Atopic dermatitis (AD), psoriasis and xerosis are characterized by alterations in the skin barrier leading to symptoms that severely impair patients' quality of life (QoL). This multicenter, prospective study evaluated the benefits of a 4-week ceramide-containing regimen on the symptoms and QoL of patients with AD, psoriasis, or xerosis.

Clinical assessments (SCORAD, PASI, VAS), QoL and adherence to the treatment were evaluated at baseline and after 4 weeks.

A total of 312 patients (109 AD, 97 psoriasis and 106 xerosis) participated in the study; 59.3% female, mean age 42.4 years, no family history of AD, psoriasis or xerosis in ∼70% of patients. Significant clinical improvements after 4 weeks were reported: 61.2% reduction in SCORAD in AD; 65.5% reduction in PASI in psoriasis; and reductions in VAS for dryness, erythema and other symptoms in xerosis patients. QoL improved in all groups (67.2% AD, 64.7% psoriasis, 77.3% xerosis), with a significant proportion of patients reducing their concomitant treatments. Most patients adhered to the regimen, and no adverse reactions were reported.

A ceramide-containing regimen reduced the symptoms commonly associated with AD, psoriasis, and xerosis and improves patients' QoL. Limitations include the lack of control group and limiting conclusions about ceramides' contribution on effectiveness.

The skin, as the outermost layer of the body, serves as a crucial protective barrier against environmental insults while maintaining homeostasis. Atopic dermatitis (AD), a chronic inflammatory skin disorder characterized by recurrent eczema and type 2 inflammation, affects a significant global population. The pathophysiology of AD is closely linked to skin barrier dysfunction, which contributes to increased permeability, immune dysregulation, and microbial imbalances. Historically, skin barrier research has centered on the stratum corneum (SC) and intercellular lipids within the epidermis, primarily conceptualized through the "brick-and-mortar" model. However, recent advancements have revealed a more intricate interplay among various barrier components. Two key determinants of skin barrier-SC pH and SC ceramides-have gained substantial attention. Elevated SC pH leads to enhanced serine protease activity, impaired lipid metabolism, and microbiome dysbiosis, all of which exacerbate barrier dysfunction and inflammation in AD. Concurrently, alterations in SC ceramide profiles and structures compromise skin barrier function. Emerging evidence underscores the potential of SC pH and ceramides as biomarkers for disease progression and as therapeutic targets for barrier restoration. Advances in lipid analyses and non-invasive pH assessment offer promising prospects for personalized dermatologic interventions. This review explores the complex interactions of SC pH and ceramides in AD pathogenesis, discussing their implications for predicting disease flares, guiding treatment strategies, and identifying novel drug targets. A deeper understanding of these mechanisms could pave the way for next-generation therapeutic approaches in AD and other skin barrier-related disorders.

Although sensitive skin (SS) is a syndrome characterized by cutaneous hypersensitivity to environmental factors, its pathophysiology remains elusive.

We aimed to explore the characteristics of ceramides (CERs) and intercellular lipid (ICL) structures of individuals with and without facial SS and their relationship with skin hypersensitivity.

Healthy Japanese females were divided into SS or non-SS groups based on self-perception and lactic acid stinging test (LAST). Stratum corneum (SC) lipids were analyzed using a liquid chromatograph-mass spectrometer, and the orthorhombic-hexagonal lateral packing structure of ICLs was assessed using electron diffraction.

According to the mean LAST score, individuals with SS (n = 48) had mild-to-moderate skin hypersensitivity. SS exhibited not significantly but slightly impaired skin barrier function (p = 0.072) and lower levels of CER[NH], [NP], [EOS], [EOH] (all p < 0.05), and [EOP] (p = 0.073) in the SC compared with non-SS (n = 18). Notably, the CER[NP]/[NS] ratio, a marker of skin barrier function, was positively correlated with the orthorhombic-hexagonal lateral packing ratio of ICLs (p = 0.002), whereas it was negatively correlated with the LAST score (p = 0.015) and the interleukin (IL)-1 receptor antagonist/IL-1α ratio (p = 0.003) in the SC, an indicator of chronic inflammation. Moreover, corneocyte size was reduced in SS (p < 0.001), suggesting inferior SC maturation, and was positively correlated with the CER[NP]/[NS] (p < 0.001) and the orthorhombic-hexagonal ratios (p = 0.011).

Individuals with SS showed an abnormal CER profile, particularly the altered CER[NP]/[NS] ratio, which was in turn associated with disordered ICL structure and skin hypersensitivity. Abnormal epidermal turnover may be an underlying mechanism of the abnormalities.

Sensitive skin (SS) is characterized by subjective symptoms, including burning, stinging, and itching, which occur with the use of cosmetics. Over 40% of the population experiences skin sensitivity, yet no clear standards for evaluating SS have been established.

To diagnose SS by combining lactic acid sting test (LAST), skin irritation tests, and biophysical measurements with a developed questionnaire, validating the characteristics through quantitative analysis of natural moisturizing factors (NMF) and lipid profiles.

The diagnostic questionnaires were administered to 975 healthy women from Beijing and Shanghai to evaluate their skin sensitivity. Among these, 154 participants from Beijing and 153 from Shanghai underwent physiological testing, which included a patch test, LAST, and biophysical assessments. For stratum corneum (SC) sampling, D-squame tape was used, and the levels of NMFs and lipids were quantitatively analyzed using UPLC-MS/MS.

The diagnostic questionnaires, especially when combined with LAST, improved sensitivity and reduced false negatives for identifying SS. The SS group exhibited notable differences compared to the NS group, including higher hydration and lower pH on the forehead, reduced ceramide and fatty acid levels, and fewer amino acids in the stratum corneum, although skin irritation scores were not significantly different.

The combination of our diagnostic questionnaire with LAST was found to effectively distinguish key characteristics of SS. This methodology offers a valuable approach for enhancing the diagnosis and assessment of SS, which could, in turn, aid in the development of more targeted products for SS.

