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Background on Malassezia
The skin surface micro-environment is colonised by a wide range of microorganisms, including bacteria, archaea, viruses, and fungi. Collectively this is referred to as the skin microbial community or microbiome. Malassezia was discovered in the 19th century by Malassez and Sabaouraud. Malassezia is the major component of the fungal skin microbiota, is present on all humans (and warm-blooded animals), and is most abundant on sebaceous (oily) body sites. It is a lipid dependent microbe, which is quite unusual.
As shown below, in different areas of the body, even if it is oily, moist or dry, Malassezia is the only resident fungi found on all skin. The only skin area with a higher diversity is the toes and the feet, where there is a rich diversity of skin fungi. For example, there are a variety of different fungi related to athlete's foot and nail fungus. Of course, our feet are our connection to the outside environment so this makes sense, as evolutionarily speaking feet would have a higher diversity of fungi because they (without wearing shoes) are exposed to more microbes than other areas of the skin.
Recent Studies
Professor Thomas Dawson is a major player in skin microbiota and has spent his career understanding this specific microbe called Malassezia. His work has been aimed at uncovering whether Malassezia is commensal, pathogenic, or protective (mutualistic), and this work is what we will focus on here.
A literature review paper ‘Cutaneous Malassezia: Commensal, Pathogenic, or Protector?’ (Chandra et al 2021) in which Tom Dawson is the lead author, is a significant article and one to which we would like to draw attention. The study had two main objectives; firstly, to advance our understanding of Malassezia in the context of pathogenicity, commensalism, and mutualism, and secondly to share what we know about microbe-microbe and host-microbe interactions.
The skin fungal population is almost always overlooked, as over the last decade the focus has been primarily on 16S rRNA sequencing specific to bacteria. However, fungi are increasingly found to be important for human health and disease. Consequently, work to uncover the importance of this microbe is extremely important and valuable.
What we know
Commonly published articles reference that skin is occupied by 90-95% bacteria. However, this misrepresents the proportion of the microbial community, as it counts the number of genomes. As Malassezia are huge compared to bacteria, Malassezia have 200-500 times the cellular biomass per genome relative to Staphylococcus epidermidis, a representative and common skin bacterium. Hence, they have similar biomass to bacteria on the sebaceous areas, for example places like the forehead where there is a lot of oil and lipids. Moreover, Malassezia have haploid genomes of 8-9Mb, emphasizing how well adapted they are to their specific environment and which makes them have among the smallest genomes for free-living fungi.
Malassezia genomes encode lipases, phospholipases, and acid sphingomyelinases for utilisation of lipids, and proteases for utilisation of proteins. Thus, they are equipped with everything they need to be able to survive on our skin. Lipases secreted by Malassezia decompose the human skin sebum-derived lipids, such as mono-, di-, and triglycerides, into saturated and unsaturated fatty acids. The saturated fatty acids, which are healthy for skin, are consumed by Malassezia for survival, whereas the unsaturated fatty acids accumulate on the stratum corneum. One theory is that this accumulation might interfere with the permeability of the skin barrier thereby leading to various skin disorders. One such example of this is scalp dandruff.
In this article the Malassezia clade is subdivided into three major groups; Group A, Group B, and Group C. Group A are considered M. furfur-like, are more robust in culture, less frequent inhabitants of human skin, and more often linked to skin or septic disease. Group B are common on healthy human skin, with M. restricta and M. globosa by far the most common and found on the skin of all humans, followed by M. sympodialis, then distantly by the other Group B members. The Group B exception is M. pachydermatis, which can cause human septic infections but is only normally found on animal skin. Group C are divergent Malassezia, found specifically on animal species such as rabbit ears and bats.
Phylogenetic tree for Malassezia species, taken from Chandra et al 2021.
Malassezia in Ageing Skin
The amount of Malassezia on skin changes throughout a person's lifetime. At birth, neonatal sebaceous glands are turned on by hormones present in the maternal circulation and therefore produce lipids supporting initial Malassezia colonization and growth until around 3 months. Malassezia then decrease in number as the sebaceous glands shut down from lack of stimulatory androgens. Upon puberty androgen secretion increases, sebaceous glands turn back on, and the Malassezia population again takes over. This sebaceous activity is slowly lost with the decline of androgen stimulation during adulthood, where skin is typically drier. This effect is particularly apparent during menopause.
A depiction on the amount of Malassezia present on the skin over a lifetime, Sequential.
As Malassezia are among the major commensal fungi in neonates, it is hypothesised that they may also induce and establish specific immune tolerance pathways, involving regulatory T cells (Tregs), in essence “training” our immune systems as to what is “self” and what is not (Dhariwala et al 2021). So, early exposure to Malassezia is critical in training our immune system to be familiar with Malassezia, as we need Malassezia as a commensal or protective mutualist on our skin. Importantly, this happens regardless of whether birth is vaginal or via caesarean.
