The skin is the primary barrier against environmental insults, safeguarding the body from mechanical, chemical and pathogenic threats. The frequent exposure of the skin to environmental challenges requires an immune response that incorporates a sophisticated combination of defenses. Tissue-resident lymphocytes are pivotal for skin immunity, working in tandem with commensal bacteria to maintain immune surveillance and homeostasis, as well as participating in the pathogenesis of several skin diseases. Indeed, it has been estimated that the human skin harbors nearly twice as many T cells as found in the circulation. Effective treatment of skin diseases and new therapy development require a thorough understanding of the complex interactions among skin tissue, immune cells and the microbiota, which together regulate the skin's immune balance. This Review explores the latest developments and understanding of this critical barrier organ, with a specific focus on the role of skin-resident T cells.

Everyday actions such as eating, tooth brushing or applying cosmetics inherently modulate our microbiome. Advances in sequencing technologies now facilitate detailed microbial profiling, driving intentional microbiome-targeted product development. Inspired by an academic-industry workshop held in January 2024, this review explores the oral, skin and gut microbiomes, focussing on the potential long-term implications of perturbations. Key challenges in microbiome safety assessment include confounding factors (ecological variability, host influences and external conditions like geography and diet) and biases from experimental measurements and bioinformatics analyses. The taxonomic composition of the microbiome has been associated with both health and disease, and perturbations like regular disruption of the dental biofilm are essential for preventing caries and inflammatory gum disease. However, further research is required to understand the potential long-term impacts of microbiome disturbances, particularly in vulnerable populations including infants. We propose that emerging technologies, such as omics technologies to characterize microbiome functions rather than taxa, leveraging artificial intelligence to interpret clinical study data and in vitro models to characterize and measure host-microbiome interaction endpoints, could all enhance the risk assessments. The workshop emphasized the importance of detailed documentation, transparency and openness in computational models to reduce uncertainties. Harmonisation of methods could help bridge regulatory gaps and streamline safety assessments but should remain flexible enough to allow innovation and technological advancements. Continued scientific collaboration and public engagement are critical for long-term microbiome monitoring, which is essential to advancing safety assessments of microbiome perturbations.

Host life is inextricably linked to commensal microbiota, which play a crucial role in maintaining homeostasis and immune activation. A diverse array of commensal microbiota on the skin interacts with the host, influencing the skin physiology in various ways. Early-life exposure to commensal microbiota has long-lasting effects, and disruption of the epidermal barrier or transient exposure to these microorganisms can lead to skin dysbiosis and inflammation. Several commensal skin microbiota have the potential to function as either commensals or pathogens, both influencing and being influenced by the pathogenesis of skin inflammatory diseases. Here we explore the impact of various commensal skin microbiota on the host and elucidate the interactions between skin microbiota and host systems. A deeper understanding of these interactions may open new avenues for developing effective strategies to address skin diseases.

Immune health and metabolic functions are intimately connected via diet and the microbiota. Immune cells are continuously exposed to a wide range of microbes and microbial-derived compounds, with important mucosal and systemic ramifications. Microbial fermentation of dietary components in vivo generates thousands of molecules, some of which are integral components of the molecular circuitry that regulates immune and metabolic functions. These in turn protect against aberrant inflammatory or hyper-reactive processes and promote effector immune responses that quickly eliminate pathogens, such as SARS-CoV-2. Potent tolerance mechanisms should ensure that these immune cells do not over-react to non-pathogenic factors (e.g. food proteins), while maintaining the ability to respond to infectious challenges in a robust, effective and well controlled manner. In this review we examine the factors and mechanisms that shape microbiota composition and interactions with the host immune system, their associations with immune mediated disorders and strategies for intervention.

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder in which patients experience recurrent eczematous lesions and intense itching. The colonization of Staphylococcus aureus (S. aureus) is correlated with the severity of the disease, but its role in AD development remains elusive. Using single-cell RNA sequencing, we uncovered that keratinocytes activate a distinct immune response characterized by induction of Il24 when exposed to methicillin-resistant S. aureus (MRSA). Further experiments using animal models showed that the administration of recombinant IL-24 protein worsened AD-like pathology. Genetic ablation of Il24 or the receptor Il20rb in keratinocytes alleviated allergic inflammation and atopic march. Mechanistically, IL-24 acted through its heterodimeric receptors on keratinocytes and augmented the production of IL-33, which in turn aggravated type 2 immunity and AD-like skin conditions. Overall, these findings establish IL-24 as a critical factor for onset and progression of AD and a compelling therapeutic target.

