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

biodiversity with predominance of Staphylococcus aureus (S.
Atopic dermatitis (AD) is the most common chronic inflam- aureus) in AD.1,4‑7 Whether these microorganisms are colo-
matory skin disorder worldwide.1 Its pathogenesis is mul- nizers, true pathogens, or more nuanced pathobionts is still
tifactorial,2,3 and different AD treatments purport to focus not fully understood. Some studies suggest that AD skin
on one or more of the pathogenic mechanisms. The most is permissive to S. aureus colonization and more suscepti-
common treatment target is the disordered immune system ble to S. aureus virulence.1,5 In turn, S. aureus disrupts the
and resulting inflammation,2 but there is an emerging body epidermal barrier and induces Th2 response, both patho-
of research suggesting that the skin microbiome can be ma- genic mechanisms implicated in AD,5 but not all microbes
nipulated for AD treatment. have detrimental effects on the skin. Some coagulase-neg-
A growing body of literature has reinforced the relation- ative Staphylococcus species, which are deficient in lesional
ship between AD severity and alterations in the species 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 the case of disagreement, a third reviewer made the deci-
Roseomonas mucosa,10 Vitreoscilla filiformis,11 Lactobacillus sion to include or exclude a publication after reviewing the
johnsonii NCC 533,12 and Streptococcus thermophilus13 ap- study. Studies were included if they met the following in-
pear to reduce inflammation and may decrease AD severity clusion criteria: not a review or published abstract, pub-
as well. lished in a peer-reviewed journal, published in English,
Metabolic pathways provide another potential target in subjects with atopic dermatitis, and investigated the effect
altering the skin microbiome for AD treatment. Metage- of metabolites of the skin microbiome or prebiotics on
nomic studies suggest that alterations in the skin micro- atopic dermatitis. An exclusion criterion based on type of
biome’s metabolism may influence AD severity.14,15 Pre- study was not included due to the lack of research in this
biotics are substrates in the metabolic pathway that can field.
selectively increase or limit the population of beneficial
and detrimental microbes, respectively.16 Postbiotics are QUALITY ASSESSMENT
the metabolites produced by the microbiome that can in-
fluence microbial diversity and inflammation.14,15,17 Many Two independent reviewers assessed the quality of each
studies demonstrate the positive effect of oral prebiotics publication using the appropriate quality assessment tool.
and postbiotics on the gut microbiome in a variety of condi- Randomized controlled trials (RCT), quasi-experimental
tions and found potential benefit towards AD,17‑20 but few studies, and case-control studies were assessed with the re-
studies have investigated the effect of topical prebiotics on spective Joanna Briggs Institute (JBI) critical appraisal tool.
the skin microbiome of AD patients. To determine the risk of bias in an animal study, the SYR-
While the literature suggests that the skin microbiome CLE’s risk of bias tool was used (Hooijmans). Reviewers
plays an important role in the pathogenesis of AD, there judged if the publication had a low, moderate, or high risk
have not yet been larger studies analyzing the effects of al- of bias based on the criteria of each tool. In the event that
tering the metabolic pathways of the skin microbiome in there was a discrepancy in score between the two reviewers,
the setting of AD. This systematic review aims to assess a third reviewer made the final judgment for that publica-
the current literature investigating the effects of prebiotics tion.
and metabolites of the skin microbiome on AD. The present
study also evaluates the current literature’s quality to help OUTCOME MEASUREMENTS
guide investigators in designing and effectively conducting
For the purpose of this study, treatment outcome was de-
future studies such that protocols are optimized to reduce
fined as any statistically significant change in AD severity
bias.
reported by the authors. Treatment was considered clini-
cally relevant if the mean change in SCORAD was 8.7 or
MATERIALS AND METHODS higher.21 Adverse effects were identified and recorded.

