Skin-based interventions for AD and FA prevention
An increased understanding of the role of the skin barrier and
microbiome in AD and FA pathogenesis has sparked interest in developing
skin-based interventions for allergy prevention. In the past decade,
randomized controlled trials have explored the use of prophylactic skin
interventions from early life to prevent development of AD and FA. A
Cochrane individual participant data (IPD) meta-analysis found no
benefit of a variety of skin interventions inclusive of emollients,
oils, and bathing advice overall for AD and FA
prevention.71 Another meta-analysis by Zhong et
al. found that prophylactic emollients were effective against AD
development in high-risk infants only and in those without an interval
between treatment cessation and AD outcome
assessment.72
A small study in high-risk infants who received emollients (n=11 in the
intervention arm and n=12 controls) from birth to age 6 months found
greater skin microbiota diversity, lower skin pH, and shifts inStreptococcus abundance on skin, specifically higher S.
salivarius and lower S. mitis relative abundance, compared to
controls.73 The relative abundance of S.
salivarius also correlated negatively with skin pH, suggesting that the
lowering of skin pH due to long-term emollient use may either be one of
the mechanisms through which changes in skin microbiota composition
impact AD development or that these microbial fluctuations merely occur
alongside skin barrier changes due to the intervention. Differentiating
between these possibilities could not be achieved from this study alone
and will require in-depth mechanistic studies such as in murine models
to understand the causal interactions between skin emollients,
microbiota and the skin barrier. There have also been no studies
investigating the role of the skin microbiome in FA prevention.
Skin microbiome-based
approaches for AD treatment
In contrast to broad-spectrum antibiotic therapies, repurposing
commensal and symbiotic microbes for therapeutic strategies could allow
more targeted antimicrobial effects against pathogenic microbes without
unintended collateral impact on the rest of the healthy microbiota.
Microbiome studies have now investigated numerous microbial mechanisms
by which AD skin could benefit from a microbial driven anti-inflammatory
outcome. The earliest studies utilized a bacterial lysate ofVitreoscilla filiformis as AD therapeutics. The proposed
mechanism was via host antimicrobial peptides and anti-inflammatory
effects. In a randomized, double-blind, vehicle-controlled trial, mild
AD subjects (n=75 aged 6-70 years) who received topical applications ofV. filiformis experienced improvements in SCORAD and pruritus
scores, as well as downward trend of S. aureus skin burden and
drop-outs related to lack of efficacy.74
A subsequent MRSA skin infection murine study demonstrated that CoNS
species can play an important role in activating other microbes and can
also interact with the epidermis to maintain homeostasis, and interact
or compete with S. aureus .75 S.
epidermidis is an important CoNS that has been shown to reduce skin
inflammation by regulating TLR pathways and can produce sphingomyelinase
to aid in the production of ceramides to maintain the skin barrier in
mouse and in vitro models. 76, 77 These
functions highlight the important role S. epidermidis has on the
skin and the potential that could be harnessed for AD. However, the use
of S. epidermidis without attenuation would be complex, and
potentially controversial, due to its dual roles in protection from
pathogens but also ability to stimulate inflammation or cause systemic
infections in certain situations.78
Transplantation of CoNS commensal microbe S. hominis from healthy
patients onto AD skin has been investigated. CoNS strains from healthy
volunteers produced potent AMPs that reduced S. aureus on the
skin of 5 adult AD subjects.35 A subsequent follow-up
phase 1 clinical trial using the S. hominis A9 (ShA9) strain in
54 adult AD patients demonstrated safety; however, eczema severity was
not significantly different when examined among all treated
participants.79 A post-hoc analysis showed that a
subgroup of patients who were colonized by S. aureus strains
which were sensitive to killing by ShA9 showed significant clinical
improvement compared with vehicle.79 A phase 2
clinical trial [ClinicalTrials.gov ID: NCT05177328] is ongoing to
further investigate this approach.
Another bacteriotherapy approach used Roseomonas mucosa (R.
mucosa) , a skin commensal harvested from healthy donors, as topical
therapy for AD. An open-label phase I/II trial with ten adult and 5
pediatric subjects who received skin treatment with R .mucosa demonstrated improved disease severity, reduced topical
steroid requirements, and decreased S. aureusburden.80 However, the phase II placebo-controlled
clinical trial [ClinicalTrials.gov ID: NCT04936113] which combined
three strains of R. mucosa for a live therapeutic product
(FB-401) in AD patients was terminated because it failed to demonstrate
any significant differences in patients for achieving the primary
outcome of EASI-50 (the proportion of subjects with a minimum of 50%
improvement in AD disease severity as measured by the Eczema Area and
Severity Index (EASI) score).
Additionally, there have also been recent potential biotherapeutic
approaches using the non-bacterial components of the microbiome such as
bacteriophages to target S. aureus but not S.
epidermidis .81 Bacteriophage endolysin-based
therapies have also been developed as AD therapeutics. Staphefekt SA.100
is a commercialized topically administered recombinant phage endolysin
which was able to reduce AD symptom and skin inflammation in early phase
studies. However, in a follow-on double-blinded, vehicle-controlled
randomized superiority trial in adults with non-clinically infected
moderate-to-severe AD [ClinicalTrials.gov ID: NCT02840955], the
endolysin intervention failed to demonstrate superiority over placebo in
topical steroid usage, clinical efficacy, quality of life, or S.
aureus burden.82However, this trial excluded
patients with clinically infected AD and only half of the cohort were
colonized with S. aureus prior to enrolment.
Due to the individuality of skin microbiomes at the strain level in both
healthy individuals and AD patients, bacteriotherapy may be effective
only in heavily colonized or clinically infected AD, but may be less
effective in other circumstances. It is therefore likely that these
microbial therapeutic approaches will require careful patient selection
to identify specific subgroups who will benefit from such interventions,
and optimization of therapeutic design to achieve sustained clinical
responses.79, 82