How does systemic therapy influence dysbiosis?

One aim of the multicenter observational study ProRaD is to gain a better understanding of the mechanisms that influence the course of atopic dermatitis (AD). In a sub-project, researchers used modern sequencing technologies to investigate the effects of system therapeutics on the skin microbiome in AD patients. It is hoped that research projects such as these will optimize treatment strategies for AD.

Microbiome research (Greek mikrós “small” and bios “life”) has increasingly become the focus of interest in recent years and the methods of molecular analysis of microbial populations are constantly being further developed [1]. Nowadays, next-generation sequencing (NGS) is often used as a measurement method in microbiome analyses [1]. NGS can be used to determine the identities of bacteria, fungi and other microorganisms in a sample in the form of genome segments and to estimate the relative frequencies with which they are represented in it [2]. Intensive and systematic research into the human cutaneous and intestinal microbiome using NGS was carried out, for example, as part of the “Human Microbiome Project”, an initiative of the US National Institutes of Health [3]. In the meantime, NGS has been used in numerous studies to investigate the microbiome and interesting insights have been gained into the skin microbiome in atopic dermatitis (AD) [4]. Particularly during an acute attack of AD, a greatly reduced bacterial diversity of the microbiota and a high relative abundance of Staphylococcus aureus (S. aureus) can be observed [5].

Microbiome analyses as part of the ProRaD collective

In order to investigate the effect of local and systemic therapeutics on the human skin microbiome in patients with AD, skin samples were collected and analyzed as part of the prospective longitudinal study ProRaD in Augsburg and Bonn between 2017 and 2019 [6].

Methods: The researchers analyzed and evaluated a total of 1077 skin microbiome swabs and drug treatment data from 462 subjects in a cross-sectional study design. The skin microbiome of the patients was recorded using 16S rRNA amplicon sequencing of the V1-V3 region**. The “AnnotIEM” algorithm was used for the bioinformatic analysis, which compares the RNA sequence of the bacteria with numerous databases, allowing the subsequent determination of the individual microbiome down to the specific bacterial level with high accuracy [1,6].

** The composition of the microbiota can be determined by sequencing the variable regions (V1-V9) of the bacterial 16S rDNA. www.gtl.hhu.de/verfuegbare-workflows-proben request/next-generation-sequencing/microbiome-profiling-16s-amplicon sequencing

The current AD treatment regimen was documented and the patients were divided into treatment groups according to the recommendations of the EuroGuiDerm guidelines [6].

Analysis results: A strong correlation between skin condition and the frequency of S. aureus in skin lesions of AD patients was confirmed. No correlation between the relative abundance of S. aureus and age or sex was found. In order to exclude the skin condition as a confounding factor, separate examinations of the skin microbiome were carried out for mild, moderate and severe courses of the disease. In patients with moderate AD, there was a significantly lower relative abundance of S. aureus in those who received systemic therapy compared to those who received only topical treatment. In addition, the AD patients treated with systemic drugs tended to differ depending on the systemic drug administered. The average relative abundance of S. aureus was found to be lower in participants receiving therapy with the biologic (bDMARD) dupilumab compared to participants receiving systemic therapy with conventional immunosuppressants (csDMARD).

Conclusion : This pilot study described possible associations between AD treatment and microbiome changes within the ProRaD cohort. The results demonstrate the relevance of specific immunological processes in the microbial interplay in AD and point to the associated implications for system-therapeutic treatment. In particular, there were indications that treatment with dupilumab has a favorable effect on the dysbiosis associated with AD.

The microbiome also normalized under dupilumab in TREATgermany

Hartmann et al. reported on a study published in the journal “Allergy” in 2023, which investigated how the skin microbiome in AD is influenced by various system therapies [7].

Methodology: For their analysis, the researchers used a data set from the TREATgermany register study. Skin swabs from 157 AD patients were analyzed by 16S rRNA amplicon sequencing before and after three months of treatment with dupilumab or ciclosporin and compared with 258 population-based healthy controls. The severity of the disease was assessed using established instruments such as the “Eczema Area and Severity Index” (EASI) [15].

Analysis results: This study also confirmed a high relative abundance of S. aureus correlated with AD severity (EASI). Treatment with dupilumab led to a shift in microbial colonization towards a pattern similar to that observed in healthy controls. In the course of treatment, the relative frequency of Staphylococcus and especially S. aureus decreased significantly on both lesional and non-lesional AD skin, while the frequency of Staphylococcus hominis increased. These changes were largely independent of the degree of clinical improvement and were not observed during treatment with cyclosporine.

Conclusion: In the present analyses, systemic treatment with dupilumab tended to normalize the skin microbiome in AD in contrast to ciclosporin. This was found to be largely independent of the clinical response, suggesting that the IL-4 receptor alpha blockade induced by dupilumab per se may have an impact on the microbiome, the study authors said. However, further empirical studies are required to find out more about this [7].

Hypotheses on the underlying mechanisms

According to Hartmann et al. the blockade of type 2 cytokines can have direct and/or indirect effects on the composition of the skin microbiome [7]. Direct effects relate to skin barrier function and include, for example, normalization of epidermal lipid composition, increased levels of natural moisturizing peptides and increased production of antimicrobial peptides accompanied by reduced uptake of S. aureus [8–10] or a tendency for increased S. aureus clearance [11,12]. However, the experimental setup described in the analysis of the TREATgermany dataset does not allow any clear conclusions to be drawn about direct interactions, according to Hartmann et al. It therefore remains unclear whether the changes in the composition of the microbiome observed with dupilumab are a result of direct drug-specific effects and/or indirect effects of reduced cutaneous inflammation. Patients with a response >EASI90 showed the most pronounced recovery of bacterial diversity, which was comparable to that of healthy controls except for a residual microbial signature characterized by the presence of only a few AD-associated amplicon sequence variants (ASV) at different frequencies.

Congress: ADF Annual Meeting

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