In fact, one study had patients treated for 15
days between screening and baseline visit and disqualified
any patients whose SCORAD did not improve at least 25%,
excluding patients that may be treatment resistant.23 The
results of these current studies indicate that topical pre-
biotics may be efficacious in reducing AD symptoms, but
more studies are required to conclude if topical prebiotics
provide any benefit for patients with more severe or hard-
to-treat AD.
The vehicle of a topical prebiotic may or may not in-
herently affect its efficacy, given the results of a recent
study that reported no difference in efficacy between lo-
tions, creams, gels, and ointments.28 One study comparing
prebiotic body wash to body cream found no significant dif-
ference in the AD severity of the two treatment groups.24
However, the actual ingredients within a preparation
clearly matter. A recent meta-analysis found that combin-
ing emollients with a topical active treatment provides a
clinically significant improvement in comparison to regular
emollients alone.29 Topical prebiotics are promising alter-
native active ingredients that may make emollients more
efficacious in treating AD. Studies comparing topical prebi-
otics to vehicle controls suggest that topical prebiotics may
help decrease AD severity more than other emollients,22,23
but more randomized, controlled trials with larger sample
sizes are required.
The studies did not report any severe adverse effects
with topical prebiotic use. Because the results of these
comparative studies suggest that topical prebiotics may
have some additional benefit over emollients, this is clearly
an approach worthy of more investigation.
METABOLITES OF THE SKIN MICROBIOME
IAId is a tryptophan metabolite produced by the skin mi-
crobiome that was shown to decrease the inflammatory re-
sponse and subsequent barrier dysfunction related to AD.26
It was able to decrease epidermal thickness, suggesting
that it may even be efficacious in patients suffering from
chronic AD with lichenification.26 IAId acts by modulating
expression of thymic stromal lymphopoietin (TSLP) in ker-
atinocytes, which is a cytokine implicated in Th2-mediated
inflammation in AD.26 These novel findings suggest that
modulating microbial metabolites may be another potential
method of treating AD, including direct administration of
microbial metabolites in topical or systemic treatment, or
altering the skin microbiome to promote production of spe-
cific beneficial metabolites.
RISK OF BIAS IN THE CURRENT LITERATURE
Although the current literature does not generally suffer
from high risk of bias, several components of their study
design have the potential to introduce bias. Based on the
quality assessment performed, there was a risk of bias in
the selection process, determination of treatment efficacy,
and statistical analyses.
Journal of Integrative Dermatology
Most commonly, studies lacked controls against selec-
tion bias or did not adequately describe their protocol for
selection. In two studies, the authors explicitly stated that
their study was double-blind and randomized, but they did
not detail how subjects were randomized.22,23 As a result, it
is not possible to determine whether the subjects were ran-
domized and allocated into groups appropriately to prevent
bias. In a third study, it is unclear if the mice were random-
ized at all.26
Yu et al (2019) also did not mention if the investigators
were blinded to whether the mice in the AD model were
given treatment or not, which could lead to performance
and detection bias.26 However, the authors attempted to
decrease detection bias by preparing more objective out-
come measurements including quantitative measurements
of ear and epidermal thickness.
Some studies potentially had attrition bias due to their
chosen method of statistical analysis. Seite et al (2017)
and Antao et al (2017) followed a per protocol (PP) rather
than intention-to-treat (ITT) protocol.23,24 With this pro-
tocol, data analysis only includes subjects who completed
the treatment according to the protocol and disregards sub-
jects who were non-adherent or lost to follow-up. Although
it is acceptable to use a PP principle for statistical analysis,
it does have the potential to overestimate treatment effect.
LIMITATIONS
This study did not use any criteria that excluded studies
based on study design as research in this field of study is
relatively new and there were few studies found. Conse-
quently, a meta-analysis was not conducted because of the
variations in study design, including open label versus dou-
ble-blind studies along with differences in statistical analy-
sis methods.
CONCLUSION
The studies included in this systematic review suggest that
topical prebiotics may be a valuable therapeutic modality
for patients with mild-to-moderate AD. They have demon-
strated potential in modifying the skin microbiome to de-
crease AD severity, but many questions remain about the
specific prebiotic or prebiotics, dosing, administration, and
optimal patient selection. Current results highlighting the
influence of metabolites of the skin microbiome provide
the basis for developing multiple new methods of AD treat-
ment. However, both areas of study require more investi-
gation. Future studies on prebiotics should aim to perform
more randomized, controlled trials with larger patient pop-
ulations and double blinding, and further investigation is
required on the skin microbiome’s metabolism before po-
tential treatments can be developed.
6
 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...