The selection process is outlined in Figure 1. This sys-

RESULTS
tematic review was conducted in accordance with PRISMA
guidelines. Articles were retrieved from PubMed, Embase,
The initial search resulted in 1,124 studies. During the ini-
and Web of Science database from the earliest records to
tial screening, 112 duplicate studies were removed, and 906
March 2022 using the search formula: (“atopic dermatitis”
studies were excluded. The remaining 106 studies were as-
OR eczema) AND ((metabolite* OR metabolom* OR
sessed based on the full article, and 100 articles were ex-
metabonom* OR “metabolic profile” OR “fatty acid
cluded because they did not meet the inclusion criteria.
metabol*” OR ceramide* OR “fatty acid” OR sphingo* OR
Five articles were included in this systematic review.
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 SUMMARY OF STUDY DESIGN
OR ointment)).
Four out of the five studies were clinical trials investigating
SCREENING the effect of topical prebiotic application on atopic der-
matitis (Table 1). Of these studies, 50% (2/4) were double-
Initial screening was conducted using Rayyan. Duplicates blinded22,23 and 50% (2/4) were open-label.24,25 Only one
were deleted, and two independent reviewers assessed each study included a control.22 All four studies used SCORAD as
article’s title and abstract to exclude articles that were re- the primary evaluation method of AD severity.
views or published abstracts, not in English, not published Table 2 summarizes the study design for trials investi-
in a peer-reviewed journal, did not use human subjects, not gating the utility of topical prebiotics. Exclusion criteria
on AD, and not investigating metabolites of the skin mi- included: severe AD,24,25 psychological disease,24 immun-
crobiome or topical prebiotics. In the case of disagreement, odeficiencies,22 pregnancy,22 and simultaneous AD treat-
a third reviewer made the decision to include or exclude a ment.24,25 Two studies allowed concomitant treatment.24,
publication after reviewing the study. 25 Antao et al (2017) allowed topical corticosteroid use, but
Subsequently, two independent reviewers screened the Rigoni et al (2018) was more stringent and did not allow
remaining publications by evaluating the entire article. In any simultaneous topical or systemic treatment except for

Journal of Integrative Dermatology 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- DISCUSSION
jects rated the prebiotic emollient as very good and good,
respectively.25 Historically, there has been a debate concerning whether
AD follows an “outside-in” hypothesis or “inside-out” hy-
RISK OF BIAS pothesis.27 That is to say, whether immune dysregulation
causes skin barrier dysfunction or that skin barrier dysfunc-
The studies demonstrated varying levels of bias (Figure 2). tion is primary with resultant secondary inflammation. Re-
One study was judged to not have high risk of bias in any gardless of which aspect may come first, it is now abun-
criteria but did have moderate bias in two criteria.22 All dantly clear that AD is characterized by both intrinsic and
other studies had high risk of bias in 8% (1/12) to 25% (5/ extrinsic factors, and that the skin microbiome is intimately
20) of the graded criteria in their respective quality assess- entwined with these processes. An emerging area of re-
ment tools.24 search focuses on the metabolic pathways of the skin mi-
Table 3 summarizes the risk of bias for each criterion. crobiome and demonstrates potential treatment avenues.
The JBI checklist for RCT was used to assess two publi-
cations.22,23 Both demonstrated moderate risk of selection THERAPEUTIC POTENTIAL FOR TREATMENT
bias in randomization and allocation concealment. Of the
ALTERNATIVES
two publications, one also had high risk of attrition bias be-
cause they chose to analyze patients because they did not PREBIOTICS
include every randomized subject in their analysis.23
The JBI checklist for quasi-experimental studies was All studies found that AD severity decreased with topical
used to assess two publications.24,25 Both lacked a control prebiotic treatment, but the difference between the treat-
group and were open label. Furthermore, one study demon- ment and placebo group at endpoint was not clinically
strated moderate risk of selection bias in the baseline char- meaningful in two studies.23,25 Rigoni et al (2018) reported
acteristics of their subjects. a statistically significant change in SCORAD, and Seite et
Yu et al (2019) required evaluation based on both the JBI al (2017) found a significant SCORAD variation between
checklist for case-control and SYRCLE’s risk of bias tool be- the two groups such that the calculated decrease in SCO-
cause their publication included multiple study designs.26 RAD from initial to final treatment was significantly dif-
There was moderate risk of selection bias in subject re- ferent between patients using topical prebiotics and those
cruitment, but they appropriately matched subjects in both on placebo. These results suggest that topical prebiotics
groups. In the animal study, there was high risk of se- + emollients may provide more clinical improvement than
lection bias in randomization and allocation concealment, emollients alone.23
high risk of performance bias, and some moderate risk of Although all four studies suggest some therapeutic ben-
attrition and reporting bias. efit from topical prebiotic use, the results may not be gen-
eralizable to the entire population of AD patients because