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that significantly impairs patients' quality of life as a result of intense itching and persistent eczematous lesions. Although AD has a multifaceted etiology-including genetic predisposition, environmental triggers, barrier dysfunction, and dysregulated immune responses-interleukin-4 (IL-4) has a recognized central role in its pathogenesis. This narrative review explores the role of IL-4 in the pathophysiology of AD, its contribution to the atopic march, and the therapeutic impact of IL-4 inhibition. IL-4 plays a critical role in skin barrier dysfunction, dysbiosis, pruritus, and inflammation, all of which contribute to the debilitating symptoms of AD. Moreover, IL-4 is implicated in other atopic conditions, such as asthma, allergic rhinitis, and food allergies, underscoring its role beyond AD and its importance in the atopic march. Recent advances in targeted therapies, particularly IL-4/IL-13 signaling inhibitors, have changed AD management. Dupilumab, an IL-4 receptor antagonist, has demonstrated significant efficacy in reducing AD symptoms and enhancing patient outcomes in both children and adults. In addition to symptomatic relief, suppressing IL-4 signaling may also offer potential for disease modification, altering AD's progression and possibly preventing the onset of other atopic conditions. This review highlights the crucial role of IL-4 as a therapeutic target in AD. By understanding the role of IL-4 in AD pathogenesis and exploring the therapeutic implications of targeting IL-4 pathways, this work can contribute to guide future research concerning treatment approaches and also emphasize the need for early and targeted interventions to mitigate disease impact and ultimately improve patient quality of life.

Ceramides in the stratum corneum (SC) are important for epidermal barrier function. We previously developed a synthetic pseudo-ceramide for medical (SPCM)-containing steroid cream [SPCM (+)]. This cream forms films on the skin surface and exerts anti-inflammatory effects through steroids. However, the preventive effects of this cream on the disruption of the skin barrier remained unclear. Therefore, in this study, we aimed to evaluate the protective role of SPCM (+) cream against atopic dermatitis (AD)-associated protease allergens on the skin in recovery from barrier-broken skin. We used three-dimensional (3D) skin and mouse models of disrupted skin barriers to evaluate the protective effect of SPCM (+) cream against V8 protease produced by Staphylococcus aureus. In NC/Nga mice with itching caused by living mites, SPCM (+) cream was repeatedly applied once a day for 2 weeks, and scratching behaviour was assessed every week using the MicroAct system. In the 3D skin model, the SPCM (+) cream directly blocked SC degradation by V8 protease of S. aureus and suppressed the expression of interleukin-36 gamma. The application of SPCM (+) cream to mite-parasitised mice suppressed scratching, reduced elevated activity of skin proteases, and inhibited upregulation of thymic stromal lymphopoietin. These beneficial effects of SPCM (+) cream were not observed with steroid creams without SPCM. These results suggest that the SPCM (+) cream is effective in relieving inflammation and itching by protecting the skin from proteases and allergens through its lamellar structure. This cream may be a promising treatment option for skin barrier disorders including AD and xerosis.

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.

The promotion of epidermal barrier dysfunction is attributed to abnormalities in the lipid-microbiome positive feedback loop which significantly influences the imbalance of the epithelial immune microenvironment (EIME) in atopic dermatitis (AD). This imbalance encompasses impaired lamellar membrane integrity, heightened exposure to epidermal pathogens, and the regulation of innate and adaptive immunity. The lipid-microbiome loop is substantially influenced by intense adaptive immunity which is triggered by abnormal loop activity and affects the loop's integrity through the induction of atypical lipid composition and responses to dysregulated epidermal microbes. Immune responses participate in lipid abnormalities within the EIME by downregulating barrier gene expression and are further cascade-amplified by microbial dysregulation which is instigated by barrier impairment.

This review examines the relationship between abnormal lipid composition, microbiome disturbances, and immune responses in AD while progressively substantiating the crosstalk mechanism among these factors. Based on this analysis, the "lipid-microbiome" positive feedback loop, regulated by immune responses, is proposed.

The review delves into the impact of adaptive immune responses that regulate the EIME, driving AD, and investigates potential mechanisms by which lipid supplementation and probiotics may alleviate AD through the up-regulation of the epidermal barrier and modulation of immune signaling. This exploration offers support for targeting the EIME to attenuate AD.

Inhibition of IL-4/IL-13-driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).

Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.

Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography-mass spectrometry proteomic analysis and targeted metabolomics.

Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both P < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (P < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants.

Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity.

In this study, skin sampling by tape stripping for lipid analysis was optimized by examining the lipid profiles of the stratum corneum (SC), focusing on the composition and levels of ceramides (Cer), diacylglycerols (DG), and triacylglycerols (TG), using nanoflow ultrahigh performance liquid chromatography-tandem mass spectrometry. Significant variations in the number and composition of the identified lipids, particularly Cer and neutral lipid species, were observed across different skin locations, including the forearm, forehead, cheek, and neck. Analysis of the layer-to-layer lipid profiles of the seven consecutive layers revealed a gradual decrease in DG and TG levels from the outermost to the innermost layers, with certain Cer subclasses showing increases in the second to fourth layers and subsequent decreases. Comparative analysis of lipid profiles from adjacent spots demonstrated statistical consistency and persistent differences between spots. Pooling layers were evaluated as an alternative method for representing SC layers, and their efficiencies were assessed by varying the number of pooled layers. We found that pooling five consecutive layers was effective in terms of the number and levels of identified lipids. Additionally, investigations into the matrix effect and extraction efficiency upon pooling layers indicated that pooling up to five layers did not significantly affect ionization suppression or reduce extraction recovery.

Changes in the level or profile of ceramides are associated with decreased stratum corneum (SC) barrier function. Topical application of a pseudo-ceramide (pCer)-containing moisturizer can improve barrier function. Additionally, pCer that absorbs into the SC may improve ceramide profiles.

