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The skin microbiome is an extensive community of bacteria, fungi, mites, viruses and archaea colonizing the skin. Fluctuations in the composition of the skin microbiome have been observed in atopic dermatitis (AD) and food allergy (FA), particularly in early life, established disease, and associated with therapeutics. However, AD is a multifactorial disease characterized by skin barrier aberrations modulated by genetics, immunology, and environmental influences, thus the skin microbiome is not the sole feature of this disease. Future research should focus on mechanistic understanding of how early-life skin microbial shifts may influence AD and FA onset, to guide potential early intervention strategies or as microbial biomarkers to identify high-risk infants who may benefit from possible microbiome-based biotherapeutic strategies. Harnessing skin microbes as AD biotherapeutics is an emerging field, but more work is needed to investigate whether this approach can lead to sustained clinical responses., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Atopic dermatitis (AD) is a common chronic skin condition in children (15-20%) that can significantly impair their quality of life. As a result of its relapsing nature and enrichment of Staphylococcus aureus during flares, clinical management can include eradicating S aureus from the skin of children; however, this does not extend to their healthy caregivers, who are potential reservoirs., Objective: Our aim was to understand skin microbiome sharing and microbial features in children with AD and their healthy adult caregivers., Methods: We utilized whole-metagenome profiling at 4 body sites (volar forearm, antecubital fossae, cheeks, and lesions) in combination with sequencing of S aureus isolates to characterize a cohort of children with AD and their healthy caregivers (n = 30 families) compared to matched pairs from control households (n = 30 families)., Results: Metagenomic analysis revealed distinct microbiome configurations in the nonlesional skin of AD children and their healthy caregivers versus controls, which were sufficient to accurately predict case-control status (area under the receiver operating characteristic curve > 0.8). These differences were accompanied by significant microbiome similarity between children and their caregivers, indicating that microbiome sharing may play a role in recurrent disease flares. Whole-genome comparisons with high-quality S aureus isolate genomes (n = 55) confirmed significant strain sharing between AD children and their caregivers and AD-specific enrichment of strains expressing enterotoxins Q and K/K2., Conclusion: Our results highlight the distinctive skin microbiome features of healthy caregivers for children with AD and support their inclusion in strategies for the treatment of recurrent pediatric AD., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Observational studies suggest an increased risk of eczema in children living in hard versus soft water areas, and there is, therefore, an interest in knowing whether softening water may prevent eczema. We evaluated the feasibility of a parallel-group assessor-blinded pilot randomized controlled trial to test whether installing a domestic ion-exchange water softener before birth in hard water areas reduces the risk of eczema in infants with a family history of atopy., Methods: Pregnant women living in hard water areas (>250 mg/L calcium carbonate) in and around London UK, were randomized 1:1 antenatally to either have an ion-exchange water softener installed in their home or not (ie to continue to receive usual domestic hard water). Infants were assessed at birth and followed up for 6 months. The main end-points were around feasibility, the primary end-point being the proportion of eligible families screened who were willing and able to be randomized. Clinical end-points were evaluated including frequency of parent-reported doctor-diagnosed eczema and visible eczema on skin examination. Descriptive analyses were conducted, and no statistical testing was performed as this was a pilot study., Results: One hundred and forty-nine families screened were eligible antenatally and 28% (41/149) could not have a water softener installed due to technical reasons or lack of landlord approval. Eighty of 149 (54%) were randomized, the primary end-point. Two participants withdrew immediately after randomization, leaving 39 participants in each arm (78 total). Attrition was 15% (12/78) by 6 months postpartum. All respondents (n = 69) to the study acceptability questionnaire reported that the study was acceptable. Fifty-six of 708 (7.9%) water samples in the water softener arm were above the hard water threshold of 20 mg/L CaCO 3 . At 6 months of age 27/67 infants (40%) developed visible eczema, 12/36 (33%) vs. 15/31 (48%) in the water softener and control groups, respectively, difference -15% (95% CI -38, 8.3%), with most assessments (≥96%) remaining blinded. Similarly, a lower proportion of infants in the water softener arm had parent-reported, doctor-diagnosed eczema by 6 months compared to the control arm, 6/17 (35%) versus 9/19 (47%), difference -12% (95% CI -44, 20%)., Conclusion: A randomized controlled trial of water softeners for the prevention of atopic eczema in high-risk infants is feasible and acceptable., Trial Registration: NCT03270566 (clinicaltrials.gov)., (© 2021 John Wiley & Sons Ltd.)