Journal of Integrative Dermatology 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 Most commonly, studies lacked controls against selec-
moderate AD. In fact, one study had patients treated for 15 tion bias or did not adequately describe their protocol for
days between screening and baseline visit and disqualified selection. In two studies, the authors explicitly stated that
any patients whose SCORAD did not improve at least 25%, their study was double-blind and randomized, but they did
excluding patients that may be treatment resistant.23 The not detail how subjects were randomized.22,23 As a result, it
results of these current studies indicate that topical pre- is not possible to determine whether the subjects were ran-
biotics may be efficacious in reducing AD symptoms, but domized and allocated into groups appropriately to prevent
more studies are required to conclude if topical prebiotics bias. In a third study, it is unclear if the mice were random-
provide any benefit for patients with more severe or hard- ized at all.26
to-treat AD. Yu et al (2019) also did not mention if the investigators
The vehicle of a topical prebiotic may or may not in- were blinded to whether the mice in the AD model were
herently affect its efficacy, given the results of a recent given treatment or not, which could lead to performance
study that reported no difference in efficacy between lo- and detection bias.26 However, the authors attempted to
tions, creams, gels, and ointments.28 One study comparing decrease detection bias by preparing more objective out-
prebiotic body wash to body cream found no significant dif- come measurements including quantitative measurements
ference in the AD severity of the two treatment groups.24 of ear and epidermal thickness.
However, the actual ingredients within a preparation Some studies potentially had attrition bias due to their
clearly matter. A recent meta-analysis found that combin- chosen method of statistical analysis. Seite et al (2017)
ing emollients with a topical active treatment provides a and Antao et al (2017) followed a per protocol (PP) rather
clinically significant improvement in comparison to regular than intention-to-treat (ITT) protocol.23,24 With this pro-
emollients alone.29 Topical prebiotics are promising alter- tocol, data analysis only includes subjects who completed
native active ingredients that may make emollients more the treatment according to the protocol and disregards sub-
efficacious in treating AD. Studies comparing topical prebi- jects who were non-adherent or lost to follow-up. Although
otics to vehicle controls suggest that topical prebiotics may it is acceptable to use a PP principle for statistical analysis,
help decrease AD severity more than other emollients,22,23 it does have the potential to overestimate treatment effect.
but more randomized, controlled trials with larger sample
sizes are required. LIMITATIONS
The studies did not report any severe adverse effects
with topical prebiotic use. Because the results of these This study did not use any criteria that excluded studies
comparative studies suggest that topical prebiotics may based on study design as research in this field of study is
have some additional benefit over emollients, this is clearly relatively new and there were few studies found. Conse-
an approach worthy of more investigation. quently, a meta-analysis was not conducted because of the
variations in study design, including open label versus dou-
METABOLITES OF THE SKIN MICROBIOME
ble-blind studies along with differences in statistical analy-
sis methods.
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 CONCLUSION
It was able to decrease epidermal thickness, suggesting
that it may even be efficacious in patients suffering from The studies included in this systematic review suggest that
chronic AD with lichenification.26 IAId acts by modulating topical prebiotics may be a valuable therapeutic modality
expression of thymic stromal lymphopoietin (TSLP) in ker- for patients with mild-to-moderate AD. They have demon-
atinocytes, which is a cytokine implicated in Th2-mediated strated potential in modifying the skin microbiome to de-
inflammation in AD.26 These novel findings suggest that crease AD severity, but many questions remain about the
modulating microbial metabolites may be another potential specific prebiotic or prebiotics, dosing, administration, and
method of treating AD, including direct administration of optimal patient selection. Current results highlighting the
microbial metabolites in topical or systemic treatment, or influence of metabolites of the skin microbiome provide
altering the skin microbiome to promote production of spe- the basis for developing multiple new methods of AD treat-
cific beneficial metabolites. 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-
RISK OF BIAS IN THE CURRENT LITERATURE
ulations and double blinding, and further investigation is
required on the skin microbiome’s metabolism before po-
Although the current literature does not generally suffer
tential treatments can be developed.
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 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: [email protected]
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 royalties paid and is a Board member and Scientific Advi-
sory Committee Member of the National Eczema Associa-
Dr. Lio reports research grants/funding from AOBiome, Re- tion and an investor at LearnSkin. The other authors de-
generon/Sanofi Genzyme, and AbbVie; is on the speaker’s clare no conflicts of interest.
bureau for Regeneron/Sanofi Genzyme, Pfizer, Incyte, Eli
Lilly, LEO, Galderma, and L’Oreal; reports consulting/advi- FUNDING
sory boards for Almirall, ASLAN Pharmaceuticals, Bristol-
Meyers, Concerto Biosciences (Stock Options), UCB, Der- This research did not receive any specific grant from fund-
mavant, Regeneron/Sanofi Genzyme, Merck, Pfizer, LEO ing agencies in the public, commercial, or not-for-profit
Pharmaceuticals, AbbVie, Eli Lilly, Micreos, L’Oreal, Pierre- sectors.
Fabre, Johnson & Johnson, Level Ex, KPAway (Stock),
Unilever, Menlo Therapeutics, Theraplex, IntraDerm, Ex- Submitted: September 22, 2022 PDT, Accepted: June 14, 2023
eltis, AOBiome, Realm Therapeutics, Altus Labs, Galderma, PDT
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

