Dermatology Disruptors: Next-Generation Skin Microbiome Testing and Bacteriophage Therapy

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Human skin is home to trillions of microorganisms, a bustling community of bacteria, viruses, fungi, and archaea that form a complex and dynamic ecosystem known as the microbiome. Balance of this ecosystem is essential for skin health and overall well-being, as the gut-skin-brain axis suggests the deep interconnectedness of human health. Dysbiosis, a disruption in normal microbiome homeostasis characterized by decreased richness (total number of bacterial species) and altered evenness (proportion of microorganisms in a community), predisposes a pro-inflammatory environment and the development of clinical disease, as observed in acne, rosacea, hidradenitis suppurativa, and folliculitis.¹

Although broad-spectrum antibiotics are a first-line therapy for these dermatoses, their widespread use resulted in antimicrobial resistance (AMR) at a scale characterized as a global health crisis. The World Health Organization projects that over 50 million people will die from an antibiotic-resistant infection by 2050, highlighting that once treatable infections are now a significant challenge. As antibiotic resistance increases, a surprising new treatment is stepping into the spotlight: bacteriophage therapy.

Phages in Dermatology: Reviving a Forgotten Remedy

Bacteriophages, or phages, are viruses that destroy specific pathogenic bacteria by infecting and replicating within their target bacteria, resulting in bacterial cell lysis. Unlike broad-spectrum antibiotics that target both pathogenic and commensal bacteria, phages are highly specific for particular strains of bacteria, leaving the rest of the microbiome intact. This precision makes phages an appealing alternative to antibiotics, especially in the sensitive ecosystem of the skin. Phages are ubiquitous—in soil, water, and on our bodies—and outnumber bacteria 10 to 1. In addition, they are considered safe in humans and achieved “generally regarded as safe” status by the US Food and Drug Administration (FDA) since the early 2000s. This safety, combined with their precision, positions phages as a promising agent in the fight against antibiotic resistance (Figure 1).

A Brief History of Phage Therapy

Use of bacteriophages to treat bacterial infections, or phage therapy, was proposed in the early 20th century by Félix d'Hérelle, a French-Canadian microbiologist who discovered these viruses and recognized their medical potential. By the 1930s, phage therapy was used to treat various skin infections. However, the advent of mass-produced, broad-spectrum antibiotics in the 1940s, with their efficacy and simplicity, displaced phage therapy to the sidelines—at least in the West.

In Eastern Europe, phage therapy thrived. In Georgia and Russia, preparations termed “pyophage” were developed to combat a variety of bacterial infections, including skin infections, yielding a century of experience and research documenting the safety and efficacy of phage therapy.^2,3 Compassionate use cases in the United States and personalized phages in Belgium, where patients with multidrug-resistant infections have been successfully treated with phages, have further fueled interest in phage therapy.^4,5 Although no phage-based drugs have yet received FDA approval in the United States, several are in the pipeline, signaling a renewed focus on this old but promising field. The challenge now is to fully unlock the potential of phage therapy by deepening our understanding of the specific microbes responsible for various skin conditions—a knowledge gap that has long hindered the effectiveness of this approach.

The Microbiome Revolution: Transforming Dermatology

The study of the human microbiome has undergone a dramatic transformation since the National Institutes of Health started the Human Microbiome Project in 2007, thanks to advances in high-throughput DNA sequencing technologies. These innovations allow scientists to explore the once-hidden world of unculturable microbes, beginning with the gut, followed by the skin, scalp, and oral microbiomes. What was once a vague and general understanding of microbial life on the skin is becoming a clear, detailed, quantitative picture of microbial communities and their intricate relationships with health and disease.

Recently, several biotech startup companies have leveraged phage technology to address the threat of AMR. Utilizing whole-metagenome shotgun DNA sequencing has enabled a comprehensive analysis of microbial communities, identifying not just the species present, but the specific genes and functions associated with them. Whole-metagenome sequencing works by randomly sequencing small pieces of all the DNA extracted from a sample such as a skin swab. Due to developments in cost-efficiency and methods to interpret the massive quantities of unstructured data generated by the method, whole-metagenome sequencing is overtaking 16S rRNA sequencing, which previously dominated microbiome work. Drawbacks of 16S rRNA sequencing include the inability to detect viruses and yeast, specific genes (such as AMR genes), and microbial taxa at the species level, which is critical for most health applications.