Staphylococcus aureus (S. aureus) is a Gram-positive bacterium of significant clinical importance, known for its versatility and ability to cause a wide array of infections, such as osteoarticular, pulmonary, cardiovascular, device-related, and hospital-acquired infections. This review describes the most recent evidence of the pathogenic potential of S. aureus, which is commonly part of the human microbiota but can lead to severe infections. The prevalence of pathogenic S. aureus in hospital and community settings contributes to substantial morbidity and mortality, particularly in individuals with compromised immune systems. The immunopathogenesis of S. aureus infections involves intricate interactions with the host immune and non-immune cells, characterized by various virulence factors that facilitate adherence, invasion, and evasion of the host's defenses. This review highlights the complexity of S. aureus infections, ranging from mild to life-threatening conditions, and underscores the growing public health concern posed by multidrug-resistant strains, including methicillin-resistant S. aureus (MRSA). This article aims to provide an updated perspective on S. aureus-related infections, highlighting the main diseases linked to this pathogen, how the different cell types, virulence factors, and signaling molecules are involved in the immunopathogenesis, and the future perspectives to overcome the current challenges to treat the affected individuals.

Human skin acts as a physical barrier to prevent the entry of pathogenic microbes while simultaneously providing a home for commensal bacteria and fungi. Microbiome sequencing studies have demonstrated the unappreciated diversity and selectivity of these microbes. Functional studies have demonstrated the impact of specific strains to tune the immune system, sculpt the microbial community, provide colonization resistance, and promote epidermal barrier integrity. Recent studies have integrated the microbiome, immunity, and tissue integrity to understand their interplay in common disorders such as atopic dermatitis. In this Review, we explore microbiome shifts associated with cutaneous disorders with an eye toward how the microbiome can be mined to identify new therapeutic opportunities.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. AD is a highly complex disease with different subtypes. Many elements of AD pathophysiology have been described, but if/how they interact with each other or which mechanisms are important in which patients is still unclear. Langerhans cells (LCs) are antigen-presenting cells (APCs) in the epidermis. Depending on the context, they can act either pro- or anti-inflammatory. Many different studies have investigated LCs in the context of AD and found them to be connected to all major mechanisms of AD pathophysiology. As APCs, LCs recruit other immune cells and shape the immune response, especially adaptive immunity via polarization of T cells. As sentinel cells, LCs are primary sensors of the skin microbiome and are important for the decision of immunity versus tolerance. LCs are also involved with the integrity of the skin barrier by influencing tight junctions. Finally, LCs are important cells in the neuro-immune crosstalk in the skin. In this review, we provide an overview about the many different roles of LCs in AD. Understanding LCs might bring us closer to a more complete understanding of this highly complex disease. Potentially, modulating LCs might offer new options for targeted therapies for AD patients.

Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood.

We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity.

We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures.

S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21.

CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation. Scratching-induced inflammation required pain-sensing nociceptors, the neuropeptide substance P, and the mast cell receptor MrgprB2. Scratching also increased cutaneous inflammation and augmented host defense to superficial Staphylococcus aureus infection. Thus, through the activation of nociceptor-driven neuroinflammation, scratching both exacerbated allergic skin disease and provided protection from S. aureus, reconciling the seemingly paradoxical role of scratching as a pathological process and evolutionary adaptation.

The skin microbiome is disrupted in atopic dermatitis (AD). Existing research focuses on moderate to severe, unmedicated disease.

We sought to investigate metagenomic- and culture-based bacterial strain-level differences in mild, medicated AD and the effects these have on human keratinocytes (HKs).

Skin swabs from anterior forearms were collected from 20 pediatric participants (11 participants with AD sampled at lesional and nonlesional sites and 9 age- and sex-matched controls). Participants had primarily mild to moderate AD and maintained medication use. Samples were processed for microbial metagenomic sequencing and bacterial isolation. Isolates identified as Staphylococcus aureus were tested for enterotoxin production. HK cultures were treated with cell-free conditioned media from representative Staphylococcus species to measure barrier effects.

Metagenomic sequencing identified significant differences in microbiome composition between AD and control groups. Differences were seen at the species and strain levels for Staphylococci, with S aureus found only in participants with AD and differences in Staphylococcus epidermidis strains between control and AD swabs. These strains showed differences in toxin gene presence, which was confirmed in vitro for S aureus enterotoxins. The strain from the participant with the most severe AD produced enterotoxin B levels more than 100-fold higher than the other strains (P < .001). Strains also displayed differential effects on HK metabolism and barrier function.

Strain-level differences in toxin genes from Staphylococcus strains may explain varying effects on HK, with S aureus and non-aureus strains negatively affecting viability and barrier function. These differences are likely important in AD pathogenesis.