We investigated the relationship between pCer absorption into the SC and SC properties and determined the efficacy of a pCer-containing spray compared with that of a commercial spray without pCer.

Patients with self-perceived dry and sensitive skin and decreased barrier function (transepidermal water loss [TEWL] > 10 g/m2h) were randomized into two groups to topically apply a pCer-containing spray (test group; N = 33) or commercial spray without pCer (control group; N = 19) twice daily as a single-blind study. SC function and ceramide properties were investigated before and after 4 weeks of application.

In the test group, the ceramide (NP)/(NS) ratio proportionally increased with the pCer application level after 4 weeks of pCer-containing spray application. In the control group, there were no changes in SC function after topical application of the commercially available spray without pCer; however, the SC water content, TEWL, SC cell area, and scaling score improved in the test group. Furthermore, the changes in TEWL in the test group were significantly negatively correlated with the pCer application level.

The efficacy of pCer-containing sprays for those who have sensitive skin with impaired barrier function was demonstrated. Furthermore, the improvement in SC barrier function induced by pCer may contribute to normalizing the SC ceramide profile.

Hyaluronan (HA) is a commonly used material in cosmetics and pharmaceuticals because of its various pharmacological activities. However, because of its large molecular weight, HA penetrates the skin very poorly and most of it remains on the skin surface. Thus, topically applied HA could not be expected to function biologically in the skin. However, we have confirmed that HA tetrasaccharides (HA4), which is the smallest unit of HA, penetrate into the skin by passive diffusion and affect epidermal metabolism. Topical treatment of HA4 rescues the epidermal damage caused by long-term UVA irradiation. Furthermore, various biological functions of HA4 to maintain healthy skin was observed in cell culture studies. This review describes the skin permeability of HA4 and how it contributes to healthy skin.

Ceramides are key components of the skin's permeability barrier. In atopic dermatitis, pathological hydrolysis of ceramide precursors - glucosylceramides and sphingomyelin - into lysosphingolipids, specifically glucosylsphingosine (GS) and sphingosine-phosphorylcholine (SPC), and free fatty acids (FFAs) has been proposed to contribute to impaired skin barrier function. This study investigated whether replacing ceramides with lysosphingolipids and FFAs in skin lipid barrier models would exacerbate barrier dysfunction. When applied topically to human stratum corneum sheets, SPC and GS increased water loss, decreased electrical impedance, and slightly disordered lipid chains. In lipid models containing isolated human stratum corneum ceramides, reducing ceramides by ≥ 30% significantly increased permeability to four markers, likely due to loss of long-periodicity phase (LPP) lamellae and phase separation within the lipid matrix, as revealed by X-ray diffraction and infrared spectroscopy. However, when the missing ceramides were replaced by lysosphingolipids and FFAs, no further increase in permeability was observed. Conversely, these molecules partially mitigated the negative effects of ceramide deficiency, particularly with 5%-10% SPC, which reduced permeability even compared to control with "healthy" lipid composition. These findings suggest that while ceramide deficiency is a key factor in skin barrier dysfunction, the presence of lysosphingolipids and FFAs does not aggravate lipid structural or functional damage, but may provide partial compensation, raising further questions about the behavior of lyso(sphingo)lipids in rigid multilamellar lipid environments, such as the stratum corneum, that warrant further investigation.

Skin barrier impairment is becoming increasingly common due to changes in lifestyle and modern living environments. Oily sensitive skin (OSS) is a condition that is characterized by an impaired skin barrier. Thus, examining the differences between OSS and healthy skin will enable a more objective evaluation of the characteristics of OSS and facilitate investigations of potential treatments. Initially, a self-assessment questionnaire was used to identify patients with OSS. Biophysical measurements and LAST scores were used to determine whether skin barrier function was impaired. Epidermal biophysical properties, including skin hydration, transepidermal water loss (TEWL), sebum content, erythema index (EI), and a* value, were measured with noninvasive instruments. We subsequently devised a noninvasive D-square sampling technique to identify changes in the skin metabolome in conjunction with an untargeted metabolomics analysis with an Orbitrap Q ExactiveTM series mass spectrometer. In the stratum corneum of 47 subjects, 516 skin metabolites were identified. In subjects with OSS, there was an increase in the abundance of 15 metabolites and a decrease in the abundance of 48 metabolites. The participants with OSS were found to have the greatest disruptions in sphingolipid and amino acid metabolism. The results revealed that an impaired skin barrier is present in patients with OSS and offers a molecular target for screening for skin barrier damage.

The skin epidermis provides a barrier that is imperative for preventing transepidermal water loss (TEWL) and protecting against environmental stimuli. The underlying molecular mechanisms for regulating barrier functions and sustaining its integrity remain unclear. RORα is a nuclear receptor highly expressed in the epidermis of normal skin. Clinical studies showed that the epidermal RORα expression is significantly reduced in the lesions of multiple inflammatory skin diseases. In this study, we investigate the central roles of RORα in stabilizing skin barrier function using mice with an epidermis-specific Rora gene deletion (RoraEKO). While lacking spontaneous skin lesions or dermatitis, RoraEKO mice exhibited an elevated TEWL rate and skin characteristics of barrier dysfunction. Immunostaining and Western blot analysis revealed low levels of cornified envelope proteins in the RoraEKO epidermis, suggesting disturbed late epidermal differentiation. In addition, an RNA-seq analysis showed the altered expression of genes related to "keratinization" and "lipid metabolism" in RORα deficient epidermis. A lipidomic analysis further uncovered an aberrant ceramide composition in the RoraEKO epidermis. Importantly, epidermal Rora ablation greatly exaggerated percutaneous allergic inflammatory responses to oxazolone in an allergic contact dermatitis (ACD) mouse model. Our results substantiate the essence of epidermal RORα in maintaining late keratinocyte differentiation and normal barrier function while suppressing cutaneous inflammation.