Table 3. Summary of risk of bias in each criterion for included studies. Red denotes high risk, blue denotes
moderate risk, and green denotes low risk of bias.

JBI Checklist for Randomized Controlled Trials

Noll et al. (2021) Seite et al. (2017)
Selection bias – randomization
Selection bias – allocation concealment
Selection bias – baseline characteristics
Performance bias – blinding
Performance bias – treatment
Detection bias – blinding
Detection bias – outcome measurement
Attrition bias – differences in follow-up
Attrition bias – intention-to-treat
Reporting bias
Other bias – statistical analysis
JBI Checklist for Quasi-Experimental Studies
Rigoni et al. (2018) Antao et al. (2017)
Selection bias – baseline characteristics
Performance bias – control group
Performance bias – treatment
Detection bias
Attrition bias
Other bias – statistical analysis
Other bias – cause vs. effect
JBI Checklist for Case-Control Studies
Yu et al. (2019)
Selection bias – baseline characteristics
Selection bias – matched cases and controls
Selection bias – recruitment methods
Detection bias – outcome measurement
Detection bias – confounding factors
Other bias – statistical analysis
SYRCLE’s Risk of Bias Tool
Yu et al. (2019)
Selection bias – randomization
Selection bias – allocation concealment
Selection bias – baseline characteristics
Performance bias – random housing
Performance bias – blinding
Detection bias – random outcome assessment
Detection bias – blinding
Attrition bias
Reporting bias
Other bias

CORRESPONDING AUTHOR 874 American Pacific Dr

Henderson, NV, USA
Sheshanna Phan Phone: (657) 222-5078
Department of Clinical Sciences Email: sphan3@student.touro.edu
College of Osteopathic Medicine
Touro University Nevada

Journal of Integrative Dermatology 7

 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...

CONFLICTS OF INTEREST
Dr. Lio reports research grants/funding from AOBiome, Re-
generon/Sanofi Genzyme, and AbbVie; is on the speaker’s
bureau for Regeneron/Sanofi Genzyme, Pfizer, Incyte, Eli
Lilly, LEO, Galderma, and L’Oreal; reports consulting/advi-
sory boards for Almirall, ASLAN Pharmaceuticals, Bristol-
Meyers, Concerto Biosciences (Stock Options), UCB, Der-
mavant, Regeneron/Sanofi Genzyme, Merck, Pfizer, LEO
Pharmaceuticals, AbbVie, Eli Lilly, Micreos, L’Oreal, Pierre-
Fabre, Johnson & Johnson, Level Ex, KPAway (Stock),
Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Ex-
eltis, AOBiome, Realm Therapeutics, Altus Labs, Galderma,
Verrica, Arbonne, Amyris, Bodewell, Burt’s Bees, My-Or Di-
agnostics, Sibel Health, and Kimberly-Clark. In addition,
Dr. Lio has a patent pending for a Theraplex product with
royalties paid and is a Board member and Scientific Advi-
sory Committee Member of the National Eczema Associa-
tion and an investor at LearnSkin. The other authors de-
clare no conflicts of interest.
FUNDING
This research did not receive any specific grant from fund-
ing agencies in the public, commercial, or not-for-profit
sectors.
Submitted: September 22, 2022 PDT, Accepted: June 14, 2023
PDT

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License
(CC0). View this license’s legal deed at https://creativecommons.org/publicdomain/zero/1.0 and legal code at https://cre-
ativecommons.org/publicdomain/zero/1.0/legalcode for more information.