Atopic dermatitis, commonly referred to as atopic eczema, is a persistent inflammatory skin disorder that predominantly manifests in children but may endure into adulthood. Its clinical management poses challenges due to the absence of a definitive cure, and its prevalence varies across ethnicities, genders, and geographic locations. The epigenetic landscape of AD includes changes in DNA methylation, changes in histone acetylation and methylation, and regulation by non-coding RNAs. These changes affect inflammatory and immune mechanisms, and research has identified AD-specific variations in DNA methylation, particularly in the affected epidermis. Histone modifications, including acetylation, have been associated with the disruption of skin barrier function in AD, suggesting the potential therapeutic benefit of histone deacetylase inhibitors such as belinostat. Furthermore, non-coding RNAs, particularly microRNAs and long non-coding RNAs (lncRNAs), have been implicated in modulating various cellular processes central to AD pathogenesis. Therapeutic implications in AD include the potential use of DNA methylation inhibitors and histone deacetylase inhibitors to correct aberrant methylation patterns and modulate gene expression related to immune responses and skin barrier functions. Additionally, the emerging role of lncRNAs suggests the possibility of using small interfering RNAs or antisense oligonucleotides to inhibit lncRNAs and adjust their regulatory impact on gene expression. In conclusion, the importance of epigenetic elements in AD is becoming increasingly clear as studies highlight the contribution of DNA methylation, histone modifications and, control by non-coding RNAs to the onset and progression of the disease. Understanding these epigenetic changes provides valuable insights for developing targeted therapeutic strategies.

Staphylococcus aureus is a leading cause of death by infectious diseases worldwide. Treatment of S aureus infections is difficult due to widespread antibiotic resistance, necessitating alternative approaches and measures for prevention of infection. Because S aureus infections commonly arise from asymptomatic colonisation, decolonisation is considered a key approach for their prevention. Current decolonisation procedures include antibiotic-based and antiseptic-based eradication of S aureus from the nose and skin. However, despite the widespread implementation and partial success of such measures, S aureus infection rates remain worrisome, and resistance to decolonisation agents is on the rise. In this Review we outline the epidemiology and mechanisms of S aureus colonisation, describe how colonisation underlies infection, and discuss current and novel approaches for S aureus decolonisation, with a focus on the latest findings on probiotic strategies and the intestinal S aureus colonisation site.

Atopic dermatitis (AD), a prevalent skin condition often complicated by microbial infection, poses a significant challenge in identifying the responsible pathogen for its effective management. However, a reliable, safe tool for pinpointing the source of these infections remains elusive. In this study, a novel on-site pathogen detection that combines chemically functionalized nanotopology with genetic analysis is proposed to capture and analyze pathogens closely associated with severe atopic dermatitis. The chemically functionalized nanotopology features a 3D hierarchical nanopillar array (HNA) with a functional polymer coating, tailored to isolate target pathogens from infected skin. This innovative nanotopology demonstrates superior pathogenic capture efficiency, favorable entrapment patterns, and non-cytotoxicity. An HNA-assembled stick is utilized to directly retrieve bacteria from infected skin samples, followed by extraction-free quantitative loop-mediated isothermal amplification (direct qLAMP) for validation. To mimic human skin conditions, porcine skin is employed to successfully capture Staphylococcus aureus, a common bacterium exacerbating AD cases. The on-site detection method exhibits an impressive detection limit of 103 cells mL-1. The HNA-assembled stick represents a promising tool for on-site detection of bacteria associated with atopic dermatitis. This innovative approach enables to deepen the understanding of AD pathogenesis and open avenues for more effective management strategies for chronic skin conditions.

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.

Natural products are widely used in the pharmaceutical and cosmetics industries due to their high-value bioactive compounds, which make for "greener" and more environmentally friendly ingredients. These natural compounds are also considered a safer alternative to antibiotics, which may result in antibiotic resistance as well as unfavorable side effects. The development of cosmeceuticals, which combine the cosmetic and pharmaceutical fields to create skincare products with therapeutic value, has increased the demand for unique natural resources. The objective of this review is to discuss the biological properties of extracts derived from larvae of the black soldier fly (BSF; Hermetia illucens), the appropriate extraction methods, and the potential of this insect as a novel active ingredient in the formulation of new cosmeceutical products. This review also addresses the biological actions of compounds originating from the BSF, and the possible association between the diets of BSF larvae and their subsequent bioactive composition.

A literature search was conducted using PubMed and Google Scholar to identify and evaluate the various biological properties of the BSF.

One such natural resource that may be useful in the cosmeceutical field is the BSF, a versatile insect with numerous potential applications due to its nutrient content and scavenging behavior. Previous research has also shown that the BSF has several biological properties, including antimicrobial, antioxidant, anti-inflammatory, and wound healing effects.

Given the range of biological activities and metabolites possessed by the BSF, this insect may have the cosmeceutical potential to treat a number of skin pathologies.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease characterized by epidermal barrier dysfunction, immune system dysregulation, and skin microbiome alterations. Skin microbiome studies in AD have demonstrated that disease flares are associated with microbial shifts, particularly Staphylococcus aureus predominance. AD-associated S. aureus strains differ from those in healthy individuals across various genomic loci, including virulence factors, adhesion proteins, and proinflammatory molecules-which may contribute to complex microbiome barrier-immune system interactions in AD. Different microbially based treatments for AD have been explored, and their future therapeutic successes will depend on a deeper understanding of the potential microbial contributions to the disease.

