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Staphylococcus aureus colonizes patients with atopic dermatitis (AD) and exacerbates disease by promoting inflammation. The present study investigated the safety and mechanisms of action of Staphylococcus hominis A9 (ShA9), a bacterium isolated from healthy human skin, as a topical therapy for AD. ShA9 killed S. aureus on the skin of mice and inhibited expression of a toxin from S. aureus (psmα) that promotes inflammation. A first-in-human, phase 1, double-blinded, randomized 1-week trial of topical ShA9 or vehicle on the forearm skin of 54 adults with S. aureus-positive AD (NCT03151148) met its primary endpoint of safety, and participants receiving ShA9 had fewer adverse events associated with AD. Eczema severity was not significantly different when evaluated in all participants treated with ShA9 but a significant decrease in S. aureus and increased ShA9 DNA were seen and met secondary endpoints. Some S. aureus strains on participants were not directly killed by ShA9, but expression of mRNA for psmα was inhibited in all strains. Improvement in local eczema severity was suggested by post-hoc analysis of participants with S. aureus directly killed by ShA9. These observations demonstrate the safety and potential benefits of bacteriotherapy for AD.

SUMMARY Netherton syndrome (NS) is a monogenic skin disease resulting from loss of function of lymphoepithelial Kazal-type-related protease inhibitor (LEKTI-1). In this study we examine if bacteria residing on the skin are influenced by the loss of LEKTI-1 and if interaction between this human gene and resident bacteria contributes to skin disease. Shotgun sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis). Isolates of either species from NS subjects are able to induce skin inflammation and barrier damage on mice. These microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. These findings demonstrate the critical need for maintaining homeostasis of host and microbial proteases to prevent a human skin disease., Graphical Abstract, In Brief Williams et al. show how an abnormal skin microbiome promotes inflammation associated with Netherton syndrome, a monogenic disorder in the human protease inhibitor SPINK5. Subjects with Netherton syndrome have excess colonization by S. aureus or S. epidermidis that then produce and promote increased protease production in the epidermis.

Importance Atopic dermatitis (AD) can be negatively affected by Staphylococcus aureus. The skin microbiome of AD is deficient in coagulase-negative Staphylococcus (CoNS) that can kill S aureus. Objective To evaluate if the antimicrobial-producing CoNS (CoNS-AM+) of a patient with AD can be autologously reintroduced to the same patient to inhibit survival of S aureus and improve clinical outcomes. Design, setting, and participants This double-blind, vehicle-controlled, single-center randomized clinical trial of 11 adult patients with moderate to severe AD who were randomized to receive either an autologous CoNS-AM+ (n = 5) or the vehicle (n = 6) was conducted between April 2016 and May 2018. The data were analyzed from May 2018 to July 2019. Interventions Autologous CoNS-AM+ was isolated from swabs that were obtained from the nonlesional skin of each patient with AD, expanded by culture, and then reapplied topically to the forearms at a concentration of 107 colony-forming units/g. Main outcomes and measures The primary end point of this study was to assess S aureus abundance after 1 week of application of autologous CoNS-AM+ on patients with AD by culture-based and DNA-based methods. The secondary end points were to assess the safety and clinical outcomes. Results Eleven patients (4 men [36.4%] and 7 women [63/6%]) were recruited based on the inclusion criteria. There were no serious adverse events in groups treated with autologous CoNS-AM+ or the vehicle. Staphylococcus aureus colonization on lesional skin at the end of treatment on patients who were treated with autologous CoNS-AM+ (mean of log10 ratio to baseline, -1.702; 95% CI, -2.882 to -0.523) was reduced by 99.2% compared with vehicle treatment (mean of log10 ratio to baseline, 0.671; 95% CI, -0.289 to 1.613; P = .01) and persisted for 4 days after treatment (CoNS-AM+: mean of log10 ratio to baseline, -1.752; 95% CI, -3.051 to -0.453; vehicle: mean of log10 ratio to baseline, -0.003; 95% CI, -1.083 to 1.076; P = .03). Importantly, local Eczema Area And Severity Index scores that were assessed at day 11 on patients who received CoNS-AM+ (mean of percentage change, -48.45; 95% CI, -84.34 to -12.55) were significantly improved compared with vehicle treatment (mean of percentage change, -4.52; 95% CI, -36.25 to 27.22; P = .04). Conclusions and relevance The data from this randomized clinical trial suggest that bacteriotherapy with an autologous strain of skin commensal bacteria can safely decrease S aureus colonization and improve disease severity. Although larger studies will be needed, this personalized approach for S aureus reduction may provide an alternative treatment for patients with AD beyond antibiotics, immunosuppression, and immunomodulation. Trial registration ClinicalTrials.gov Identifier: NCT03158012.

SUMMARY Staphylococcus aureus is a major human bacterial pathogen responsible for deep tissue skin infections. Recent observations have suggested that rapid, localized digestion of hyaluronic acid in the extracellular matrix (ECM) of the dermis may influence bacterial invasion and tissue inflammation. In this study we find that cell migration-inducing protein (Cemip) is the major inducible gene responsible for hyaluronan catabolism in mice. Cemip−/− mice failed to digest hyaluronan and had significantly less evidence of infection after intradermal bacterial challenge by S. aureus. Stabilization of large-molecular-weight hyaluronan enabled increased expression of cathelicidin antimicrobial peptide (Camp) that was due in part to enhanced differentiation of preadipocytes to adipocytes, as seen histologically and by increased expression of Pref1, PPARg, and Adipoq. Cemip−/− mice challenged with S. aureus also had greater IL-6 expression and neutrophil infiltration. These observations describe a mechanism for hyaluronan in the dermal ECM to regulate tissue inflammation and host antimicrobial defense., In Brief In this paper, Dokoshi et al. describe how the mammalian hyaluronidase Cemip is induced in the dermis during S. aureus infection. Cemip digests hyaluronan in the skin to regulate reactive adipogenesis and subsequent antimicrobial activity and skin inflammation., Graphical Abstract

Background Staphylococcus aureus and Staphylococcus epidermidis are the most abundant bacteria found on the skin of patients with atopic dermatitis (AD). S aureus is known to exacerbate AD, whereas S epidermidis has been considered a beneficial commensal organism. Objective In this study, we hypothesized that S epidermidis could promote skin damage in AD by the production of a protease that damages the epidermal barrier. Methods The protease activity of S epidermidis isolates was compared with that of other staphylococcal species. The capacity of S epidermidis to degrade the barrier and induce inflammation was examined by using human keratinocyte tissue culture and mouse models. Skin swabs from atopic and healthy adult subjects were analyzed for the presence of S epidermidis genomic DNA and mRNA. Results S epidermidis strains were observed to produce strong cysteine protease activity when grown at high density. The enzyme responsible for this activity was identified as EcpA, a cysteine protease under quorum sensing control. EcpA was shown to degrade desmoglein-1 and LL-37 in vitro, disrupt the physical barrier, and induce skin inflammation in mice. The abundance of S epidermidis and expression of ecpA mRNA were increased on the skin of some patients with AD, and this correlated with disease severity. Another commensal skin bacterial species, Staphylococcus hominis, can inhibit EcpA production by S epidermidis. Conclusion S epidermidis has commonly been regarded as a beneficial skin microbe, whereas S aureus has been considered deleterious. This study suggests that the overabundance of S epidermidis found on some atopic patients can act similarly to S aureus and damage the skin by expression of a cysteine protease.