What lives on our skin? – the skin microbiome

By Ashley Lai

We all know that skin is an important barrier of the immune system, but do we realise it is actually the largest epithelial interaction site with microbes – at least 30m² when taking into account all the appendage structures. (Gallo, 2017) The different microenvironments of the skin such as pH and moisture provide a large range of distinct niches for a variety of microbes to thrive, typically including over a thousand species of bacteria, viruses, fungi and arthropods. (Eisenstein, 2020) Using 16S rRNA gene phylotyping, scientists have looked into the population of different phyla of bacteria. The largest phyla population is Actinobacteria, followed by Firmicutes and Proteobacteria. And the most predominant species in moist and dry sites of the skin are Corynebacterium and β-Proteobacteria respectively. (Schommer and Gallo, 2013) The way these microbes interact with skin cells can greatly influence our immune response and disturbances to their population can lead to the development of several skin diseases. 

One of the benefits of having a healthy skin microbiome community is to suppress the colonisation of other pathogenic microbes, which is closely associated with the host innate immune response. Some antimicrobial peptides, Epidermin, Pep5 and epilancin K7 are produced by gram-positive bacteria that have colonized our skin. These peptides containing lanthionine and methyllanthionine have similar pore-forming activity, in addition to antimicrobial peptides produced by host keratinocytes, for example, defensins, contributing to the human innate immune responses together. (Gallo and Nakatsuji, 2011) Research by Cogen et al. has proposed that PSMγ and PSMδ synthesized by Staphylococcus epidermidis act as an important antimicrobial peptide on human skin. Without affecting its own population, the antimicrobial peptide it produced can inhibit the growth of pathogenic bacteria such as Staphylococcus aureus by interacting and causing the leakages of lipid vesicles, hence eliminating the pathogen. (Cogen et al., 2010) Besides producing harmful peptides to act against and compete with pathogens for more nutrients and spaces, these microbes can also help to shape an unfavourable environment for the growth of other skin pathogens by altering the pH. (Belkaid and Segre, 2014) 

Several components of the human immune system are directly influenced by these skin microbes. A study suggests skin microbes can act as mediators to amplify and enhance the IL-1 signalling pathways that stimulate the activity of T effector cells. (Naik et al., 2012) Mast cells that can mediate inflammatory responses against viruses are also influenced by lipoteichoic acid (LTA) produced by skin microbes. LTA can activate Toll-like receptor 2 and its downstream signalling pathway, leading to recruitment and upregulation of cathelicidin production in mast cells. Cathelicidin was shown to be able to enhance the ability of mast cells to act against vaccinia viruses with greater antiviral response. (Wang, Macleod and Di Nardo, 2012) Regarding skin tissue injuries, skin microbes such as S. epidermidis have been shown to respond to and promote tissue repair by stimulating specific CD8+ T cells. These induced CD8+ T cells, which accumulate at the edge of wounds after injuries, are found to express genes related to tissue repair at a higher level compared to pathogen-stimulated CD8+ T cells. Amphiregulin, one of the example molecule produced by these induced CD8+ T cells, can act as a ligand for epidermal growth factor receptor to stimulate mitosis and keratinocytes proliferation. (Linehan et al., 2018)

Nevertheless, imbalance in the population of skin microbiome can cause several inflammatory skin disorders. Most commonly seen in teenage years is acne vulgaris, a chronic inflammatory skin condition. Propionibacterium acnes are commonly found in the pilosebaceous follicles. In response to the over-colonization of P. acnes, innate immune responses are activated. TLR2 receptors on macrophages in pilosebaceous follicles are greatly stimulated and the downstream NF-ĸB pathway is activated to produce proinflammatory cytokines, IL-12 and IL-8, alongside monocytes. (Kim, 2005) P. acne, associated with inflammasome, can also activate caspase 1 of monocytes and sebocytes, inducing the expression of IL-1β in acne lesions. In addition, peripheral blood mononuclear cells are activated to produce IL-17 for positive responses from Th17 and Th1 cells. AMPs and degradative matrix metalloproteinases are released to contribute to inflammation in acne vulgaris. (McLaughlin et al., 2019) Hence for a healthy skin microbiome population, Staphylococcus epidermidis, as an essential inhibitor of P. acne, is also found to be co-existing. S. epidermidis can inhibit the growth of P. acnes to prevent its over-colonisation. Inside the anaerobic microenvironment of acne lesions, it can produce succinic acid from glycerol through the fermentation process. Succinic acid is then able to inhibit inflammation and the production of pro-inflammatory cytokines such as IL-2 by activating G-protein coupled receptors. (Wang et al., 2014)

In conclusion, maintaining a balanced population of the skin microbiome is crucial for our health. While the gut microbiome has been studied extensively, more research on the skin microbiome has to be carried out for us to gain further understanding about their interaction with the host via the immune system, as well as the role of skin microbial dysbiosis plays in different skin disorders’ development.