Journal of Integrative Dermatology 8

 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...
REFERENCES
1. Edslev S, Agner T, Andersen P. Skin Microbiome in
Atopic Dermatitis. Acta Derm Venereol.
2020;100(12):adv00164. doi:10.2340/00015555-3514
2. Bieber T. Atopic dermatitis: an expanding
therapeutic pipeline for a complex disease. Nat Rev
Drug Discov. 2022;21(1):21-40. doi:10.1038/s41573-0
21-00266-6
3. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, et
al. Common loss-of-function variants of the
epidermal barrier protein filaggrin are a major
predisposing factor for atopic dermatitis. Nat Genet.
2006;38(4):441-446. doi:10.1038/ng1767
4. Higaki S, Morohashi M, Yamagishi T, Hasegawa Y.
Comparative study of staphylococci from the skin of
atopic dermatitis patients and from healthy subjects.
Int J Dermatol. 1999;38(4):265-269. doi:10.1046/j.136
5-4362.1999.00686.x
5. Paller AS, Kong HH, Seed P, et al. The microbiome
in patients with atopic dermatitis. J Allergy Clin
Immunol. 2019;143(1):26-35. doi:10.1016/j.jaci.2018.1
1.015
6. Park HY, Kim CR, Huh IS, et al. Staphylococcus
aureusColonization in Acute and Chronic Skin
Lesions of Patients with Atopic Dermatitis. Ann
Dermatol. 2013;25(4):410. doi:10.5021/ad.2013.25.4.4
10
7. Tauber M, Balica S, Hsu CY, et al. Staphylococcus
aureus density on lesional and nonlesional skin is
strongly associated with disease severity in atopic
dermatitis. J Allergy Clin Immunol.
2016;137(4):1272-1274.e3. doi:10.1016/j.jaci.2015.0
7.052
8. Nakatsuji T, Chen TH, Narala S, et al.
Antimicrobials from human skin commensal bacteria
protect against Staphylococcus aureus and are
deficient in atopic dermatitis. Sci Transl Med.
2017;9(378). doi:10.1126/scitranslmed.aah4680
9. Zipperer A, Konnerth MC, Laux C, et al. Human
commensals producing a novel antibiotic impair
pathogen colonization. Nature.
2016;535(7613):511-516. doi:10.1038/nature18634
10. Myles IA, Earland NJ, Anderson ED, et al. First-in-
human topical microbiome transplantation with
Roseomonas mucosa for atopic dermatitis. JCI Insight.
2018;3(9). doi:10.1172/jci.insight.120608
Journal of Integrative Dermatology
11. Gueniche A, Knaudt B, Schuck E, et al. Effects of
nonpathogenic gram-negative bacteriumVitreoscilla
filiformislysate on atopic dermatitis: a prospective,
randomized, double-blind, placebo-controlled
clinical study. Br J Dermatol. 2008;159(6):1357-1363.
doi:10.1111/j.1365-2133.2008.08836.x
12. Blanchet-Réthoré S, Bourdès V, Mercenier A,
Haddar CH, Verhoeven PO, Andres P. Effect of a
lotion containing the heat-treated probiotic strain
Lactobacillus johnsonii NCC 533 on Staphylococcus
aureus colonization in atopic dermatitis. Clin Cosmet
Investig Dermatol. 2017;10:249-257. doi:10.2147/cci
d.s135529
13. Di Marzio L, Centi C, Cinque B, et al. Effect of the
lactic acid bacteriumStreptococcus thermophiluson
stratum corneum ceramide levels and signs and
symptoms of atopic dermatitis patients. Exp
Dermatol. 2003;12(5):615-620. doi:10.1034/j.1600-06
25.2003.00051.x
14. Chng KR, Tay ASL, Li C, et al. Whole metagenome
profiling reveals skin microbiome-dependent
susceptibility to atopic dermatitis flare. Nat Microbiol.
2016;1(9):16106. doi:10.1038/nmicrobiol.2016.106
15. Li W, Yosipovitch G. The Role of the Microbiome
and Microbiome-Derived Metabolites in Atopic