Atopic dermatitis (AD) is a chronic recurrent inflammatory skin disease with a bipolar age distribution in childhood, adolescence and middle adulthood. Up to 50% of AD patients show ocular involvement, which can be potentially sight threatening. Clinically, the majority of cases present with atopic blepharo(kerato)conjunctivitis or atopic keratoconjunctivitis (AKC); other clinical variants from this group of inflammatory ocular surface diseases are keratoconjunctivitis vernalis in childhood and adolescence and allergic conjunctivitis. In addition to the aforementioned blepharitis, keratitis and conjunctivitis, AD is also associated with eyelid involvement with subsequent eyelid malposition, limbal insufficiency with the development of pseudopterygia, (chronic) cicatrizing conjunctivitis with symblephara formation and fornix shortening, as well as ocular surface malignancies such as conjunctival intraepithelial neoplasia (CIN) and squamous cell carcinoma. In addition, an association with AD or AKC has been described for keratoconus. Whereas the therapy of AD in dermatology has made revolutionary advances in recent years through the use of biologicals, the primary use of these biologicals in ophthalmological complications is still very hesitant. Treatment here is often provided using topical steroids and calcineurin inhibitors. The following article summarises recent developments in basic and clinical dermatological research and discusses them in the context of current concepts for ophthalmological therapy.

Skin is a vital barrier tissue of the body. Immune responses in the skin must be precisely controlled, which would otherwise cause severe disease conditions such as psoriasis, atopic dermatitis, or pathogenic infection. Research evidence has increasingly demonstrated the essential roles of neural innervations, i.e., sensory and sympathetic signals, in modulating skin immunity. Notably, neuropathic changes of such neural structures have been observed in skin disease conditions, implicating their direct involvement in various pathological processes. An in-depth understanding of the mechanism underlying skin neuropathy and its immunomodulatory effects could help reveal novel entry points for therapeutic interventions. Here, we summarize the neuroimmune interactions between neuropathic events and skin immunity, highlighting the current knowledge and future perspectives of this emerging research frontier.

Innate lymphoid cells (ILCs) are a diverse population of lymphocytes classified into natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and ILCregs, broadly following the cytokine secretion and transcription factor profiles of classical T cell subsets. Nonetheless, the ILC lineage does not have rearranged antigen-specific receptors and possesses distinct characteristics. ILCs are found in barrier tissues such as the skin, lungs, and intestines, where they play a role between acquired immune cells and myeloid cells. Within the skin, ILCs are activated by the microbiota and, in turn, may influence the microbiome composition and modulate immune function through cytokine secretion or direct cellular interactions. In particular, ILC3s provide epithelial protection against extracellular bacteria. However, the mechanism by which these cells modulate skin health and homeostasis in response to microbiome changes is unclear. To better understand how ILC3s function against microbiota perturbations in the skin, we propose a role for these cells in response to Cutibacterium acnes, a predominant commensal bacterium linked to the inflammatory skin condition, acne vulgaris. In this article, we review current evidence describing the role of ILC3s in the skin and suggest functional roles by drawing parallels with ILC3s from other organs. We emphasize the limited understanding and knowledge gaps of ILC3s in the skin and discuss the potential impact of ILC3-microbiota crosstalk in select skin diseases. Exploring the dialogue between the microbiota and ILC3s may lead to novel strategies to ameliorate skin immunity.

Eczema is a chronic, relapsing skin condition commonly managed by emollients and topical corticosteroids. Prevalence of use and demand for effective botanical therapies for eczema is high worldwide, however, clinical evidence of benefit is limited for many currently available botanical treatment options. Robustly-designed and adequately powered randomised controlled trials (RCTs) are essential to determine evidence of clinical benefit. This protocol describes an RCT that aims to investigate whether a mānuka oil based emollient cream, containing 2% ECMT-154, is a safe and effective topical treatment for moderate to severe eczema.

This multicentre, single-blind, parallel-group, randomised controlled trial aims to recruit 118 participants from community pharmacies in Aotearoa New Zealand. Participants will be randomised 1:1 to receive topical cream with 2% ECMT-154 or vehicle control, and will apply assigned treatment twice daily to affected areas for six weeks. The primary outcome is improvement in subjective symptoms, assessed by change in POEM score. Secondary outcomes include change in objective symptoms assessed by SCORAD (part B), PO-SCORAD, DLQI, and treatment acceptability assessed by TSQM II and NRS.

Recruitment through community pharmacies commenced in January 2022 and follow up will be completed by mid-2023. This study aims to collect acceptability and efficacy data of mānuka oil based ECMT-154 for the treatment of eczema. If efficacy is demonstrated, this topical may provide an option for a novel emollient treatment. The community-based design of the trial is anticipated to provide a generalisable result.

