Skin health is key to our overall wellbeing but a complex interplay of many components – both internal and external – affect its condition and how it looks and feels. These factors include the interaction of the skin microbiome and genetic/inherited traits, as well as environmental influences such as exposure to pollution and UV.
The additive influence of these factors can affect the skin in various ways – primarily through skin homeostatic imbalances and skin barrier disruption. Skin barrier function is essential for maintaining skin health but its disruption by internal factors (e.g. genetics and hormonal changes that alter the skin’s natural pH balance), external factors (e.g. particles that trigger inflammation), the microbiome (e.g. imbalances caused by pathogenic bacteria) and interactions between these three components can lead to skin sensitivity and irritation (1,2).
Although certain products have been created by developers to help manage sensitive skin and skin irritation, these products tend to aim to alleviate the symptoms rather than addressing the underlying cause. There is therefore a need for new strategies that address these issues at a cellular level and work to restore skin barrier function and health.
In this article, we will address one innovative route forward – in situ biomanufacturing using skin-resident microbes. This refers to the potential to develop cosmetic solutions that harness our skin microbes and use their natural biological processes to produce beneficial metabolites, such as anti-inflammatory lipid mediators, on the surface of the skin. Fungal residents of our skin, for example, demonstrate potential here as they have been shown to produce lipid metabolites with anti-inflammatory properties (3). We will explore the science underlying the key mechanisms behind this notion, as well as current microbiome-based interventions for cosmetic applications that are paving the way forward.
Microbe–host communication via lipids
Communication is key for interactions between different organisms. While humans developed advanced verbal communication tools, lower organisms developed molecular language strategies that have enabled not only inter-species communication, but also intra-species exchanges spanning different kingdoms of life.
Classic examples of cross-kingdom communications include those that occur between plants and fungal plant pathogens, which involve lipid mediators as linguistic tools (4). Several microbial-derived lipid mediators have also been shown to interact with mammalian cells.
Fungal pathogens, such as Candida albicans and Aspergillus fumigatus, predominantly produce lipid mediators with structures similar to those synthetized by humans. Human host cells recognize these molecules and respond with alterations in certain biological functions, such as decreased cytokine production, inhibited phagocytosis and anti-fungal activity, with such exchanges even leading to changes like reduced survival rate (5). Researchers have reasoned that common skin-resident microbes could also be using such mechanisms to interact with the skin of the human host – with one key example being bioactive lipid mediators produced by skin-resident Malassezia fungi on human skin (3).
Malassezia and the production of bioactive lipid mediators
Malassezia yeasts are the most prominent fungi found on human skin. Although bacteria dominate the skin microbiome in terms of number, the biomass of fungi (known as the mycobiome) is proportionally much larger in terms of genomic material: the average diameter of a Malassezia cell is 10 times larger than that of bacteria; as such, the cellular volume, and consequently the metabolically active biomass, is 100-fold greater. Yet the impact of the skin mycobiome on cutaneous health was long underestimated and understudied (6).
Most Malassezia species depend on lipids for survival but require an external source of fatty acids (FAs) as they have lost the ability to produce FAs themselves over the course of evolution. This explains in part why Malassezia yeasts are predominantly found on oily regions of the skin, such as the forehead, cheeks, scalp, chest and upper back (7). In these regions, Malassezia fungi, as well as the lipophilic Cutibacterium acnes species, secrete enzymes onto skin (8,9) to release saturated FAs and polyunsaturated fatty acids (PUFAs) from lipids produced by the host’s sebaceous glands. Of these, only the saturated FAs are consumed by Malassezia, whereas the PUFAs are left behind. The remaining PUFAs have been linked to the induction of keratinocyte hyperproliferation in the outer skin and, consequently, dandruff-like flaking of human scalp skin (10).
These PUFAs, together with de novo synthesized PUFAs and PUFAs obtained from dietary intake, also serve as precursors to produce lipid mediators – derived from omega-3 or omega-6 PUFAs. Lipid mediators are characterized by their role in host–microbe interactions (as mentioned above) as well as strong immuno-modulatory functions (4). Lipid mediators that emerge from omega-3 PUFAs have anti-inflammatory properties, whereas those with omega-6 origin are implicated in pro-inflammatory pathways.
Several Malassezia species have also been shown to directly produce a series of lipid mediators, including omega-3 PUFA-derived anti-inflammatory species, that are also found on human skin (3). These findings suggest that some of these lipid mediators are either directly produced by Malassezia on the surface of human skin or are synthesized via metabolic pathways shared between human skin cells and the skin microbiome. A detailed exploration of the genetic pathways underlying the production and secretion of these lipid mediators could ultimately translate to the discovery of novel therapeutic targets for treatment of inflammatory skin diseases, and the development of microbiome-based cosmetic solutions.
