Despite the increasing knowledge about factors shaping the human microbiome, the host genetic factors that modulate the skin-microbiome interactions are still largely understudied. This contrasts with recent efforts to characterize host genes that influence the gut microbiota. Here, we investigated the effect of genetics on skin microbiota across three different skin microenvironments through meta-analyses of genome-wide association studies (GWAS) of two population-based German cohorts. We identified 23 genome-wide significant loci harboring 30 candidate genes involved in innate immune signaling, environmental sensing, cell differentiation, proliferation and fibroblast activity. However, no locus passed the strict threshold for study-wide significance (P < 6.3 × 10⁻¹⁰for 80 features included in the analysis). Mendelian randomization (MR) analysis indicated the influence of staphylococci on eczema/dermatitis and suggested modulating effects of the microbiota on other skin diseases. Finally, transcriptional profiles of keratinocytes significantly changed after in vitro co-culturing withStaphylococcus epidermidis, chosen as a representative of skin commensals. Seven candidate genes from the GWAS were found overlapping with differential expression in the co-culturing experiments, warranting further research of the skin commensal and host genetic makeup interaction.

Background: Atopic dermatitis (AD) is driven by the interplay between a dysfunctional epidermal barrier and a skewed cutaneous immune dysregulation. As part of the complex skin barrier dysfunction, abnormalities in lipid organization and microbiome composition have been described. We set out to systematically investigate the composition of the stratum corneum lipidome, skin microbiome and skin physiology parameters at three different body sites in patients with AD and healthy volunteers.Methods: We analysed tape strips from different body areas obtained from 10 adults with AD and 10 healthy volunteers matched for FLG mutation status for 361 skin lipid species using the Metabolon mass spectrometry platform. 16S rRNA data were available from all probands.Results: Our study showed that the lipid composition differs significantly between body sites and between AD patients and healthy individuals. Ceramide species NS was significantly higher in AD patients compared to healthy volunteers and was also higher in AD patients with a FLG mutation compared to AD patients without a FLG mutation. The correlation analysis of skin lipid alterations with the microbiome showed that Staphylococcus colonization in AD is positively correlated with ceramide subspecies AS, ADS, NS and NDS.Conclusion: This is the first study to reveal site‐specific lipid alterations and correlations with the skin microbiome in AD.

Background Growing evidence suggests that atopic dermatitis (AD) is associated with an increased risk of depressive disorders and anxiety. However, existing studies were observational and may uncover correlations but cannot easily disentangle non‐causal or reverse‐causal associations because these associations could be confounded and may not reflect true causal relationships. Objectives We carried out a 2‐sample Mendelian randomization (MR) study to examine the potential effect of AD on the risk of depressive disorders and anxiety. Methods Genetic instruments from the largest available genome‐wide association study (GWAS) for AD (10,788 cases, 30,047 controls) were used to investigate the relation to broad depression (170,756 cases, 329,443 controls), major depressive disorder (MDD) (30,603 cases, 143,916 controls) and anxiety (5,580 cases, 11,730 controls). A set of complementary approaches were carried out to assess horizontal pleiotropy and related potential caveats occurring in MR studies. Results We observed no causal impact of AD on the risk of depressive disorders and anxiety, with close‐to‐zero effect estimates. The inverse weighted method revealed no associations of AD on broad depression (OR=1.014, P=0.4307), probable MDD (OR=1.004, P=0.5681), ICD‐9/10‐based MDD (OR=1.001, P=0.4659) or anxiety (OR=1.097, P=0.1801). Conclusions In summary, this MR study does not support a causal effect of AD on depression and anxiety.

Background The human skin offers diverse ecosystems for microbial symbionts. However, the factors shaping skin‐microbiome interactions are still insufficiently characterized. This contrasts to the broader knowledge about the factors influencing the gut microbiota. Objectives We aimed to investigate major patterns of associations of host traits, lifestyle, and environmental factors with skin bacteria in two German populations. Methods This is a cross‐sectional study with 647 participants from two population‐based German cohorts, PopGen (n=294) and KORA FF4 (n=353), totaling 1794 skin samples. The V1‐V2 regions of the 16S rRNA gene were sequenced. Associations were tested with two bacterial levels, community (beta‐diversity) and 16S rRNA gene amplicon sequence variants (ASVs). Results We validated known associations of the skin microbiota with skin microenvironment, age, body mass index (BMI) and sex. These factors were associated with beta diversity and abundance of ASVs in PopGen, which was largely replicated in KORA FF4. Most intriguingly, dietary macronutrients and total dietary energy were associated with several ASVs. ASVs were also associated with smoking, alcohol consumption, skin pH, skin type, transepidermal water loss, education, and several environmental exposures, including hours spent outdoors. Associated ASVs included members of the genera Propionibacterium, Corynebacterium, and Staphylococcus. Discussion We expand the current understanding of factors associated with the skin bacterial community. We show the association of diet with the skin bacteria. Finally, we hypothesize that the skin microenvironment and the host physiology would shape the skin bacterial community at greater extent in comparison to a single skin physiological feature, lifestyle and environmental exposition.

Emerging evidence suggests oxidative stress plays a role in the pathophysiology of both atopic dermatitis (AD) and psoriasis (PSO). We established in vitro models of AD and PSO skin, and characterized these models in regard to their oxidative stress state. Both AD and PSO model keratinocytes exhibited elevated reactive oxygen species (ROS) levels and accumulated more DNA damage than control cells after oxidative stress induced by 250 µmol/L H₂O₂. Elevated ROS levels and DNA damage accumulation could be inhibited by the NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI). Further, immunofluorescence analysis revealed the presence of both NOX1 and NOX4 in keratinocytes. By inhibiting NOX1, stress‐related signalling cascades and elevated ROS levels could be abrogated, and survival of AD and PSO cells improved. Taken together, this study reveals that inhibition of NOX inhibition could abrogate elevated oxidative stress in a 2D model of AD and PSO.