Dermatitis and Non-Histaminergic Itch. Am J Clin
Dermatol. 2020;21(S1):44-50. doi:10.1007/s40257-02
0-00538-8
16. Gibson GR, Roberfroid MB. Dietary modulation of
the human colonic microbiota: introducing the
concept of prebiotics. J Nutr. 1995;125(6):1401-1412.
doi:10.1093/jn/125.6.1401
17. Beretta S, Fabiano V, Petruzzi M, Budelli A,
Zuccotti GV. Fermented rice flour in pediatric atopic
dermatitis. Dermatitis. 2015;26(2):104-106. doi:10.10
97/der.0000000000000103
18. Huang R, Ning H, Shen M, Li J, Zhang J, Chen X.
Probiotics for the Treatment of Atopic Dermatitis in
Children: A Systematic Review and Meta-Analysis of
Randomized Controlled Trials. Front Cell Infect
Microbiol. 2017;7:392. doi:10.3389/fcimb.2017.00392
19. Liu Y, Tran DQ, Rhoads JM. Probiotics in Disease
Prevention and Treatment. J Clin Pharmacol.
2018;58(Suppl 10):S164-S179. doi:10.1002/jcph.1121
9
 Topical Prebiotics and Microbiome Metabolites: A Systematic Review of the Effects of Altering the Skin Microbiome in...
20. Zeng L, Yu G, Wu Y, Hao W, Chen H. The
Effectiveness and Safety of Probiotic Supplements for
Psoriasis: A Systematic Review and Meta-Analysis of
Randomized Controlled Trials and Preclinical Trials. J
Immunol Res. 2021;2021:1-14. doi:10.1155/2021/7552
546
21. Schram ME, Spuls PhI, Leeflang MMG, Lindeboom
R, Bos JD, Schmitt J. EASI, (objective) SCORAD and
POEM for atopic eczema: responsiveness and
minimal clinically important difference. Allergy.
2012;67(1):99-106. doi:10.1111/j.1398-9995.2011.027
19.x
22. Noll M, Jäger M, Lux L, Buettner C, Axt-
Gadermann M. Improvement of Atopic Dermatitis by
Synbiotic Baths. Microorganisms. 2021;9(3):527. doi:1
0.3390/microorganisms9030527
23. Seite S, Zelenkova H, Martin R. Clinical efficacy of
emollients in atopic dermatitis patients - relationship
with the skin microbiota modification. Clin Cosmet
Investig Dermatol. 2017;10:25-33. doi:10.2147/ccid.s1
21910
24. Antão H, Passerini E, Guimarães JP, Saldanha J,
Coelho JD, Fortunato M. Efficacy, tolerability and
acceptability of topical regimens containing the
prebiotic Biolin in children suffering from atopic
dermatitis. European Journal of Pediatric Dermatology.
2017;27:102-112.
Journal of Integrative Dermatology
25. Rigoni C, Cantù AM, Gelmetti C. Observational
clinical study of a new emollient in 26 patients with
atopic dermatitis. European Journal of Pediatric
Dermatology. 2018;28:218-225.
26. Yu J, Luo Y, Zhu Z, et al. A tryptophan metabolite
of the skin microbiota attenuates inflammation in
patients with atopic dermatitis through the aryl
hydrocarbon receptor. J Allergy Clin Immunol.
2019;143(6):2108-2119.e12. doi:10.1016/j.jaci.2018.1
1.036
27. Silverberg NB, Silverberg JI. Inside out or outside
in: does atopic dermatitis disrupt barrier function or
does disruption of barrier function trigger atopic
dermatitis? Cutis. 2015;96(6):359-361.
28. Ridd MJ, Santer M, MacNeill SJ, et al.
Effectiveness and safety of lotion, cream, gel, and
ointment emollients for childhood eczema: a
pragmatic, randomised, phase 4, superiority trial.
Lancet Child Adolesc Health. 2022;6(8):522-532. doi:1
0.1016/s2352-4642(22)00146-8
29. van Zuuren EJ, Fedorowicz Z, Christensen R,
Lavrijsen AP, Arents BW. Emollients and moisturisers
for eczema. Cochrane Database Syst Rev.
2017;2(2):Cd012119. doi:10.1002/14651858.cd01211
9.pub2
10