Ethics approval was obtained from Central Health and Disability Ethics Committee (reference: 2021 EXP 11490). Findings of the study will be disseminated to study participants, published in peer-reviewed journal and presented at scientific conferences.

Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12621001096842. Registered on August 18, 2021 ( https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382412&isReview=true ).

2.1 (Dated 18/05/2022).

Dupilumab is a fully humanized IgG4 monoclonal antibody, inhibiting IL-4 and IL-13 signaling, which are the main cytokines involved in type 2 inflammatory diseases. Its introduction was a breakthrough in the treatment of moderate-to-severe atopic dermatitis, but it is also used in other inflammatory diseases, including asthma, eosinophilic esophagitis and chronic rhinosinusitis with nasal polyposis. Recent advances in the understanding of inflammatory pathways have revealed that Th2-type inflammation is involved in a wider range of diseases than previously thought. The aim of our review is to examine off-label therapeutic indications of dupilumab, including bullous dermatoses (pemphigus, bullous pemphigoid) and alopecia areata, and to investigate its potential applications in cancer patients on anti-PD1 therapy.

Cutaneous colonization with Staphylococcus aureus (SA) is frequently observed in patients with atopic dermatitis. SA produces a wide variety of bacterial toxins, among which δ-toxin was found to induce degranulation of mast cells. Degranulation of mast cells could enhance bacterial clearance and protection from future SA infection but lead to exacerbation of atopic dermatitis. Because it remains to be determined how δ-toxin triggers degranulation, we investigated δ-toxin-induced changes in murine bone marrow-derived cultured mast cells in this study. We found that δ-toxin-induced degranulation could be classified into two phases, an early Ca2+-independent and a late Ca2+-dependent phase. Recent studies suggest that NOD-like receptor family, pyrin domain containing 3 is involved in the degranulation of mast cells, raising a possibility that leakage of K+ induced by δ-toxin is involved in the Ca2+-independent phase. However, Ca2+-independent degranulation remains unchanged although Ca2+-influx and degranulation induced by δ-toxin were significantly suppressed in the presence of high concentrations of K+. Because actin depolymerization was reported to induce degranulation in the absence of Ca2+ in the permeabilized rat peritoneal mast cells, a slow but steady decrease in the amount of filamentous actin observed here may be involved in Ca2+-independent degranulation induced by δ-toxin. Although Mas-related G protein-coupled receptor (MRGPR) X2 in humans and Mrgprb2 in mice are regarded as the receptors responsible for immunoglobulin E-independent degranulation, δ-toxin-induced degranulation remained unchanged in Mrgprb2-/- mast cells. Our findings pave the way for identification of the target receptors of δ-toxin.

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

This chapter will describe infectious complications of atopic dermatitis, including bacterial, viral, and fungal infections and the evolving understanding of the relationship between atopic dermatitis and infectious disease. The underlying immunological dysregulation and poor skin barrier function associated with atopic dermatitis not only increase the likelihood of infectious complications but also lend atopic dermatitis skin vulnerable to flares induced by environmental triggers. Thus, this chapter will also highlight the impact of common external environmental agents on precipitating flares of disease. Lastly, this chapter will discuss complications that can arise from treatments and the association of atopic dermatitis with more serious conditions such as lymphoma.

The skin is the largest organ in the human body, and histologically consists of the epidermis, dermis and subcutaneous tissue. Humans maintain a cooperative symbiotic relationship with their skin microbiota, a complex community of bacteria, fungi and viruses that live on the surface of the skin, and which act as a barrier to protect the body from the inside and outside. The skin is a 'habitat' and vast 'ecosystem' inhabited by countless microbes; as such, relationships have been forged through millions of years of coevolution. It is not surprising then that microbes are key participants in shaping and maintaining essential physiological processes. In addition to maintaining barrier function, the unique symbiotic microbiota that colonizes the skin increases the immune response and provides protection against pathogenic microbes. This review examines our current understanding of skin microbes in shaping and enhancing the skin barrier, as well as skin microbiome-host interactions and their roles in skin diseases, such as atopic dermatitis (AD). We also report on the current status of AD therapeutic drugs that target the skin microbiome, related research on current therapeutic strategies, and the limitations and future considerations of skin microbiome research. In particular, as a future strategy, we discuss the need for a skin-on-a-chip-based microphysiological system research model amenable to biomimetic in vitro studies and human skin equivalent models, including skin appendages.