Psoriasis is an inflammatory skin disease associated with an impaired skin barrier. The skin barrier function is dependent on the extracellular lipid matrix which surrounds the corneocytes in the stratum corneum. Ceramides comprise essential components of this matrix. Alterations in the stratum corneum ceramide profile have been directly linked to barrier dysfunction and might be an underlying factor of the barrier impairment in psoriasis. In this study, we investigated the ceramide profile and barrier function in psoriasis. Lesional and non-lesional skin of 26 patients and 10 healthy controls were analysed using in-depth ceramide lipidomics by liquid chromatography-mass spectrometry. Barrier function was assessed by measuring transepidermal water loss. Lesional skin showed a significant decrease in the abundance of total ceramides with significant alterations in the ceramide subclass composition compared to control and non-lesional skin. Additionally, the percentage of monounsaturated ceramides was significantly increased, and the average ceramide chain length significantly decreased in lesional skin. Altogether, this resulted in a markedly different profile compared to controls for lesional skin, but not for non-lesional skin. Importantly, the reduced barrier function in lesional psoriasis correlated to alterations in the ceramide profile, highlighting their interdependence. By assessing the parameters 2 weeks apart, we are able to highlight the reproducibility of these findings, which further affirms this connection. To conclude, we show that changes in the ceramide profile and barrier impairment are observed in, and limited to, lesional psoriatic skin. Their direct correlation provides a further mechanistic basis for the concomitantly observed impairment of barrier dysfunction.

Atopic dermatitis (AD), a complex and heterogeneous chronic inflammatory skin disorder, manifests in a spectrum of clinical subtypes. The application of genomics has elucidated the role of genetic variations in predisposing individuals to AD. Transcriptomics, analyzing gene expression alterations, sheds light on the molecular underpinnings of AD. Proteomics explores the involvement of proteins in AD pathophysiology, while epigenomics examines the impact of environmental factors on gene expression. Lipidomics, which investigates lipid profiles, enhances our understanding of skin barrier functionalities and their perturbations in AD. This review synthesizes insights from these omics approaches, highlighting their collective importance in unraveling the intricate pathogenesis of AD. The review culminates by projecting future trajectories in AD research, particularly the promise of multi-omics in forging personalized medicine and novel therapeutic interventions. Such an integrated multi-omics strategy is poised to transform AD comprehension and management, steering towards more precise and efficacious treatment modalities.

Lipids are important skin components that provide, together with proteins, barrier function of the skin. Keratinocyte terminal differentiation launches unique metabolic changes to lipid metabolism that result in the predominance of ceramides within lipids of the stratum corneum (SC)-the very top portion of the skin. Differentiating keratinocytes form unique ceramides that can be found only in the skin, and generate specialized extracellular structures known as lamellae. Lamellae establish tight hydrophobic layers between dying keratinocytes to protect the body from water loss and also from penetration of allergens and bacteria. Genetic and immunological factors may lead to the failure of keratinocyte terminal differentiation and significantly alter the proportion between SC components. The consequence of such changes is loss or deterioration of skin barrier function that can lead to pathological changes in the skin. This review summarizes our current understanding of the role of lipids in skin barrier function. It also draws attention to the utility of testing SC for lipid and protein biomarkers to predict future onset of allergic skin diseases.

Atopic dermatitis (AD) is a common inflammatory skin disease, in particular among infants, and is characterized, among other things, by a modification in fatty acid and ceramide composition of the skin's stratum corneum. Palmitic acid and stearic acid, along with C16-ceramide and 2-hydroxy C16-ceramide, occur strikingly in AD. They coincide with a simultaneous decrease in very long-chain ceramides and ultra-long-chain ceramides, which form the outermost lipid barrier. Ceramides originate from cellular sphingolipid/ceramide metabolism, comprising a well-orchestrated network of enzymes involving various ELOVLs and CerSs in the de novo ceramide synthesis and neutral and acid CERase in degradation. Contrasting changes in long-chain ceramides and very long-chain ceramides in AD can be more clearly explained by the compartmentalization of ceramide synthesis. According to our hypothesis, the origin of increased C16-ceramide and 2-hydroxy C16-ceramide is located in the lysosome. Conversely, the decreased ultra-long-chain and very long-chain ceramides are the result of impaired ELOVL fatty acid elongation. The suggested model's key elements include the lysosomal aCERase, which has pH-dependent long-chain C16-ceramide synthase activity (revaCERase); the NADPH-activated step-in enzyme ELOVL6 for fatty acid elongation; and the coincidence of impaired ELOVL fatty acid elongation and an elevated lysosomal pH, which is considered to be the trigger for the altered ceramide biosynthesis in the lysosome. To maintain the ELOVL6 fatty acid elongation and the supply of NADPH and ATP to the cell, the polyunsaturated PPARG activator linoleic acid is considered to be one of the most suitable compounds. In the event that the increase in lysosomal pH is triggered by lysosomotropic compounds, compounds that disrupt the transmembrane proton gradient or force the breakdown of lysosomal proton pumps, non-HLA-classified AGEP may result.

The epidermal inflammation associated with psoriasis drives skin barrier perturbations. The skin barrier is primarily located in stratum corneum (SC). Its function depends on the SC lipid matrix of which ceramides constitute important components. Changes in the ceramide profile directly correlate to barrier function. In this study, we characterized the dynamics of the barrier function and ceramide profile of psoriatic skin during anti-Interleukin-23 therapy with guselkumab. We conducted a double-blind, randomized controlled trial in which 26 mild-to-severe plaque psoriasis patients were randomization 3:1-100 mg guselkumab or placebo for 16 weeks and barrier dynamics monitored throughout. Barrier function was measured by trans-epidermal water loss measurements. Untargeted ceramide profiling was performed using liquid chromatography-mass spectrometry after SC was harvested using tape-stripping. The barrier function and ceramide profile of lesional skin normalized to that of controls during treatment with guselkumab, but not placebo. This resulted in significant differences compared to placebo at the end of the treatment. Changes in the lesional ceramide profile during treatment correlated with barrier function and target lesion severity. Nonlesional skin remained similar throughout treatment. Guselkumab therapy restored the skin barrier in psoriasis. Concomitant correlations between skin barrier function, the ceramide profile, and disease severity demonstrate their interdependency.

