The Microbiome and the Human Immune Response in Atopic Dermatitis : Exploring Microbial Targets for Personalized Treatment

Atopic dermatitis (AD) is a common chronic inflammatory skin disease. An impaired skin barrier and altered immune mechanisms are considered the two major players in AD inflammation. Alterations in the microbiome are an established finding in AD, but its role in the pathogenesis is still poorly understood. In this thesis we primarily aimed to characterize the microbial composition of the skin, nose and gut in pediatric patients with mild to severe AD. Our second aim was to estimate the prevalence of Staphylococcus (S.) aureus in patients with AD and to study the humoral immune response against S. aureus. Additionally, we designed a clinical study to test the effect of a new endolysin-based therapy that specifically targets S. aureus in AD. The results of the research described in this thesis show the relevance of the microbiome, in particular S. aureus in AD. The thesis describes associations between S. aureus, but also other microbes on the skin and in the nose with AD disease severity. Thereby, S. aureus seems to evoke immune responses via different mechanisms, as a directly stimulating antigen and as an allergen. The results of this thesis may contribute to the development of treatment strategies that target the microbiome in AD. Further prospective cohort studies and experimental research are needed to clarify the role of the microbiome in AD

Het microbioom als target voor behandeling

Het menselijk lichaam is gekoloniseerd met een diversiteit aan micro-organismen, waaronder bacteriën, virussen, schimmels en gisten. Het microbioom bevindt zich op verschillende plekken van het lichaam, waarbij de samenstelling aan micro-organismen uniek is per locatie. De micro-organismen bevinden zich niet alleen aan de oppervlakte, maar ook in het lichaam waar ze interacties aangaan met humane cellen en een belangrijke rol in fysiologische processen hebben. De afgelopen jaren is er toenemende interesse in het humane microbioom in relatie tot verschillende ziektes, waaronder constitutioneel eczeem (CE)

Fecal microbiome and food allergy in pediatric atopic dermatitis: A cross-sectional pilot study

Background: Exposure to microbes may be important in the development of atopic disease. Atopic diseases have been associated with specific characteristics of the intestinal microbiome. The link between intestinal microbiota and food allergy has rarely been studied, and the gold standard for diagnosing food allergy (double-blind placebo-controlled food challenge [DBPCFC]) has seldom been used. We aimed to distinguish fecal microbial signatures for food allergy in children with atopic dermatitis (AD). Methods: Pediatric patients with AD, with and without food allergy, were included in this cross-sectional observational pilot study. AD was diagnosed according to the UK Working Party criteria. Food allergy was defined as a positive DBPCFC or a convincing clinical history, in combination with sensitization to the relevant food allergen. Fecal samples were analyzed using 16S rRNA microbial analysis. Microbial signature species, discriminating between the presence and absence food allergy, were selected by elastic net regression. Results: Eighty-two children with AD (39 girls) with a median age of 2.5 years, and 20 of whom were diagnosed with food allergy, provided fecal samples. Food allergy to peanut and cow's milk was the most common. Six bacterial species from the fecal microbiome were identified, that, when combined, distinguished between children with and without food allergy: Bifidobacterium breve, Bifidobacterium pseudocatenulatum, Bifidobacterium adolescentis, Escherichia coli, Faecalibacterium prausnitzii, and Akkermansia muciniphila (AUC 0.83, sensitivity 0.77, specificity 0.80). Conclusions: In this pilot study, we identified a microbial signature in children with AD that discriminates between the absence and presence of food allergy. Future studies are needed to confirm our findings

Molecular clustering of genes related to the atopic syndrome

Background: The atopic syndrome consists of heterogeneous manifestations, in which multiple associated genetic loci have recently been identified. It is hypothesized that immune dysregulation plays a role in the pathogenesis. In primary immunodeficiency diseases (PIDs), which are often monogenic immunodysregulation disorders, the atopic syndrome is a frequently occurring comorbidity. Based on the genetic defects in PIDs, novel gene/pathway-targeted therapies have been evaluated, which could be relevant in the atopic syndrome as well. Therefore, we aimed to define subclasses within the atopic syndrome based on the expression profiles of immune cell lineages of healthy mice. Methods: Overlap between known atopy-related genes as described in the Human Gene Mutation Database and disease-causing genes of monogenic PIDs was evaluated. Clusters of atopy-related genes were based on the overlap in their co-expressed genes using the gene expression profiles of immune cell lineages of healthy mice from the Immunological Genome Project. We analyzed pathways involved in the atopic syndrome using Ingenuity Pathway Analysis. Results: Twenty-two (5.3%) genes were overlapping between the atopy-related genes (n = 160) and PID-related genes (n = 278). We identified seven distinct clusters of atopy-related genes. Functional pathway analysis of all atopy-related genes showed relevance of T helper cell-mediated pathways. Conclusions: This study shows a model to define clusters within the atopic syndrome based on gene expression profiles of immune cell lineages. Our results support the hypothesis that both genetic mechanisms and immune dysregulation play a role in the pathogenesis. It also opens up the possibility for novel therapeutic targets and a more tailored approach towards personalized medicine

The influence of treatment in alpine and moderate maritime climate on the composition of the skin microbiome in patients with difficult to treat atopic dermatitis

Background: The skin microbiome, characterized by an overgrowth of Staphylococcus aureus, plays an important role in the pathogenesis of atopic dermatitis (AD). Multidisciplinary treatment in alpine climate is known for its positive effect on disease severity in children with AD and can result in a different immune response compared with moderate maritime climate. However, the effect on the composition of the skin microbiome in AD is unknown. Objective: To determine the effect of treatment in alpine climate and moderate maritime climate on the microbiome for lesional and non-lesional skin in children with difficult to treat AD. Results: Alpine climate treatment led to a significant change in the microbiota on lesional skin, whereas no significant change was found after moderate maritime climate. On both lesional and non-lesional skin, we observed a significant increase in Shannon diversity and a significant decrease in both Staphylococcus abundance and S aureus load after alpine climate treatment. The decrease in S aureus was significantly larger on lesional skin following alpine climate treatment compared with moderate maritime climate treatment. Staphylococcus epidermidis load was stable over time. Conclusions and clinical relevance: Alpine climate treatment leads to significant changes in the composition of the skin microbiome in children with AD, mainly caused by a reduction in the Staphylococcus genus. This study shows new perspectives in the potential mode of action for therapies in AD