Studies have demonstrated that bleach baths improve atopic dermatitis (AD) severity; however, the effects on itch, skin barrier, and cutaneous microbial composition are less clear. We examined whether bleach baths reduce itch, normalize skin barrier function, reduce S. aureus absolute abundance, and increase microbial diversity in adults with AD who were colonized with S. aureus on their non-lesional skin. This was an open label, non-randomized, controlled trial performed at a single academic center. Fifteen AD and five non-atopic healthy controls (NA) were instructed to take two bleach baths (0.005% NaClO; 5-10 min duration) per week for a total of 12 weeks as add-on therapy. Adults 18 to 65 years (inclusive) with mild to severe AD were recruited with EASI score > 6.0, S. aureus culture positivity, access to a bathtub, and ability and willingness to maintain current topical or systemic treatments. They were evaluated at baseline (before bleach baths), 6 weeks, and 12 weeks after the intervention of twice-weekly bleach baths. Efficacy measurements included EASI as well as 5-D Pruritus and ItchyQoL™. Transepidermal water loss (TEWL) and stratum corneum (SC) integrity assay were performed to assess the skin barrier. Skin dysbiosis was measured by S. aureus cultivation, S. aureus abundance (qPCR of thermonuclease gene), and V1-V3 16S rRNA gene sequencing on non-lesional and lesional AD skin. After 12 weeks of bleach baths, 8/15 (53.3%) AD subjects achieved an EASI50 and a significant reduction in itch as measured by 5-D pruritus and Itchy QoL. Eighty-seven percent reported improvements in sleep quality. At study entry, AD subjects had higher non-lesional TEWL values than NA subjects, and only AD subjects experienced a reduction with bleach baths (p = 0.006). Similarly, SC integrity improved as early as 6 weeks after bleach baths in AD subjects. Notably, bleach baths had no significant effect on S. aureus culture-positivity, qPCR absolute abundance, or microbial diversity. The addition of twice-weekly bleach baths improves investigator-assessed AD severity, patient-reported pruritus and sleep as well as physiological measures of skin barrier function in adult AD subjects while having no effect on qualitative and quantitative measures of cutaneous S. aureus. Trial Registration: ClinicalTrials.gov Identifier: NCT01996150, Date of registration: November 27th, 2013.

The skin is a tightly regulated, balanced interface that maintains our integrity through a complex barrier comprising physical or mechanical, chemical, microbiological, and immunological components. The skin's microbiota affect various properties, one of which is the establishment and maintenance of the physical barrier. This is achieved by influencing multiple processes, including keratinocyte differentiation, stratum corneum formation, and regulation of intercellular contacts. In this review, we summarize the potential contribution of Cutibacterium acnes to these events and outline the contribution of bacterially induced barrier defects to the pathogenesis of acne vulgaris. With the combined effects of a Westernized lifestyle, microbial dysbiosis, epithelial barrier defects, and inflammation, the development of acne is very similar to that of several other multifactorial diseases of barrier organs (e.g., inflammatory bowel disease, celiac disease, asthma, atopic dermatitis, and chronic rhinosinusitis). Therefore, the management of acne requires a complex approach, which should be taken into account when designing novel treatments that address not only the inflammatory and microbial components but also the maintenance and strengthening of the cutaneous physical barrier.

Following descriptive studies on skin microbiota in health and disease, mechanistic studies on the interplay between skin and microbes are on the rise, for which experimental models are in great demand. Here, we present a novel methodology for microbial colonization of organotypic skin and analysis thereof.

An inoculation device ensured a standardized application area on the stratum corneum and a homogenous distribution of bacteria, while preventing infection of the basolateral culture medium even during prolonged culture periods for up to 2 weeks at a specific culture temperature and humidity. Hereby, host-microbe interactions and antibiotic interventions could be studied, revealing diverse host responses to various skin-related bacteria and pathogens.

Our methodology is easily transferable to a wide variety of organotypic skin or mucosal models and different microbes at every cell culture facility at low costs. We envision that this study will kick-start skin microbiome studies using human organotypic skin cultures, providing a powerful alternative to experimental animal models in pre-clinical research. Video Abstract.

Staphylococci are major causes of infections in mammals. Mammals are colonized by diverse staphylococcal species, often with moderate to strong host specificity, and colonization is a common source of infection. Staphylococcal infections of animals not only are of major importance for animal well-being but have considerable economic consequences, such as in the case of staphylococcal mastitis, which costs billions of dollars annually. Furthermore, pet animals can be temporary carriers of strains infectious to humans. Moreover, antimicrobial resistance is a great concern in livestock infections, as there is considerable antibiotic overuse, and resistant strains can be transferred to humans. With the number of working antibiotics continuously becoming smaller due to the concomitant spread of resistant strains, alternative approaches, such as anti-virulence, are increasingly being investigated to treat staphylococcal infections. For this, understanding the virulence mechanisms of animal staphylococcal pathogens is crucial. While many virulence factors have similar functions in humans as animals, there are increasingly frequent reports of host-specific virulence factors and mechanisms. Furthermore, we are only beginning to understand virulence mechanisms in animal-specific staphylococcal pathogens. This review gives an overview of animal infections caused by staphylococci and our knowledge about the virulence mechanisms involved.