Background: Atopic dermatitis (AD) is a common skin disease affecting up to 20% of the global population, with significant clinical heterogeneity and limited information about molecular subtypes and actionable biomarkers. Although alterations in the skin microbiome have been described in subjects with AD during progression to flare state, the prognostic value of baseline microbiome configurations has not been explored., Objective: Our aim was to identify microbial signatures on AD skin that are predictive of disease fate., Methods: Nonlesional skin of patients with AD and healthy control subjects were sampled at 2 time points separated by at least 4 weeks. Using whole metagenome analysis of skin microbiomes of patients with AD and control subjects (n = 49 and 189 samples), we identified distinct microbiome configurations (dermotypes A and B). Blood was collected for immunophenotyping, and skin surface samples were analyzed for correlations with natural moisturizing factors and antimicrobial peptides., Results: Dermotypes were robust and validated across 2 additional cohorts (63 individuals), with strong enrichment of subjects with AD in dermotype B. Dermotype B was characterized by reduced microbial richness, depletion of Cutibacterium acnes, Dermacoccus and Methylobacterium species, individual-specific outlier abundance of Staphylococcus species (eg, S epidermidis, S capitis, S aureus), and enrichment in metabolic pathways (eg, branched chain amino acids and arginine biosynthesis) and virulence genes (eg, β-toxin, δ-toxin) that defined a pathogenic ecology. Skin surface and circulating host biomarkers exhibited a distinct microbial-associated signature that was further reflected in more severe itching, frequent flares, and increased disease severity in patients harboring the dermotype B microbiome., Conclusion: We report distinct clusters of microbial profiles that delineate the role of microbiome configurations in AD heterogeneity, highlight a mechanism for ongoing inflammation, and provide prognostic utility toward microbiome-based disease stratification., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The skin microbiome plays a central role in inflammatory skin disorders such as atopic dermatitis (AD). In AD patients, an imbalance between pathogenic Staphylococcus aureus (S. aureus) and resident skin symbionts creates a state of dysbiosis which induces immune dysregulation and impairs skin barrier function. There are now exciting new prospects for microbiome-based interventions for AD prevention. In the hopes of achieving sustained control and management of disease in AD patients, current emerging biotherapeutic strategies aim to harness the skin microbiome associated with health by restoring a more diverse symbiotic skin microbiome, while selectively removing pathogenic S. aureus. Examples of such strategies are demonstrated in skin microbiome transplants, phage-derived anti-S. aureus endolysins, monoclonal antibodies, and quorum sensing (QS) inhibitors. However, further understanding of the skin microbiome and its role in AD pathogenesis is still needed to understand how these biotherapeutics alter the dynamics of the microbiome community; to optimize patient selection, drug delivery, and treatment duration; overcome rapid recolonization upon treatment cessation; and improve efficacy to allow these therapeutic options to eventually reach routine clinical practice., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive., Objective: To understand the underlying cause of barrier defect, we investigated aberrant expression of specific microRNAs (miRNAs) in AD. Delineating the molecular mechanism of dysregulated miRNA network, we focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD., Methods: A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently downregulated miRNA in AD. Using in silico prediction combined with experimental validation, we characterized downstream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin., Results: miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6. By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation. In AD lesional skin, miR-335 expression is aberrantly lost. SOX6 is abnormally expressed throughout the epidermis, where it impairs skin barrier development. We demonstrate that miR-335 is epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that can restore epidermal miR-335 expression and rescue the defective skin barrier in AD., Conclusion: Belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Atopic eczema affects 20% of UK children, and environmental factors are important in its aetiology. Several observational studies suggest an increased risk of atopic eczema in children living in hard water areas. The Softened Water for Eczema Prevention pilot trial tests the feasibility of installing domestic ion-exchange water softeners around the time of birth to reduce the risk of atopic eczema in children with a family history of atopy. A further aim is to explore the pathophysiological mechanisms for this in an embedded mechanistic study., Methods and Analysis: Multicentre parallel group assessor-blinded randomised controlled pilot trial. Participants are newborn babies (n=80) living in a hard water (>250 mg/L calcium carbonate) area at risk of developing atopic eczema because of a family history of atopy. Participants will be randomised prior to birth in a 1:1 ratio. The intervention group will have an ion-exchange water softener installed prior to birth. The control group will receive their usual domestic hard water supply. Follow-up will be until 6 months of age. Data will be collected at birth (baseline), 1, 3 and 6 months of age. The main outcome is the proportion of eligible families screened who are willing and able to be randomised. Several secondary feasibility and clinical endpoints will also be evaluated, alongside mechanistic outcomes. Data will be analysed on an intention-to-treat basis. There will be no hypothesis testing for the clinical outcomes. Study acceptability will be evaluated through semistructured interviews., Ethics and Dissemination: This study has been reviewed and given a favourable opinion by the North West-Liverpool East Research Ethics Committee (Ref: 17/NW/0661). The results of the study will be reported at international conferences and in peer-reviewed scientific journals. We will send participating families a summary of the pilot trial results., Trial Registration Number: NCT03270566., Competing Interests: Competing interests: CF has received investigator-led research funding from Sanofi. His department has received clinical trial funding from Sanofi and AbbVie to test novel therapeutics in patients with paediatric atopic eczema. MJC is an investigator and consultant for Regeneron, Sanofi Genzyme, Pfizer, Leo, Galapagos, Novartis, Boots, L’Oreal, Dermavant, Menlo, Reckitt Benckiser, Oxagen, Johnson & Johnson, Hyphens, Astellas, Amlar, AbbVie, Galderma and Procter & Gamble. Harvey Water Softeners (HWS) contributed to the design and operational running of the study (supply and installation of water softeners, testing of water samples). Final decisions around design and conduct were made independently by investigators. HWS will not be involved in the analysis or interpretation of the results., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)