Whole-metagenome sequencing shows distinct advantages over standard microbiologic culture methods. Whereas cultivation techniques require extensive training and experience, DNA sequencing methods only require simple, standardized, automatable, and scalable wet lab manipulations and replicable computational methods. Microbial cultivation is also haphazard, with only certain specific media able to support the growth of particular strains of bacteria, making it impossible to comprehensively cultivate every microbe in a sample. Whole-metagenome sequencing enables the comprehensive identification of DNA from any organism found in the sample, regardless of the ability to cultivate it. Microbial cultivation is also only nominally quantitative, due to variation in the plating efficiency of different strains in different metabolic states depending on the freshness of the sample. Many anaerobes suffer rapid death during sample transport, leading to underreporting by cultivation. Whole-metagenome sequencing measures DNA remnants of a cell, so the sample can be preserved at the time of collection without transport affecting detection of sensitive microbes such as anaerobes. Furthermore, new methods allow for scalable absolute quantification of microbes in whole-metagenome sequencing data, with quantitative accuracy similar to flow cytometry.⁶

The level of detail provided by whole-metagenome sequencing is critical in dermatology, where skin conditions are often linked to specific microbial imbalances or the presence of particular bacterial strains. By moving beyond the identification of infectious agents to uncover the roles of pathobionts—microbes that can cause disease under certain conditions—this technology has opened new avenues for targeted treatments. Based on the science conducted and the medical literature, we now understand that diseases like acne and seborrheic dermatitis are rarely caused by a single pathogenic organism, but more likely from dysbiosis in which multiple microbial species contribute to inflammation and disease.^7,8 The ability to identify species- or strain-specific relationships with disease may be a game changer, setting the stage for phage therapy that may address the relational causes of skin conditions with unprecedented accuracy.

Integrating DNA Testing and Phage Therapy: A New Era in Dermatology

The future of dermatology is being reshaped by the convergence of DNA-based skin microbiome testing and phage therapy—a pairing that promises to deliver highly personalized care. In traditional dermatology, antibiotics have long been the first-line therapy against bacterial infections and inflammatory skin conditions. However, the overuse of antibiotics has led to significant problems, including the rise of antibiotic-resistant bacteria and the disruption of the skin’s natural microbial balance.

A new approach grounded in microbiome dermatology begins with a comprehensive quantitative analysis of a patient’s skin microbiome, for example, by a simple skin swab, identifying microbial imbalances that may be contributing to skin conditions. Based on these results, patients can benefit from a range of personalized products, from cosmeceuticals to compounded prescriptions, all designed to target specific microbial strains identified through advanced testing methods. This tailored approach not only addresses the root causes of skin conditions but also supports antibiotic stewardship by reducing the need for broad-spectrum antibiotics (Figure 2).

In cosmetic dermatology, the microbiome dermatology framework introduces a model to manage “inflammaging,” a portmanteau referring to the low-level, chronic inflammation associated with cellular senescence that underpins declining skin structure and function, as well as other age-related health conditions, such as arthritis, type 2 diabetes, and dementia. Skin barrier function and the skin microbiome are thought to play a key role in the development of inflammaging in part due to the large surface area of the skin and the ubiquity and persistence of the skin microbiome, which influences skin barrier function.^6,9,10 While interventions such as botulinum toxin and hyaluronic acid filler offer visible improvements in fine lines and wrinkles, they fail to address the inflammatory degradation of skin integrity associated with skin dysbiosis.¹⁰ Innovative use of precision phages and tailored prescriptions can target these microbial imbalances, reducing inflammation at its source. This approach not only amplifies the effectiveness of cosmetic procedures but also fosters lasting skin health.

A Vision for the Future

The broader implications for phage therapy in dermatology are becoming clear. Preliminary research demonstrates that phage therapy reduces target bacterial populations and improves skin conditions, such as acne, eczema, and seborrheic dermatitis (Figure 3).^6,9-12 However, the complexity of inflammatory skin conditions, which often involve multiple microbial species, underscores the need for further skin microbiome research and refinement of phage therapy.