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 11. Gueniche A, Knaudt B, Schuck E, et al. Effects of
Atopic Dermatitis. Acta Derm Venereol. nonpathogenic gram-negative bacteriumVitreoscilla
2020;100(12):adv00164. doi:10.2340/00015555-3514 filiformislysate on atopic dermatitis: a prospective,
randomized, double-blind, placebo-controlled
2. Bieber T. Atopic dermatitis: an expanding clinical study. Br J Dermatol. 2008;159(6):1357-1363.
therapeutic pipeline for a complex disease. Nat Rev doi:10.1111/j.1365-2133.2008.08836.x
Drug Discov. 2022;21(1):21-40. doi:10.1038/s41573-0
21-00266-6 12. Blanchet-Réthoré S, Bourdès V, Mercenier A,
Haddar CH, Verhoeven PO, Andres P. Effect of a
3. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, et lotion containing the heat-treated probiotic strain
al. Common loss-of-function variants of the Lactobacillus johnsonii NCC 533 on Staphylococcus
epidermal barrier protein filaggrin are a major aureus colonization in atopic dermatitis. Clin Cosmet
predisposing factor for atopic dermatitis. Nat Genet. Investig Dermatol. 2017;10:249-257. doi:10.2147/cci
2006;38(4):441-446. doi:10.1038/ng1767 d.s135529

4. Higaki S, Morohashi M, Yamagishi T, Hasegawa Y. 13. Di Marzio L, Centi C, Cinque B, et al. Effect of the
Comparative study of staphylococci from the skin of lactic acid bacteriumStreptococcus thermophiluson
atopic dermatitis patients and from healthy subjects. stratum corneum ceramide levels and signs and
Int J Dermatol. 1999;38(4):265-269. doi:10.1046/j.136 symptoms of atopic dermatitis patients. Exp
5-4362.1999.00686.x Dermatol. 2003;12(5):615-620. doi:10.1034/j.1600-06
25.2003.00051.x

5. Paller AS, Kong HH, Seed P, et al. The microbiome

in patients with atopic dermatitis. J Allergy Clin 14. Chng KR, Tay ASL, Li C, et al. Whole metagenome
Immunol. 2019;143(1):26-35. doi:10.1016/j.jaci.2018.1 profiling reveals skin microbiome-dependent
1.015 susceptibility to atopic dermatitis flare. Nat Microbiol.
2016;1(9):16106. doi:10.1038/nmicrobiol.2016.106

6. Park HY, Kim CR, Huh IS, et al. Staphylococcus

aureusColonization in Acute and Chronic Skin 15. Li W, Yosipovitch G. The Role of the Microbiome
Lesions of Patients with Atopic Dermatitis. Ann and Microbiome-Derived Metabolites in Atopic
Dermatol. 2013;25(4):410. doi:10.5021/ad.2013.25.4.4 Dermatitis and Non-Histaminergic Itch. Am J Clin
10 Dermatol. 2020;21(S1):44-50. doi:10.1007/s40257-02
0-00538-8