Deploying skin-resident microbes as in situ bio-factories for anti-inflammatory mediators
The beneficial effects of omega-3 PUFAs – the building blocks for anti-inflammatory lipid mediators – range from maintenance of skin barrier function to regulation of several inflammatory skin disorders and protection against oxidative stress-induced apoptosis (11,12). Lipid mediators also have the potential to reverse inflammatory reactions caused by pollution, UV and photoaging, as well as chronological aging due to impaired resolution of inflammation in aged human skin (13).
When it comes to skincare, a key route for investigation is whether the production of bioactives by skin-resident microbes can be harnessed and controlled for cosmetic purposes – such as to increase the production of beneficial metabolites. Continuing the discussion above, it has been found that dietary supplementation of omega-3-rich fish oil increases cutaneous lipid mediator concentrations (14). One hypothesis for this is that the conversion of these nutritional omega-3 PUFAs into the bioactive lipid mediators is also mediated by the enzymatic activity of skin-resident Malassezia yeasts. Through such mechanisms, topically applied omega-3 PUFAs, formulated into cosmetic skincare products, could hypothetically be directly metabolized on site into lipid mediators with anti-inflammatory activities by skin-resident microbes. Several inflammatory skin disorders associated with Malassezia (such as seborrheic dermatitis and dandruff, atopic dermatitis and psoriasis (15)) could be prevented, relieved or even resolved as a consequence of the enzymatic activity of the potentially causative fungi itself, along with many other potential skin health benefits
The therapeutic potential of nutritional omega-3 PUFA metabolites for inflammatory skin diseases has been previously noted (16), but topical omega-3 PUFA application to increase in situ microbial production of soothing metabolites directly on the skin may prove to be more effective and sustainable. In line with this, topical omega-3 PUFA cosmetic products are already in demand due to their antioxidant and anti-inflammatory properties – for example, products that integrate microalgae, which are capable of synthesizing both omega-3 and omega-6 PUFAs, as a postbiotic ingredient are an emerging trend in the personal skincare cosmetic industry (17). Yet the discovery that skin-resident Malassezia yeasts can produce lipid mediators raises the question of whether it is not the omega-3 PUFAs contained within cosmetic products that contribute to the anti-inflammatory effects, but rather their enzymatic derivatives.
Although questions remain, a key role of the skin microbiome has now been identified for the fine-tuning of anti-inflammatory bioactives that are synthesized on the skin. This opens up the possibility of modulating specific microbial species to indirectly control levels of these bioactives as a strategy for personalized microbiome intervention.
Exploring current microbiome-based interventions for cosmetic applications
The integration of bioactive ingredients (including microbiome modulators) into skincare products for such benefits is not new (18). In addition, despite being a neglected area in the cosmetic skin industry, products that claim to boost the production of lipid mediators in skin do exist – such as Gatuline® Skin-Repair AF. Yet cosmetic solutions that harness skin microbiome components as central elements for in situ bio-manufacturing of beneficial metabolites, such as anti-inflammatory lipid mediators, are not currently available.
The use of microorganisms as topical probiotics for production of beneficial postbiotics on skin has, however, been explored previously. For example, ammonia-oxidizing strains of Nitrosomonas eutropha produce nitric oxide, which has antimicrobial and anti-inflammatory properties. Topical application of N. eutropha as a probiotic has been shown to improve pruritis (19) and to reduce the appearance of wrinkles (20). Similarly, the opportunistic skin pathogen C. acnes produces propionic acid, which may be an effective and non-toxic alternative solution for hyperpigmentation (21).
As another example, skin ceramide levels diminish with increasing age – and this decrease has been observed in correlation with increased transepidermal moisture loss and skin disease incidence. Recent work showed that Staphylococcus epidermidis, a commensal bacterial species that is abundant on the human skin, secretes sphingomyelinase (SMase) – an enzyme that help maintains skin barrier homeostasis. SMase is key in the bacteria’s acquisition of nutrients, but also supports host production of ceramides (22). Stimulation of ceramide production on skin through modulation of SMase activity via microbiome-based interventions could therefore help revert skin-aging processes and restore moisture levels.
However, to advance microbiome-based interventions for effective cosmetic and therapeutic use, it will also be crucial to understand how different members of cutaneous microbial communities interact with each other, as well as the host’s skin.
Discussion and future directions
In the past, research has been limited to characterizing the complex compositions of skin microbial communities at a genomic level. Yet emerging technologies such as multi-omics analyses and advanced bioinformatics now offer the possibility to better characterize the underlying genetic and biosynthetic pathways of skin microbial species – and the wider interactions of the overall skin microbiome and host. Taking advantage of such opportunities will enable precise manipulations of the skin microbiome composition and, ultimately, enable topical supplementation using substrates for in situ biomanufacturing of beneficial compounds (as well as the repression of microbial pathways associated with the production of harmful metabolites).
In this way, harnessing the live skin microflora for in situ biomanufacturing of beneficial metabolites offers a wide array of potential uses for cosmetic and therapeutic applications. The resulting products would be non-invasive, with a topical application allowing in situ manufacturing and supplementation of bioactives within the skin itself, and would address challenges such as limited shelf- and half-lives of the desired bioactives and excessive dosage and side-effects, as well as reducing cost and environmental burdens as the substates can be derived from a natural and sustainable source. Through such routes, the potential for innovation for microbiome-based function cosmetic solutions is high.