References:

Belkaid, Y. & Segre, J. A. (2014) Dialogue between skin microbiota and immunity. Science. 346 (6212), 954. Available from: http://science.sciencemag.org/content/346/6212/954.abstract.

Cogen, A. L., Yamasaki, K., Sanchez, K. M., Dorschner, R. A., Lai, Y., MacLeod, D. T., Torpey, J. W., Otto, M., Nizet, V., Kim, J. E. & Gallo, R. L. (2010) Selective Antimicrobial Action Is Provided by Phenol-Soluble Modulins Derived from Staphylococcus epidermidis, a Normal Resident of the Skin. Journal of Investigative Dermatology. 130 (1), 192-200. Available from: https://www.sciencedirect.com/science/article/pii/S0022202X15345486.

Eisenstein, M. (2020) The skin microbiome. Nature Outline. Available from: https://doi.org/10.1038/d41586-020-03523-7.

Gallo, R. L. (2017) Human Skin Is the Largest Epithelial Surface for Interaction with Microbes. The Journal of Investigative Dermatology. 137 (6), 1213-1214. Available from: https://pubmed.ncbi.nlm.nih.gov/28395897  .

Gallo, R. L. & Nakatsuji, T. (2011) Microbial Symbiosis with the Innate Immune Defense System of the Skin. Journal of Investigative Dermatology. 131 (10), 1974-1980. Available from: https://www.sciencedirect.com/science/article/pii/S0022202X15350351.

Kim, J. (2005) Review of the Innate Immune Response in Acne vulgaris: Activation of Toll-Like Receptor 2 in Acne Triggers Inflammatory Cytokine Responses. Dermatology. 211 (3), 193-198. Available from: https://www.karger.com/DOI/10.1159/000087011.

Linehan, J. L., Harrison, O. J., Han, S., Byrd, A. L., Vujkovic-Cvijin, I., Villarino, A. V., Sen, S. K., Shaik, J., Smelkinson, M., Tamoutounour, S., Collins, N., Bouladoux, N., Dzutsev, A., Rosshart, S. P., Arbuckle, J. H., Wang, C., Kristie, T. M., Rehermann, B., Trinchieri, G., Brenchley, J. M., O’Shea, J., J. & Belkaid, Y. (2018) Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair. Cell. 172 (4), 784-796.e18. Available from: https://pubmed.ncbi.nlm.nih.gov/29358051  .

McLaughlin, J., Watterson, S., Layton, A. M., Bjourson, A. J., Barnard, E. & McDowell, A. (2019) Propionibacterium acnes and Acne Vulgaris: New Insights from the Integration of Population Genetic, Multi-Omic, Biochemical and Host-Microbe Studies. Microorganisms. 7 (5), 128. Available from: https://pubmed.ncbi.nlm.nih.gov/31086023 .

Naik, S., Bouladoux, N., Wilhelm, C., Molloy, M. J., Salcedo, R., Kastenmuller, W., Deming, C., Quinones, M., Koo, L., Conlan, S., Spencer, S., Hall, J. A., Dzutsev, A., Kong, H., Campbell, D. J., Trinchieri, G., Segre, J. A. & Belkaid, Y. (2012) Compartmentalized Control of Skin Immunity by Resident Commensals. Science. 337 (6098), 1115. Available from: http://science.sciencemag.org/content/337/6098/1115.abstract.

Schommer, N. N. & Gallo, R. L. (2013) Structure and function of the human skin microbiome. Trends in Microbiology. 21 (12), 660-668. Available from: https://www.sciencedirect.com/science/article/pii/S0966842X13001996.

Wang, Y., Kuo, S., Shu, M., Yu, J., Huang, S., Dai, A., Two, A., Gallo, R. L. & Huang, C. (2014) Staphylococcus epidermidis in the human skin microbiome mediates fermentation to inhibit the growth of Propionibacterium acnes: implications of probiotics in acne vulgaris. Applied Microbiology and Biotechnology. 98 (1), 411-424. Available from: https://pubmed.ncbi.nlm.nih.gov/24265031.

Wang, Z., MacLeod, D. T. & Di Nardo, A. (2012) Commensal Bacteria Lipoteichoic Acid Increases Skin Mast Cell Antimicrobial Activity against Vaccinia Viruses. The Journal of Immunology. 189 (4), 1551. Available from: http://www.jimmunol.org/content/189/4/1551.abstract.