The skin microbiome is increasingly being treated as a living interface and dynamic extension of the skin, capable of influencing barrier performance, inflammation, and susceptibility to exacerbations. Cutting-edge methods , from shotgun metagenomics to metatranscriptomics, are helping R&D teams to interpret this crosstalk, shedding light on long-standing questions about what is present, what is alive, and what is actually active on the skin.
Why skin microbiome is hard to measure
Investigating the skin microbial landscape has always been challenging for the scientific community. It is common knowledge that skin samples exhibit low microbial biomass and are dominated by host DNA [1]. This has the effect of reducing sequencing depth and making results more vulnerable to background contamination from reagents and the environment [2]. Compared to other body districts, the skin is highly heterogeneous: adjacent sites can differ in sebum, hydration, pH, and follicle density, producing real biological variation that can be confused with technical variability unless sampling and controls are rigorous. Skin microbiome research has relied on marker-gene profiling, frequently 16S rRNA sequencing, which is efficient for bacteria identification but can result in the under-representation of fungi and viruses. Moreover, this approach may provide limited resolution for closely related taxa. Finally, standard DNA sequencing cannot distinguish living communities from relic DNA (i.e. dead microbes and extracellular fragments), while providing only an indirect view of functional potential.
What’s new in microbiome analysis
The latest technological advances in microbiome analysis are addressing long-standing challenges in skin research.
1. From marker genes to whole-metagenome sequencing.
Shotgun metagenomics sequences the full DNA mixture in a sample rather than a single marker gene. Recent findings suggest that, compared to 16S gene sequencing, optimized collection and extraction procedures within whole-metagenome sequencing procedures allows for broader taxonomic coverage, capturing non-bacterial members and inferring the functional potential of low-density skin samples [3].
2. Measuring living microbes, not leftover DNA.
In a 2025 study, Thiruppathy et al. combined relic-DNA depletion with shotgun metagenomics to estimate the living fraction of skin communities; filtering out genomic material from dead cells prior to sequencing has revealed that up to 90% of microbial DNA recovered from skin might be from dead microbes [4].
3. Moving from “who’s there” to “who’s active.”
The third frontier is metatranscriptomics, whose sequencing of microbial RNA provides a real-time window into microbial behavior, specifically which genes are being expressed, rather than merely cataloging which species are present [5]. Even so, early skin datasets illustrate a point that matters for product testing: microbial’s DNA profile can diverge from its functional state [6]. Recent findings on several skin sites suggest that Staphylococcus species and fungi Malassezia made outsized contributions to the RNA pool despite being only moderate in DNA abundance [7]. Together, these emerging methodologies are evolving host-microbiome research from a basic descriptive science toward a more functional readout.
How microbes talk to skin cells
Scientists categorize microbe–skin cell interactions into a few broad categories [8]: metabolites, immune signals, and physical/chemical modulation of the barrier.
- Chemistry at the surface: skin microbes produce metabolites, including organic acids and other small signaling molecules (indole-3-aldehyde [9]) that can engage host receptors and modulate keratinocyte programs relevant to differentiation and barrier maintenance. Microorganisms further influence the cutaneous environment through the secretion of short-chain fatty acids (SCFAs), with proven activity in reducing skin pH and even exerting localized anti-inflammatory effects [10]. A notable example is Cutibacterium acnes, which ferments glycerol to produce propionate and butyrate: theseSCFAs have demonstrated to act as Histone Deacetylase (HDAC) inhibitors, modulating the epigenetic landscape and promoting an anti-inflammatory state [11].
- Immune sensing: skin cells detect microbe-associated molecules via pattern-recognition receptors, including Toll-like receptors [12], modulating the production of antimicrobial peptide and the inflammatory tone [13], [14]. By signaling through these receptors, commensal microbes encourage a state of immune tolerance, allowing the host to distinguish between residents and transient, opportunistic pathogens.
- Ecological competition: Microbes modulate the skin microenvironment, influencing pH, oxygen, and nutrient availability, and compete with opportunists via inhibitory compounds or signaling interference [15]. Commensals further contribute to colonization resistance: for example, Staphylococcus hominis can release autoinducing peptide signals that specifically inhibit Staphylococcus aureus, blocking this pathogen from forming biofilms on the skin [16]. There’s also evidence that microbial signals encourage skin cells to produce essential lipids and regulate sebum composition [17]. Finally, the impact of skin commensals on wound healing is complex and dependent on context, highlighting the need to define microorganisms’ specific roles and functional states [18].
What thi means for R&D and claims
Moving toward this enhanced level of resolution, alongside the emergence of viability-aware workflows and functional outcomes, is gradually redefining how the industry approaches and validates microbiome-related narratives. The main priority is becoming causation, not just correlation, moving from observing microbe-host associations to testing interventions. Future product testing may involve verifying whether a formula alters microbial gene expression or metabolite levels, complementing the identification of “who is there” with insights into “what is it doing”. In short, the skin microbiome is entering a new era of measured, functional understanding, an exciting development for researchers and product innovators willing to embrace the complexity of this living layer.
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