Ceramides are essential lipids for skin barrier function, and various classes and species exist in the human stratum corneum (SC). To date, the relationship between skin conditions and ceramide composition in healthy individuals has remained largely unclear. In the present study, we measured six skin condition parameters (capacitance, transepidermal water loss, scaliness, roughness, multilayer exfoliation, and corneocyte cell size) for the SC of the cheeks and upper arms of 26 healthy individuals and performed correlation analyses with their SC ceramide profiles, which we measured via liquid chromatography-tandem mass spectrometry. In the cheeks, high levels and/or ratios of two free ceramide classes containing an extra hydroxyl group in the long-chain moiety and a protein-bound ceramide class containing 6-hydroxysphingosine correlated with healthy skin conditions. In contrast, the ratios of two other free ceramide classes, both containing sphingosine, and a protein-bound ceramide class containing 4,14-sphingadiene correlated with unhealthy skin conditions, as did shortening of the carbon chain of the fatty acid portion of two ceramide classes containing non-hydroxy fatty acids. Thus, our findings help to elucidate the relationship between skin conditions and ceramide composition.

Allergic diseases display significant heterogeneity in their pathogenesis. Understanding the influencing factors, pathogenesis, and advancing new treatments for allergic diseases is becoming more and more vital as currently, prevalence continues to rise, and mechanisms of allergic diseases are not fully understood. The upregulation of the hypoxia response is linked to an elevated infiltration of activated inflammatory cells, accompanied by elevated metabolic requirements. An enhanced hypoxia response may potentially contribute to inflammation, remodeling, and the onset of allergic diseases. It has become increasingly clear that the process underlying immune and stromal cell activation during allergic sensitization requires well-tuned and dynamic changes in cellular metabolism. The purpose of this review is to examine current perspectives regarding metabolic dysfunction in allergic diseases. In the past decade, new technological platforms such as "omic" techniques have been applied, allowing for the identification of different biomarkers in multiple models ranging from altered lipid species content, increased nutrient transporters, and altered serum amino acids in various allergic diseases. Better understanding, recognition, and integration of these alterations would increase our knowledge of pathogenesis and potentially actuate a novel repertoire of targeted treatment approaches that regulate immune metabolic pathways.

The lipids located in the outermost layer of the skin, the stratum corneum (SC), play a crucial role in maintaining the skin barrier function. The primary components of the SC lipid matrix are ceramides (CERs), cholesterol (CHOL), and free fatty acids (FFAs). They form two crystalline lamellar phases: the long periodicity phase (LPP) and the short periodicity phase (SPP). In inflammatory skin conditions like atopic dermatitis and psoriasis, there are changes in the SC CER composition, such as an increased concentration of a sphingosine-based CER (CER NS) and a reduced concentration of a phytosphingosine-based CER (CER NP). In the present study, a lipid model was created exclusively forming the SPP, to examine whether alterations in the CER NS:CER NP molar ratio would affect the lipid organization. Experimental data were combined with molecular dynamics simulations of lipid models containing CER NS:CER NP at ratios of 1:2 (mimicking a healthy SC ratio) and 2:1 (observed in inflammatory skin diseases), mixed with CHOL and lignoceric acid as the FFA. The experimental findings show that the acyl chains of CER NS and CER NP and the FFA are in close proximity within the SPP unit cell, indicating that CER NS and CER NP adopt a linear conformation, similarly as observed for the LPP. Both the experiments and simulations indicate that the lamellar organization is the same for the two CER NS:CER NP ratios while the SPP NS:NP 1:2 model had a slightly denser hydrogen bonding network than the SPP NS:NP 2:1 model. The simulations show that this might be attributed to intermolecular hydrogen bonding with the additional hydroxide group on the headgroup of CER NP compared with CER NS.

The skin surface is an important sample source that the metabolomics community has only just begun to explore. Alterations in sebum, the lipid-rich mixture coating the skin surface, correlate with age, sex, ethnicity, diet, exercise, and disease state, making the skin surface an ideal sample source for future noninvasive biomarker exploration, disease diagnosis, and forensic investigation. The potential of sebum sampling has been realized primarily via electrospray ionization mass spectrometry (ESI-MS), an ideal approach to assess the skin surface lipidome. However, a better understanding of sebum collection and subsequent ESI-MS analysis is required before skin surface sampling can be implemented in routine analyses. Challenges include ambiguity in definitive lipid identification, inherent biological variability in sebum production, and methodological, technical variability in analyses. To overcome these obstacles, avoid common pitfalls, and achieve reproducible, robust outcomes, every portion of the workflow-from sample collection to data analysis-should be carefully considered with the specific application in mind. This review details current practices in sebum sampling, sample preparation, ESI-MS data acquisition, and data analysis, and it provides important considerations in acquiring meaningful lipidomic datasets from the skin surface. Forensic researchers investigating sebum as a means for suspect elimination in lieu of adequate fingerprint ridge detail or database matches, as well as clinical researchers interested in noninvasive biomarker exploration, disease diagnosis, and treatment monitoring, can use this review as a guide for developing methods of best-practice.

Atopic dermatitis is characterized by chronic inflammation and dryness accompanied by severe itching. The combined use of moisturizers and topical anti-inflammatory drugs is essential for alleviating atopic dermatitis. We have developed a topical anti-inflammatory drug with a steroid and a moisturizer with heparinoid, both in lamellar structure-based formulations containing synthetic pseudo-ceramides. Here, assessed the efficacy of this combination in the treatment of atopic dermatitis.

We included 22 patients with mild to moderate atopic dermatitis and subjected them to a seven-week treatment with the test formulations, followed by a four-week post-treatment period.

