An unexpected transplant

The awareness that microbiota is essential for human health and has an important role in human physiology is increasing among the general public. The advances in molecular biology techniques have allowed a better understanding of the skin microbiome and host-microbe interactions (1). Nowadays, the microbiota can be considered a health mediator in therapeutic development. Bacteriotherapy such as topical bacterial derived enzymes, probiotics, and microbiota transplantation is being studied for skin diseases (2). Recently, the novel technique of microbiota transplantation, which is the transfer of a functioning microbiota from a healthy volunteer to patients, started to be actively investigated in dermatology, and skin microbiome transplant was already tested in humans, with promising results (3). To begin with, it is important to clarify a common misunderstanding among people outside the field: microbiota refers to the collection of all the microorganisms that inhabit you, such as fungus, viruses, and even arthropods, not only bacteria (1). Another important concept is dysbiosis, which is the medical term for microbial imbalance (4). Even though microbiota is individual, we can still expect some patterns. Certain species are known to live in harmony with your skin, but conditions can shift them to pathological contributing to infections, acne, and chronic wounds (1). Thus, healthy microbiota is all about equilibrium, and this fine balance could be controlled with the manipulation of the microbial community.

The skin hosts a complex microbial community that is crucial to maintain itself healthy and protected from external aggressors. By educating the immune system and protecting the skin against harmful microbes. Therefore, besides the skin barrier impairment and immune dysregulation, skin disorders are usually related to dysbiosis. Thought-provoking, all these factors can be directly or indirectly influenced by each other, which explains the microbiota component in many skin diseases. Although, still little is understood about this relationship (1). The skin conditions associated with changes in the skin microbial ecosystem are vast: atopic dermatitis, psoriasis, vitiligo, acne, aging, seborrheic dermatitis, epidermolysis bullosa, rosacea, blepharitis, skin cancer; however some are still under investigation (5). Therefore, skin microbiota transplantation presents great potential as a therapeutic option for several skin diseases. Another advantage of microbiota transplant in dermatology is the many suitable topical delivery methods, including spray (6), thus it can provide high treatment compliance. In addition, the limitations associated with the use of broad-spectrum antibiotics in skin diseases demonstrate the need for more selective methods to combat the right microbes. Skin microbiota transplantation is a good candidate because it aims to inhibit the pathogenic bacteria by restoring the healthy microbiota (2).

Atopic dermatitis, also known as eczema, is a skin disease characterized by dysbiosis, with an increase of the bacteria Staphyloccocus aureus and a decrease of microbial diversity. Which sustains a vicious cycle of inflammation, itch, and skin barrier disruption (2). After successful results using in vitro techniques and animal models, the first in-human topical microbiome transplantation of the bacteria Roseomonas mucosa took place and demonstrated to be capable of improving atopic dermatitis. This study was performed with 15 patients, adults and children. The transplanted bacteria were isolated from healthy volunteers and after preparation and selection processes it was applied in the form of spray during a 6-week treatment. The transplant was able to decrease the disease severity and the use of topical steroids and to lower Staphylococcus aureus burden. The clinical improvement occurred due to several mechanisms affecting the skin barrier, the immune system, and the S. aureus infection. However, the results were different for different anatomical sites, and no clinical response was detected for most patients with a family history of skin disease. These findings demonstrate the exciting potential of the technique, but also its limitations such as the variability of results in different contexts. Moreover, a larger clinical trial is still needed (3, 7). Nevertheless, considering the great variability in the microbiota, and its susceptibility to several endogenous and exogenous factors, differences in patient response are expected. Regarding the safety of the method, no toxicity was detected as well as no adverse effect was reported during the study. Given that the microbiota transplantation technique is very recent and has many emerging applications, the regulations are still insufficient. In fact, it is a big challenge to define suitable guidelines and regulations for the manipulation of this alive and highly dynamic transplant, when even its classification as a drug, biological product, or tissue is still on debate (8). Another study of an autologous microbiome transplant also showed that protective commensal bacteria from the skin were able to inhibit S. aureus colonization in atopic dermatitis patients. The trial used an isolated coagulase-negative Staphylococcus strain with anti-S. aureus activity, formulated as a cream (9). Thus, ongoing clinical trials of skin bacterial transplants may soon provide more valuable information in the field and make better treatments available for atopic dermatitis patients in the near future.

In conclusion, skin microbiota transplantation provides a promising therapeutic option in dermatology. That can potentially decrease the application of overused drugs such as antibiotics and corticosteroids, therefore improve treatments. Following the topical microbiome transplant of Roseomonas mucosa for treating eczema with satisfactory efficacy and safety results, and the projections of the ongoing clinical trials, the scientific community may move forces further. To research and development of skin microbiota transplants for skin diseases other than atopic dermatitis. Nevertheless, for the successful use of bacteriotherapy in modulating microbiota, a deep understanding of the microbial ecosystem and its role in the pathogenesis of the target disease is necessary (10). Therefore the elucidation of these matters for skin diseases is the first step. Furthermore, the variability in the therapeutic response may suggest the need for personalized treatments, which can be the next challenge in skin microbiota transplantation.

BIBLIOGRAPHY

1. Grice, E. A., & Segre, J. A. The skin microbiome. Nature Reviews Microbiology 9 (4), 244-253 (2011).

2. Hendricks, A. J., Mills, B. W. & Shi, V. Y. Skin bacterial transplant in atopic dermatitis: Knowns, unknowns and emerging trends. J. Dermatol. Sci. 95, 56–61 (2019).

3. Topical microbiome transplant could be key to alleviating eczema, say researchers. https://www.nutraingredients-usa.com/Article/2018/05/10/Topical-microbiome-transplant-may-improve-atopic-dermatitis-Study# (accessed on March 9, 2020)

4. Dysbiosis. https://www.nature.com/subjects/dysbiosis (accessed on March 17, 2020)

5. Maguire, M. & Maguire, G. The role of microbiota, and probiotics and prebiotics in skin health. Arch. Dermatol. Res. 309, 411–421 (2017).

6. Zhang, F. et al. Microbiota transplantation: concept, methodology and strategy for its modernization. Protein Cell 9, 462–473 (2018).

7. Myles, I. A. et al. First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI insight 3, 1–13 (2018).

8. Hoffmann, D., Palumbo, F., Ravel, J., Roghmann, M. C., Rowthorn, V., & von Rosenvinge, E. Improving regulation of microbiota transplants. Science, 358, 6369, 1390-1391 (2017).

9. Nakatsuji, T. et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl. Med. 9, 1–12 (2017).

10. Stehlikova, Z. et al. Dysbiosis of skin microbiota in psoriatic patients: Co-occurrence of Fungal and Bacterial Communities. Front. Microbiol. 10, 1–13 (2019).