1. Song S, Lee K, Lee YM, Lee JH, Lee SI, Yu SD, et al. Acute health effects of urban fine and ultrafine particles on children with atopic dermatitis. Environmental research. 2011;111(3):394-9.
2. Eberlein-König B, Przybilla B, Kühnl P, Pechak J, Gebefügi I, Kleinschmidt J, et al. Influence of airborne nitrogen dioxide or formaldehyde on parameters of skin function and cellular activation in patients with atopic eczema and control subjects. The Journal of allergy and clinical immunology. 1998;101(1 Pt 1):141-3.
3. Ambaw YA, Pagac MP, Irudayaswamy AS, Raida M, Bendt AK, Torta FT, et al. Host/Malassezia Interaction: A Quantitative, Non-Invasive Method Profiling Oxylipin Production Associates Human Skin Eicosanoids with Malassezia. Metabolites. 2021;11(10).
4. Christensen SA, Kolomiets MV. The lipid language of plant-fungal interactions. Fungal genetics and biology : FG & B. 2011;48(1):4-14.
5. Niu M, Keller NP. Co-opting oxylipin signals in microbial disease. Cellular microbiology. 2019;21(6):e13025.
6. Dawson TL. Malassezia: The Forbidden Kingdom Opens. Cell host & microbe. 2019;25(3):345-7.
7. Findley K, Oh J, Yang J, Conlan S, Deming C, Meyer JA, et al. Topographic diversity of fungal and bacterial communities in human skin. Nature. 2013;498(7454):367-70.
8. Xu J, Saunders CW, Hu P, Grant RA, Boekhout T, Kuramae EE, et al. Dandruff-associated <i>Malassezia</i> genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens. Proceedings of the National Academy of Sciences. 2007;104(47):18730-5.
9. Marples RR, Downing DT, Kligman AM. Control of free fatty acids in human surface lipids by Corynebacterium acnes. Journal of Investigative Dermatology. 1971;56(2).
10. Dawson TL. Malassezia globosa and restricta: Breakthrough Understanding of the Etiology and Treatment of Dandruff and Seborrheic Dermatitis through Whole-Genome Analysis. Journal of Investigative Dermatology Symposium Proceedings. 2007;12(2):15-9.
11. Sawada Y, Saito-Sasaki N, Nakamura M. Omega 3 Fatty Acid and Skin Diseases. Frontiers in Immunology. 2021;11.
12. Krishnamoorthy S, Recchiuti A, Chiang N, Fredman G, Serhan CN. Resolvin D1 receptor stereoselectivity and regulation of inflammation and proresolving microRNAs. The American journal of pathology. 2012;180(5):2018-27.
13. Shaw AC, Goldstein DR, Montgomery RR. Age-dependent dysregulation of innate immunity. Nature reviews Immunology. 2013;13(12):875-87.
14. Kendall AC, Pilkington SM, Murphy SA, Del Carratore F, Sunarwidhi AL, Kiezel-Tsugunova M, et al. Dynamics of the human skin mediator lipidome in response to dietary ω-3 fatty acid supplementation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019;33(11):13014-27.
15. Gupta AK, Batra R, Bluhm R, Boekhout T, Dawson TL, Jr. Skin diseases associated with Malassezia species. Journal of the American Academy of Dermatology. 2004;51(5):785-98.
16. Sawada Y, Saito-Sasaki N, Nakamura M. Omega 3 Fatty Acid and Skin Diseases. Front Immunol. 2020;11:623052.
17. De Luca M, Pappalardo I, Limongi AR, Viviano E, Radice RP, Todisco S, et al. Lipids from Microalgae for Cosmetic Applications. Cosmetics. 2021;8(2):52
18. Yang EJ, Hendricks AJ, Beck KM, Shi VY. Bioactive: A new era of bioactive ingredients in topical formulations for inflammatory dermatoses. Dermatologic therapy. 2019;32(6):e13101.
19. Bieber T. Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nature Reviews Drug Discovery. 2022;21(1):21-40.
20. Notay M, Saric-Bosanac S, Vaughn AR, Dhaliwal S, Trivedi M, Reiter PN, et al. The use of topical Nitrosomonas eutropha for cosmetic improvement of facial wrinkles. Journal of Cosmetic Dermatology. 2020;19(3):689-93.
21. Kao H-J, Wang Y-H, Keshari S, Yang JJ, Simbolon S, Chen C-C, et al. Propionic acid produced by Cutibacterium acnes fermentation ameliorates ultraviolet B-induced melanin synthesis. Scientific reports. 2021;11(1):11980.
22. Zheng Y, Hunt RL, Villaruz AE, Fisher EL, Liu R, Liu Q, et al. Commensal <em>Staphylococcus epidermidis</em> contributes to skin barrier homeostasis by generating protective ceramides. Cell host & microbe. 2022;30(3):301-13.e9.