Clinical findings and the quality of life of participants remarkably improved after one week of treatment. Furthermore, skin hydration and transepidermal water loss considerably improved at weeks one and three, respectively. The Cer [NP]/[NS] ratio, an indicator of epidermal turnover, substantially increased during the treatment period and remained elevated even thereafter. The improvement in stratum corneum function was distinctive in participants with lower barrier function.

These findings indicated that the combined use of the anti-inflammatory drug and moisturizer, both in lamellar structure-based formulations, is effective in treating atopic dermatitis in patients with fragile barrier function.

The skin barrier is vital for protection against environmental threats including insults caused by skin-resident microbes. Dysregulation of this barrier is a hallmark of atopic dermatitis (AD) and ichthyosis, with variable consequences for host immune control of colonizing commensals and opportunistic pathogens. While Malassezia is the most abundant commensal fungus of the skin, little is known about the host control of this fungus in inflammatory skin diseases.

In this experimental study, MC903-treated mice were colonized with Malassezia spp. to assess the host-fungal interactions in atopic dermatitis. Additional murine models of AD and ichthyosis, including tape stripping, K5-Nrf2 overexpression and flaky tail mice, were employed to confirm and expand the findings. Skin fungal counts were enumerated. High parameter flow cytometry was used to characterize the antifungal response in the AD-like skin. Structural and functional alterations in the skin barrier were determined by histology and transcriptomics of bulk skin. Finally, differential expression of metabolic genes in Malassezia in atopic and control skin was quantified.

Malassezia grows excessively in AD-like skin. Fungal overgrowth could, however, not be explained by the altered immune status of the atopic skin. Instead, we found that by upregulating key metabolic genes in the altered cutaneous niche, Malassezia acquired enhanced fitness to efficiently colonise the impaired skin barrier.

This study provides evidence that structural and metabolic changes in the dysfunctional epidermal barrier environment provide increased accessibility and an altered lipid profile, to which the lipid-dependent yeast adapts for enhanced nutrient assimilation. Our findings reveal fundamental insights into the implication of the mycobiota in the pathogenesis of common skin barrier disorders.

Atopic dermatitis and psoriasis are common chronic inflammatory diseases of high incidence that share some clinical features, including symptoms of pruritus and pain, scaly lesions, and histologically, acanthosis and hyperkeratosis. Meanwhile, they are both commonly comorbid with metabolic disorders such as obesity and diabetes, indicating that both diseases may exist with significant metabolic disturbances. Metabolomics reveals that both atopic dermatitis and psoriasis have abnormalities in a variety of metabolites, including lipids, amino acids, and glucose. Meanwhile, recent studies have highlighted the importance of the microbiome and its metabolites in the pathogenesis of atopic dermatitis and psoriasis. Metabolic alterations and microbiome dysbiosis can also affect the immune, inflammatory, and epidermal barrier, thereby influencing the development of atopic dermatitis and psoriasis. Focusing on the metabolic and microbiome levels, this review is devoted to elaborating the similarities and differences between atopic dermatitis and psoriasis, thus providing insights into the intricate relationship between both conditions.

Alterations in the secretion and composition of skin surface lipids (SSL) are closely associated with the development of acne. Lipidomics is a useful tool to analyse the SSL of different types of acne. Our previous study found that phosphatidylserine and triacylglycerols dominate SSL changes in male acne and infantile acne, respectively. However, skin surface lipids as well as specific lipids in female acne patients remain to be investigated.

To analyse and compare the SSL profile of acne women and healthy women and to discuss the involvement of differential lipids in acne development.

Systematic lipidomics approach (high-throughput UPLC-QTOF-MS technology in combination with multivariate data analysis methods) was used to analyse the variations of SSL between acne and healthy groups.

Analysis revealed significant differences in lipid content and composition between the two groups. Further analysis showed that levels of 13 individual lipids were significantly different and followed the same trend as the main class and subclasses. The largest individual contributor to the subgroup was triglycerides (TG) and phosphatidylinositol (PI). In addition, female acne patients exhibited reduced ceramide chain length (CCL) and increased levels of unsaturated fatty acids (UFAs), The changes of CCL in female acne are identical to male acne.

There was a significantly higher level of TG and PI in the SSL of female acne patients. A reduction in CCL and an increase in UFAs content might contribute to the reduced skin barrier function in acne patients. The results suggest that female acne may have different pathogenesis than male acne.

Our previous study demonstrated that our novel herbal remedy, a mixture of Asarum sieboldii, Platycodon grandiflorum, and Cinnamomum Cassia extracts, exhibits a therapeutic effect in 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice by inhibiting the Th-2 inflammatory response upon oral administration. It also ameliorated imbalances in lipid metabolism related to the skin barrier function in keratinocytes, indicating its potential as a topical agent. This study aims to further investigate the therapeutic effects and metabolic mechanisms of its topical application. The anti-atopic effect was evaluated using dermatitis scores, histopathological analysis, and immune cell factors in DNCB-induced mice. Metabolomic profiling of serum and lesional skin was conducted to elucidate the metabolic mechanisms. The topical application significantly reduced dermatitis scores, mast cell infiltration, and serum levels of immunoglobulin E (IgE), IFN-γ, interleukin (IL)-4, IL-17, and thymic stromal lymphopoietin (TSLP), demonstrating its effectiveness in treating atopic dermatitis (AD). Serum metabolomics revealed alterations in fatty acid metabolism related to the pro-inflammatory response. In lesional skin, metabolic markers associated with oxidative stress, immune regulation, and AD symptoms were restored. This study demonstrated its potential as a topical agent in suppressing Th-2 inflammatory responses and improving metabolic abnormalities related to AD symptoms, providing crucial insights for developing natural AD treatments.

The effects of fructo-oligosaccharides (FOS) on atopic dermatitis (AD) have not been determined.