7. Tauber M, Balica S, Hsu CY, et al. Staphylococcus

aureus density on lesional and nonlesional skin is 16. Gibson GR, Roberfroid MB. Dietary modulation of
strongly associated with disease severity in atopic the human colonic microbiota: introducing the
dermatitis. J Allergy Clin Immunol. concept of prebiotics. J Nutr. 1995;125(6):1401-1412.
2016;137(4):1272-1274.e3. doi:10.1016/j.jaci.2015.0 doi:10.1093/jn/125.6.1401
7.052
17. Beretta S, Fabiano V, Petruzzi M, Budelli A,
8. Nakatsuji T, Chen TH, Narala S, et al. Zuccotti GV. Fermented rice flour in pediatric atopic
Antimicrobials from human skin commensal bacteria dermatitis. Dermatitis. 2015;26(2):104-106. doi:10.10
protect against Staphylococcus aureus and are 97/der.0000000000000103
deficient in atopic dermatitis. Sci Transl Med.
2017;9(378). doi:10.1126/scitranslmed.aah4680 18. Huang R, Ning H, Shen M, Li J, Zhang J, Chen X.
Probiotics for the Treatment of Atopic Dermatitis in
9. Zipperer A, Konnerth MC, Laux C, et al. Human Children: A Systematic Review and Meta-Analysis of
commensals producing a novel antibiotic impair Randomized Controlled Trials. Front Cell Infect
pathogen colonization. Nature. Microbiol. 2017;7:392. doi:10.3389/fcimb.2017.00392
2016;535(7613):511-516. doi:10.1038/nature18634
19. Liu Y, Tran DQ, Rhoads JM. Probiotics in Disease
10. Myles IA, Earland NJ, Anderson ED, et al. First-in- Prevention and Treatment. J Clin Pharmacol.
human topical microbiome transplantation with 2018;58(Suppl 10):S164-S179. doi:10.1002/jcph.1121
Roseomonas mucosa for atopic dermatitis. JCI Insight.
2018;3(9). doi:10.1172/jci.insight.120608

Journal of Integrative Dermatology 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 25. Rigoni C, Cantù AM, Gelmetti C. Observational
Effectiveness and Safety of Probiotic Supplements for clinical study of a new emollient in 26 patients with
Psoriasis: A Systematic Review and Meta-Analysis of atopic dermatitis. European Journal of Pediatric
Randomized Controlled Trials and Preclinical Trials. J Dermatology. 2018;28:218-225.
Immunol Res. 2021;2021:1-14. doi:10.1155/2021/7552
546 26. Yu J, Luo Y, Zhu Z, et al. A tryptophan metabolite
of the skin microbiota attenuates inflammation in
21. Schram ME, Spuls PhI, Leeflang MMG, Lindeboom patients with atopic dermatitis through the aryl
R, Bos JD, Schmitt J. EASI, (objective) SCORAD and hydrocarbon receptor. J Allergy Clin Immunol.
POEM for atopic eczema: responsiveness and 2019;143(6):2108-2119.e12. doi:10.1016/j.jaci.2018.1
minimal clinically important difference. Allergy. 1.036
2012;67(1):99-106. doi:10.1111/j.1398-9995.2011.027
19.x 27. Silverberg NB, Silverberg JI. Inside out or outside
in: does atopic dermatitis disrupt barrier function or
22. Noll M, Jäger M, Lux L, Buettner C, Axt- does disruption of barrier function trigger atopic
Gadermann M. Improvement of Atopic Dermatitis by dermatitis? Cutis. 2015;96(6):359-361.
Synbiotic Baths. Microorganisms. 2021;9(3):527. doi:1
0.3390/microorganisms9030527 28. Ridd MJ, Santer M, MacNeill SJ, et al.
Effectiveness and safety of lotion, cream, gel, and
23. Seite S, Zelenkova H, Martin R. Clinical efficacy of ointment emollients for childhood eczema: a
emollients in atopic dermatitis patients - relationship pragmatic, randomised, phase 4, superiority trial.
with the skin microbiota modification. Clin Cosmet Lancet Child Adolesc Health. 2022;6(8):522-532. doi:1
Investig Dermatol. 2017;10:25-33. doi:10.2147/ccid.s1 0.1016/s2352-4642(22)00146-8
21910
29. van Zuuren EJ, Fedorowicz Z, Christensen R,
24. Antão H, Passerini E, Guimarães JP, Saldanha J, Lavrijsen AP, Arents BW. Emollients and moisturisers
Coelho JD, Fortunato M. Efficacy, tolerability and for eczema. Cochrane Database Syst Rev.
acceptability of topical regimens containing the 2017;2(2):Cd012119. doi:10.1002/14651858.cd01211
prebiotic Biolin in children suffering from atopic 9.pub2
dermatitis. European Journal of Pediatric Dermatology.
2017;27:102-112.

Journal of Integrative Dermatology 10