The skin, as the body’s outermost layer of cells, plays a crucial dual role in protecting against foreign pathogens while providing a habitat for commensal microbes. Despite the skin’s harsh conditions, which include desiccation, acidity, and scarce nutrients, the skin hosts a diverse community of bacteria, fungi, and viruses. Prior work associating fluctuations in the skin microbiome with health and disease has been limited by our limited understanding of the skin microbiome composition and functions.

One way to characterise skin microbial diversity is through metagenomics. A previous investigation of the skin microbiome found that more than half of the sequenced skin metagenomic reads did not align to reference genomes, complicating the analysis of skin metagenomic datasets. To address this issue, we combined bacterial cultivation and metagenomic sequencing to create the Skin Microbial Genome Collection (SMGC), the most comprehensive catalogue of prokaryotic, eukaryotic, and viral genomes from the skin. The SMGC allows for the classification of a median of 85% of skin metagenomic sequencing reads, providing a comprehensive view of skin microbial diversity.

Using the SMGC, we investigated the skin microbiome in atopic dermatitis, a prevalent inflammatory skin condition characterized by recurring episodes of red, itchy, and swollen skin. Atopic dermatitis flares have been associated with the proliferation of various staphylococcal species, with only S. aureus strains cultured from atopic dermatitis inducing inflammation in a mouse model. Our extensive genomic survey of the skin microbiome in atopic dermatitis, supported by cultured isolates from the same samples, identified Staphylococcus strains and genomic loci associated with higher disease severity. Our work also showed that the Staphylococcus strains found in AD are influenced by factors such as geography and strain sharing within households. Additionally, our examination of the mobilome of multiple Staphylococcus species colonising the same individuals revealed widespread inter-species transfer of genetic material, highlighting the fluid nature of staphylococcal genetic composition.

In conclusion, our work shows how novel genomic approaches and the integration of sequencing data can be used to characterise the skin microbiome at an unparalleled resolution, allowing for new insights into how skin microbes vary in health and disease.