In a randomized, double-blind, placebo-controlled trial, children with AD aged 24 months to 17 years received either advanced FOS containing 4.25 g of 1-kestose or a placebo (maltose) for 12 weeks.

The SCORAD and itching scores were reduced in patients treated with both FOS (all p < 0.01) and maltose (p < 0.05 and p < 0.01). Sleep disturbance was improved only in the FOS group (p < 0.01). The FOS group revealed a decreased proportion of linoleic acid (18:2) esterified omega-hydroxy-ceramides (EOS-CERs) with amide-linked shorter chain fatty acids (C28 and C30, all p < 0.05), along with an increased proportion of EOS-CERs with longer chain fatty acids (C32, p < 0.01).

FOS may be beneficial in alleviating itching and sleep disturbance, as well as improving skin barrier function in children with AD.

Atopic dermatitis (AD) is characterized by skin barrier defects that are often measured by biophysical tools that observe the functional properties of the stratum corneum (SC).

To employ in vivo infrared spectroscopy alongside biophysical measurements to analyse changes in the chemical composition of the SC in relation to AD severity.

We conducted an observational cross-sectional cohort study where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy measurements were collected on the forearm alongside surface pH, capacitance, erythema and transepidermal water loss (TEWL), combined with tape stripping, in a cohort of 75 participants (55 patients with AD stratified by phenotypic severity and 20 healthy controls). Common FLG variant alleles were genotyped.

Reduced hydration, elevated TEWL and redness were all associated with greater AD severity. Spectral analysis showed a reduction in 1465 cm-1 (full width half maximum) and 1340 cm-1 peak areas, indicative of less orthorhombic lipid ordering and reduced carboxylate functional groups, which correlated with clinical severity (lipid structure r = -0.59, carboxylate peak area r = -0.50).

ATR-FTIR spectroscopy is a suitable tool for the characterization of structural skin barrier defects in AD and has potential as a clinical tool for directing individual treatment based on chemical structural deficiencies.

Ceramides are major constituents of stratum corneum (SC) intercellular lipids involved in skin barrier function. The ratio of molecular species of ceramides and their correlation with disease severity was examined in patients with atopic dermatitis (AD). Thirty-eight patients with AD and 32 healthy controls (HCs) were assessed for transepidermal water loss, SC collection and clinical assessment. The ceramide content of different molecular species in the samples was quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Unsaturated acyl chains of both covalently bound and free ceramides [EOS] were higher in AD lesional skin than those in AD non-lesional or normal HC skin. The proportion of unsaturated acyl chains (C30:1, C32:1 and C34:1) was higher than other ceramide molecular species among covalently bound and free ceramides [EOS] in patients with AD. The proportion of unsaturated acyl chains in covalently bound ceramides was positively correlated with transepidermal water loss (r = 0.600) when considering the total number of non-lesional and lesional skin. Additionally, thymus and activation-regulated chemokine (TARC) showed a positive correlation with unsaturated acyl chains proportion in AD non-lesional (r = 0.676) and lesional (r = 0.503) skin. Our study is the first to show the increase in unsaturated acyl chains of both covalently bound and free ceramides [EOS] in lesional and non-lesional skin in AD for each molecular species. This increase is associated with dryness and impaired barrier function, which correlates with TARC levels, a marker for the degree of type 2 inflammation. We speculate that type 2 inflammation exacerbation leads to abnormal epidermal lipid metabolism in the skin of patients with AD.

The prevalence and severity of allergic diseases have increased over the last 30 years. Understanding the mechanisms responsible for these diseases is a major challenge in current allergology, as it is crucial for the transition towards precision medicine, which encompasses predictive, preventive, and personalized strategies. The urge to identify predictive biomarkers of allergy at early stages of life is crucial, especially in the context of major allergic diseases such as food allergy and atopic dermatitis. Identifying these biomarkers could enhance our understanding of the immature immune responses, improve allergy handling at early ages and pave the way for preventive and therapeutic approaches. This minireview aims to explore the relevance of three biomarker categories (proteome, microbiome, and metabolome) in early life. First, levels of some proteins emerge as potential indicators of mucosal health and metabolic status in certain allergic diseases. Second, bacterial taxonomy provides insight into the composition of the microbiota through high-throughput sequencing methods. Finally, metabolites, representing the end products of bacterial and host metabolic activity, serve as early indicators of changes in microbiota and host metabolism. This information could help to develop an extensive identification of biomarkers in AD and FA and their potential in translational personalized medicine in early life.

Seborrheic dermatitis (SD) is a chronic inflammatory skin disease characterized by erythematous papulosquamous lesions in sebum rich areas such as the face and scalp. Its pathogenesis appears multifactorial with a disbalanced immune system, Malassezia driven microbial involvement and skin barrier perturbations. Microbial involvement has been well described in SD, but skin barrier involvement remains to be properly elucidated. To determine whether barrier impairment is a critical factor of inflammation in SD alongside microbial dysbiosis, a cross-sectional study was performed in 37 patients with mild-to-moderate facial SD. Their lesional and non-lesional skin was comprehensively and non-invasively assessed with standardized 2D-photography, optical coherence tomography (OCT), microbial profiling including Malassezia species identification, functional skin barrier assessments and ceramide profiling. The presence of inflammation was established through significant increases in erythema, epidermal thickness, vascularization and superficial roughness in lesional skin compared to non-lesional skin. Lesional skin showed a perturbed skin barrier with an underlying skewed ceramide subclass composition, impaired chain elongation and increased chain unsaturation. Changes in ceramide composition correlated with barrier impairment indicating interdependency of the functional barrier and ceramide composition. Lesional skin showed significantly increased Staphylococcus and decreased Cutibacterium abundances but similar Malassezia abundances and mycobial composition compared to non-lesional skin. Principal component analysis highlighted barrier properties as main discriminating features. To conclude, SD is associated with skin barrier dysfunction and changes in the ceramide composition. No significant differences in the abundance of Malassezia were observed. Restoring the cutaneous barrier might be a valid therapeutic approach in the treatment of facial SD.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease and presents a major public health problem worldwide. It is characterized by a recurrent and/or chronic course of inflammatory skin lesions with intense pruritus. Its pathophysiologic features include barrier dysfunction, aberrant immune cell infiltration, and alterations in the microbiome that are associated with genetic and environmental factors. There is a complex crosstalk between these components, which is primarily mediated by cytokines. Epidermal barrier dysfunction is the hallmark of AD and is caused by the disruption of proteins and lipids responsible for establishing the skin barrier. To better define the role of cytokines in stratum corneum lipid abnormalities related to AD, we conducted a systematic review of biomedical literature in PubMed from its inception to 5 September 2023. Consistent with the dominant TH2 skewness seen in AD, type 2 cytokines were featured prominently as possessing a central role in epidermal lipid alterations in AD skin. The cytokines associated with TH1 and TH17 were also identified to affect barrier lipids. Considering the broad cytokine dysregulation observed in AD pathophysiology, understanding the role of each of these in lipid abnormalities and barrier dysfunction will help in developing therapeutics to best achieve barrier homeostasis in AD patients.