Antibiotic resistance remains a global threat to human and animal health. Staphylococcus aureus is an opportunistic pathogen that causes minor to life-threatening infections. The widespread use of antibiotics in the clinical, veterinary, and agricultural setting combined with the increasing prevalence of antibiotic-resistant S. aureus strains makes it abundantly clear that alternatives to antibiotics are urgently needed. Bacteriocins represent one potential alternative therapeutic. They are antimicrobial peptides that are produced by bacteria that are generally nontoxic and have a relatively narrow target spectrum, and they leave many commensals and most mammalian cells unperturbed. Multiple studies involving bacteriocins (e.g., nisin, epidermicin, mersacidin, and lysostaphin) have demonstrated their efficacy at eliminating or treating a wide variety of S. aureus infections in animal models. This review provides a comprehensive and updated evaluation of animal studies involving bacteriocins and highlights their translational potential. The strengths and limitations associated with bacteriocin treatments compared with traditional antibiotic therapies are evaluated, and the challenges that are involved with implementing novel therapeutics are discussed.

Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin conditions worldwide. Interleukin (IL)-33 and IL-31 have been recognized to be major players who act synergistically in the pathogenesis and maintenance of different chronic inflammatory conditions and pruritic skin disorders, including AD and PsO, and their potential role as therapeutic targets is being thoroughly investigated. The bidirectional interplay between dysbiosis and immunological changes has been extensively studied, but there is still debate regarding which of these two factors is the actual causative culprit behind the aetiopathological process that ultimately leads to AD and PsO. We conducted a literature review on the Pubmed database assessing articles of immunology, dermatology, microbiology and allergology with the aim to strengthen the hypothesis that dysbiosis is at the origin of the IL-33/IL-31 dysregulation that contributes to the pathogenesis of AD and PsO. Finally, we discussed the therapeutic options currently in development for the treatment of these skin conditions targeting IL-31, IL-33 and/or the microbiome.

We characterized the population of Staphylococcus aureus from patients with atopic dermatitis (AD) in terms of (i) genetic diversity, (ii) presence and functionality of genes encoding important virulence factors: staphylococcal enterotoxins (sea, seb, sec, sed), toxic shock syndrome 1 toxin (tsst-1), and Panton-Valentine leukocidin (lukS/lukF-PV) by spa typing, PCR, drug resistance profile determination, and Western blot. We then subjected the studied population of S. aureus to photoinactivation based on a light-activated compound called rose bengal (RB) to verify photoinactivation as an approach to effectively kill toxin-producing S. aureus. We have obtained 43 different spa types that can be grouped into 12 clusters, indicating for the first-time clonal complex (CC) 7 as the most widespread. A total of 65% of the tested isolates had at least one gene encoding the tested virulence factor, but their distribution differed between the group of children and adults, and between patients with AD and the control group without atopy. We detected a 3.5% frequency of methicillin-resistant strains (MRSA) and no other multidrug resistance. Despite genetic diversity and production of various toxins, all isolates tested were effectively photoinactivated (bacterial cell viability reduction ≥ 3 log10 units) under safe conditions for the human keratinocyte cell line, which indicates that photoinactivation can be a good option in skin decolonization. IMPORTANCE Staphylococcus aureus massively colonizes the skin of patients with atopic dermatitis (AD). It is worth noting that the frequency of detection of multidrug-resistant S. aureus (MRSA) in AD patients is higher than the healthy population, which makes treatment much more difficult. Information about the specific genetic background of S. aureus accompanying and/or causing exacerbations of AD is of great importance from the point of view of epidemiological investigations and the development of possible treatment options.

The opportunistic pathogen Staphylococcus aureus frequently colonizes the inflamed skin of people with atopic dermatitis (AD) and worsens disease severity by promoting skin damage. Here, we show, by longitudinally tracking 23 children treated for AD, that S. aureus adapts via de novo mutations during colonization. Each patient's S. aureus population is dominated by a single lineage, with infrequent invasion by distant lineages. Mutations emerge within each lineage at rates similar to those of S. aureus in other contexts. Some variants spread across the body within months, with signatures of adaptive evolution. Most strikingly, mutations in capsule synthesis gene capD underwent parallel evolution in one patient and across-body sweeps in two patients. We confirm that capD negativity is more common in AD than in other contexts, via reanalysis of S. aureus genomes from 276 people. Together, these findings highlight the importance of the mutation level when dissecting the role of microbes in complex disease.