Looking ahead, there are several key areas of focus. One of the primary challenges is reducing the cost and turnaround time for personalized phage therapy products. Another important goal is the accumulation of large-scale data on the effectiveness of phage therapy in dermatology. By collecting and analyzing data from a wide range of patients and conditions, researchers can refine their understanding of the microbial causes of skin diseases and develop more effective phage therapies. This data-driven approach will also help inform the clinical development of tools and products that are responsive to the evolving needs of dermatologists and their patients.

Finally, the future of phage therapy in dermatology will likely involve the development of a broader range of phages for greater personalization. As our understanding of the skin microbiome deepens, new phages will be identified and characterized, enabling the creation of even more personalized and effective treatments.

Conclusion

Phage therapy is a potential revolution in dermatology. With the rise of antibiotic resistance and the growing understanding of the skin microbiome, the need for targeted, personalized therapies has never been more urgent. As this field continues to evolve, the integration of phage therapy into mainstream dermatologic practice may usher in a new era of skin health, offering a more effective, personalized, and sustainable approach to treating skin conditions.

Disclosures: Dr Soon is a clinical advisor for Parallel Health and a consultant for Mindera, L'Oréal, Beiersdorf, and Glo-Pharma; a share- holder in Parallel Health and Mindera; and has received honoraria from Medscape and Beiersdorf. Natalise K. Robinson and Dr Brown are shareholders in Parallel Health.

References

1. Woo TE, Sibley CD. The emerging utility of the cutaneous microbiome in the treatment of acne and atopic dermatitis. J Am Acad Dermatol. 2020;82(1):222-228. doi:10.1016/j.jaad.2019.08.078
2. Melnikova D. An alternative cure: the adoption and survival of bacteriophage therapy in the USSR, 1922–1955. J Hist Med Allied Sci. 2018;73(4):385-411. doi:10.1093/jhmas/jry024
3. Chanishvili N. Bacteriophages as therapeutic and prophylactic means: summary of the Soviet and post Soviet experiences. Curr Drug Deliv. 2016:13(3):309-323. doi:10.2174/156720181303160520193946
4. Von Hoff DD, Han H. Precision Medicine in Cancer Therapy. Springer; 2019.
5. Dedrick RM, Smith BE, Cristinziano M, et al. Phage therapy of mycobacterium infections: compassionate use of phages in 20 patients with drug-resistant mycobacterial disease. Clin Infect Dis. 2023;76(1):103-112. doi:10.1093/cid/ciac453
6. Zaramela LS, Tjuanta M, Moyne O, Neal M, Zengler K. synDNA—a synthetic DNA spike-in method for absolute quantification of shotgun metagenomic sequencing. mSystems. 2022;7(6):e0044722. doi:10.1128/msystems.00447-22
7. Fulton JE Jr, McGinley K, Leyden J, Marples R. Gram-negative folliculitis in acne vulgaris. Arch Dermatol. 1968;98(4):349-353.
8. Qian A, Sun M, Qi RQ, et al. High Staphylococcus epidermidis colonization and impaired permeability barrier in facial seborrheic dermatitis. Clin Med J. 2017;130(14):1662-1669. doi:10.4103/0366-6999.209895
9. Haque A, Woolery-Lloyd H. Inflammaging in dermatology: a new frontier for research. J Drugs Dermatol. 2021;20(2):144-149. doi:10.36849/JDD.5481
10. Pilkington SM, Bulfone-Paus S, Griffiths CEM, Watson REB. Inflammaging and the skin. J Invest Dermatol. 2021;141(4S):1087-1095. doi:10.1016/j.jid.2020.11.006
11. Solomon SEB, de Farias MR, Pimpão CT. Use of Staphylococcus aureus Phage Lysate Staphage Lysate (SPL) for the control of recurrent pyoderma eczema in dogs with atopic dermatitis. Acta Sci Vet. 2016;44(1):7. doi:10.22456/1679- 9216.81103
12. Rimon A, Rakov C, Lerer V, et al. Topical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions. Nat Commun. 2023;14(1):1005. doi:10.1038/s41467-023-36694-8