The barrier function of the skin is primarily located in the stratum corneum (SC), the outermost layer of the skin. The SC is composed of dead cells with highly organized lipid lamellae in the intercellular space. As the lipid matrix forms the only continuous pathway, the lipids play an important role in the permeation of compounds through the SC. The main lipid classes are ceramides (CERs), cholesterol (CHOL) and free fatty acids (FFAs). Analysis of the SC lipid matrix is of crucial importance in understanding the skin barrier function, not only in healthy skin, but also in inflammatory skin diseases with an impaired skin barrier. In this review we provide i) a historical overview of the steps undertaken to obtain information on the lipid composition and organization in SC of healthy skin and inflammatory skin diseases, ii) information on the role CERs, CHOL and FFAs play in the lipid phase behavior of very complex lipid model systems and how this knowledge can be used to understand the deviation in lipid phase behavior in inflammatory skin diseases, iii) knowledge on the role of both, CER subclasses and chain length distribution, on lipid organization and lipid membrane permeability in complex and simple model systems with synthetic CERs, CHOL and FFAs, iv) similarity in lipid phase behavior in SC of different species and complex model systems, and vi) future directions in modulating lipid composition that is expected to improve the skin barrier in inflammatory skin diseases.

Trajectories of stratum corneum (SC) lipid subclasses and their associations with infant atopic dermatitis (AD) are unclear. This study aimed to quantify the trajectories of 15 SC subclasses and carbon chain lengths and their associations with AD within 12 months.

In total, 213 newborns were enrolled at birth with nonlesional skin samples collected from the inner forearm at birth, 42 days, 3, 6, and 12 months, respectively. Lesional skin samples were collected from 120 AD patients at clinic with the disease onset within the first year of life. Mass spectrometry was applied to assess relative contents of 12 ceramide (CER), three free fatty acid (FFA) subclasses, and average carbon chain length (CCL). AD incident within 1 year old was diagnosed by dermatologists according to UK criteria.

Sixty-four (30.0%) cases of ADs occurred in the cohort. All SC lipid subclasses and CCLs, but EOP varied significantly during the first year. AD infants showed lower NP but higher NS, NH, AP, hydroxy FFA, and CCL of FFAs compared with nonaffected infants. After normalization by age, the differences remained and were more pronounced in lesional skin of clinical AD infants compared with non-ADs. NS, NH, and CCL of FFAs in lesional skin of AD infants showed positive and significant correlations with the levels of transepidermal water loss at 3 month; some evidence supports a negative correlation for NP.

We provide an overview of developmental trajectories of 15 CER and FFA subclasses across the first year of healthy infants and a link between the imbalance of some subclasses with the development of AD.

Individuals with atopic dermatitis (AD) are highly colonized by Staphylococcus aureus and are more susceptible to severe viral complications. We hypothesized that S. aureus secreted virulence factors may alter keratinocyte biology to enhance viral susceptibility through disruption of the skin barrier, impaired keratinocyte differentiation, and/or inflammation. To address this hypothesis, human keratinocytes were exposed to conditioned media from multiple S. aureus strains that vary in virulence factor production (USA300, HG003, and RN4220) or select purified virulence factors. We have identified the S. aureus enterotoxin-like superantigen SElQ, as a virulence factor of interest, since it is highly produced by USA300 and was detected on the skin of 53% of AD subjects (n = 72) in a study conducted by our group. Treatment with USA300 conditioned media or purified SElQ resulted in a significant increase in keratinocyte susceptibility to infection with vaccinia virus, and also significantly decreased barrier function. Importantly, we have previously demonstrated that keratinocyte differentiation influences susceptibility to viral infection, and our qPCR observations indicated that USA300 S. aureus and SElQ alter differentiation in keratinocytes. CRISPR/Cas9 was used to knock out CD40, a potential enterotoxin receptor on epithelial cells. We found that CD40 expression on keratinocytes was not completely necessary for SElQ-mediated responses, as measured by proinflammatory cytokine expression and barrier function. Together, these findings support that select S. aureus virulence factors, particularly SElQ, enhance the susceptibility of epidermal cells to viral infection, which may contribute to the increased cutaneous infections observed in individuals with AD. IMPORTANCE Staphylococcus aureus skin colonization and infection are frequently observed in individuals with atopic dermatitis. Many S. aureus strains belong to the clonal group USA300, and these strains produce superantigens including the staphylococcal enterotoxin-like Q (SElQ). Our studies highlight that SElQ may play a key role by altering keratinocyte differentiation and reducing barrier function; collectively, this may explain the AD-specific enhanced infection risk to cutaneous viruses. It is unclear what receptor mediates SElQ's effects on keratinocytes. We have shown that one putative surface receptor, CD40, was not critical for its effects on proinflammatory cytokine production or barrier function.