Atopic dermatitis (AD) is a multifactorial, chronic relapsing disease associated with genetic and environmental factors. Among skin microbes, Staphylococcus aureus and Staphylococcus epidermidis are associated with AD, but how genetic variability and staphylococcal strains shape the disease remains unclear. We investigated the skin microbiome of an AD cohort (n = 54) as part of a prospective natural history study using shotgun metagenomic and whole genome sequencing, which we analyzed alongside publicly available data (n = 473). AD status and global geographical regions exhibited associations with strains and genomic loci of S. aureus and S. epidermidis. In addition, antibiotic prescribing patterns and within-household transmission between siblings shaped colonizing strains. Comparative genomics determined that S. aureus AD strains were enriched in virulence factors, whereas S. epidermidis AD strains varied in genes involved in interspecies interactions and metabolism. In both species, staphylococcal interspecies genetic transfer shaped gene content. These findings reflect the staphylococcal genomic diversity and dynamics associated with AD.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a high prevalence worldwide, including countries from Asia, Africa, and Latin America, and in different ethnic groups. In recent years, more attention has been placed on the heterogeneity of AD associated with multiple factors, including a patient's ethnic background, resulting in an increasing body of clinical, genetic, epidemiologic, and immune-phenotypic evidence that delineates differences in AD among racial groups. Filaggrin (FLG) mutations, the strongest genetic risk factor for the development of AD, are detected in up to 50% of European and 27% of Asian AD patients, but very rarely in Africans. Th2 hyperactivation is a common attribute of all ethnic groups, though the Asian endotype of AD is also characterized by an increased Th17-mediated signal, whereas African Americans show a strong Th2/Th22 signature and an absence of Th1/Th17 skewing. In addition, the ethnic heterogeneity of AD may hold important therapeutic implications as a patient's genetic predisposition may affect treatment response and, thereby, a tailored strategy that better targets the dominant immunologic pathways in each ethnic subgroup may be envisaged. Nevertheless, white patients with AD represent the largest ethnicity enrolled and tested in clinical trials and the most treated in a real-world setting, limiting investigations about safety and efficacy across different ethnicities. The purpose of this review is to describe the heterogeneity in the pathophysiology of AD across ethnicities and its potential therapeutic implications.

Despite its harsh and dry environment, human skin is home to diverse microbes, including bacteria, fungi, viruses, and microscopic mites. These microbes form communities that may exist at the skin surface, deeper skin layers, and within microhabitats such as the hair follicle and sweat glands, allowing complex interactions with the host immune system. Imbalances in the skin microbiome, known as dysbiosis, have been linked to various inflammatory skin disorders, including atopic dermatitis, acne, and psoriasis. The roles of abundant commensal bacteria belonging to Staphylococcus and Cutibacterium taxa and the fungi Malassezia, where particular species or strains can benefit the host or cause disease, are increasingly appreciated in skin disorders. Furthermore, recent research suggests that the interactions between microorganisms and the host's immune system on the skin can have distant and systemic effects on the body, such as on the gut and brain, known as the "skin-gut" or "skin-brain" axes. Studies on the microbiome in skin disease have typically relied on 16S rRNA gene sequencing methods, which cannot provide accurate information about species or strains of microorganisms on the skin. However, advancing technologies, including metagenomics and other functional 'omic' approaches, have great potential to provide more comprehensive and detailed information about the skin microbiome in health and disease. Additionally, inter-species and multi-kingdom interactions can cause cascading shifts towards dysbiosis and are crucial but yet-to-be-explored aspects of many skin disorders. Better understanding these complex dynamics will require meta-omic studies complemented with experiments and clinical trials to confirm function. Evolving how we profile the skin microbiome alongside technological advances is essential to exploring such relationships. This review presents the current and emerging methods and their findings for profiling skin microbes to advance our understanding of the microbiome in skin disease.

Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease linked to skin microbiome dysbiosis with reduced bacterial diversity and elevated relative abundance of Staphylococcus aureus (S. aureus).

We aimed to characterize the yet incompletely understood association between the skin microbiome and patients' demographic and clinical cofactors in relation to AD severity.

The skin microbiome in 48 adult moderate-to-severe AD patients was investigated using next-generation deep sequencing (16S rRNA gene, V1-V3 region) followed by denoising (DADA2) to obtain amplicon sequence variant (ASV) composition.

In lesional skin, AD severity was associated with S. aureus relative abundance (r_S  = 0.53, p < 0.001) and slightly better with the microbiome diversity measure Evenness (r_S  = -0.58, p < 0.001), but not with Richness. Multiple regression confirmed the association of AD severity with microbiome diversity, including Shannon (in lesional skin, p < 0.001), Evenness (in non-lesional skin, p = 0.015) or S. aureus relative abundance (p < 0.012), and with patient's IgE levels (p < 0.001), race (p < 0.032), age (p < 0.034) and sex (p = 0.012). The lesional model explained 62% of the variation in AD severity, and the non-lesional model 50% of the variation.

Our results specify the frequently reported "reduced diversity" of the AD-related skin microbiome to reduced Evenness, which was in turn mainly driven by S. aureus relative abundance, rather than to a reduced microbiome Richness. Finding associations between AD severity, the skin microbiome and patient's cofactors is a key aspect in developing new personalized AD treatments, particularly those targeting the AD microbiome.