Malassezia in Skin Disease
Differently from the gut and the gut microbiome, healthy skin has a low microbial diversity dominated by a very few species: Malassezia, C acnes, and healthy Staphylococcus. Keratinocytes sense microbial populations through recognition of microbial pathogen-associated molecular pattern (PAMP) motifs via their pattern recognition receptors (PRRs), leucine rich repeat (LRRs) containing receptors, and Toll-like receptors (TLRs). These initiate a cascade of inflammation, signalling to the immune system to secrete antimicrobial peptides that can rapidly inactivate any pathogenic microorganisms.
Malassezia is associated with multiple different skin diseases, with conditions either being caused or exacerbated by alterations by Malassezia in changing skin. One possible mechanism of Malassezia mediated skin disease is host genetic susceptibility. In this hypothesis, an underlying genetic difference in individuals causes the same Malassezia or their metabolites to be toxic to some people, but not others. For example, a defect in skin barrier properties might mean a toxin could penetrate and cause trouble in people with susceptibility but not in others. In this case the same Malassezia and metabolites could be present on both individuals, but only one be affected. This is common in many fungal mediated diseases and has been clearly demonstrated in dandruff (DeAngelis et al 2005).
When there are even mild barrier defects, Malassezia can cause the common skin condition pityriasis versicolor, this is most commonly associated with M. furfur, M. globosa and M. sympodialis. There is increasing evidence about the role of Malassezia in inflammatory skin conditions, such as atopic dermatitis and psoriasis. Malassezia metabolites trigger a scalp inflammatory response causing dandruff, and in severe situations seborrheic dermatitis, and can invade and inflame hair follicles to cause folliculitis. Moreover, infantile seborrheic dermatitis associated with M. furfur shows a scaling scalp, ‘cradle cap’, which may be improved by an antifungal shampoo (although this is not a particularly targeted approach). Outside of the skin field, the contribution of Malassezia has now been found in conditions like Crohn’s disease (Limon et al 2019), and cancers such as pancreatic cancer (Aykut et al 2019), demonstrating the importance of this microbe in the fine balance of human health.
Future Directions
Looking towards the future, an improved understanding of the host-Malassezia relationship offers potential for the development of treatments to improve skin health outcomes. In a more cosmetic context, there is also opportunity to develop and introduce prebiotic or post-biotic metabolites to restore healthy skin microbiome, to normalize skin microbiome diversity, and restore functional attributes such as barrier, dryness, inflammation, and reverse dysbiosis. Thus, giving the healthy microbes which already live on our skin the right environment and the right nutrients may be used to improve skin health. However, there are still question marks and issues with using probiotics on the skin, and we are still yet to see the engineering of a beneficial probiotic in the context of Malassezia, bearing in mind here that it was only in the 2000s that Malassezia was first genetically engineered because it was indeed so difficult to do so. Ultimately, we conclude that more research is needed to address the mechanistic processes in fungal-fungal, and microbe-host for skin health and disease, but are hopefully awaiting future developments in this fast-moving arena.
References
Aykut, B., Pushalkar, S., Chen, R. et al. (2019). The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 574, 264–267. https://doi.org/10.1038/s41586-019-1608-2
Dhariwala, M., and T Scharschmidt (2021) Baby’s skin bacteria: first impressions are long-lasting. Trends Immunol., https://doi.org/10.1016/j.it.2021.10.005
Limon JJ, Tang J, Li D, Wolf AJ, Michelsen KS, Funari V, Gargus M, Nguyen C, Sharma P, Maymi VI, Iliev ID, Skalski JH, Brown J, Landers C, Borneman J, Braun J, Targan SR, McGovern DPB, Underhill DM. (2019). Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models. Cell Host Microbe. 2019 Mar 13;25(3):377-388.e6. doi: 10.1016/j.chom.2019.01.007. Epub Mar 5.
Vijaya Chandra, S. H., Srinivas, R., Dawson, T. L., Jr, & Common, J. E. (2021). Cutaneous Malassezia: Commensal, Pathogen, or Protector?. Frontiers in cellular and infection microbiology, 10, 614446. https://doi.org/10.3389/fcimb.2020.614446
Yvonne M. DeAngelis, Christina M. Gemmer, Joseph R. Kaczvinsky, Dianna C. Kenneally, James R. Schwartz, Thomas L. Dawson. (2005). Three Etiologic Facets of Dandruff and Seborrheic Dermatitis: Malassezia Fungi, Sebaceous Lipids, and Individual Sensitivity. Journal of Investigative Dermatology Symposium Proceedings. https://doi.org/10.1111/j.1087-0024.2005.10119.x.
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