The Complex Relationship Between Us, our Skin, and its Microbiota

Thanks to advancements in sequencing technologies and functional studies, our knowledge of the skin microbiota and how it relates to us, the host, and the health of our skin, is constantly improving. We now understand that individual microbes are neither simply beneficial or harmful to us, but that a complex balance must be achieved to maintain homeostasis between our skin and its resident microbes. This balance involves dynamic interactions of the skin not only with the microbes themselves, but also their metabolic products as well as the external environment, host factors, and the interplay of the mind-gut-skin axis.

With many of the underlying nuances and mechanisms yet to be elucidated, significant work is still ongoing to discover how the skin microbiome contributes to healthy or diseased skin. In this blog, we discuss some of the findings to date.

Our skin: an important site for microbial-host interactions

Our skin is a complex terrain replete with lipids and proteins and decorated with a differing arrangement of follicular units and glands, creating unique physical and chemical habitats. These differences in skin microenvironments helps to drive establishment of distinctive niches, which will house diverse communities of microbes. Our skin hosts a large and assorted collection of bacteria, viruses, fungi, and arthropods, and the composition of these inhabitants can vary between people and across different body sites [1]–[6].

It was previously thought that our skin was an exclusively flat surface with an estimated exterior of 2 m2 [7]. However, considering the epidermal invaginations of the skin appendages, the total skin topography is now estimated to be 30 m2 [7], [8]. The new approximate skin surface would be comparable to the effective area of the lungs and the gut, making it more likely to be an important site for microbial-host interactions.

Distinct communities of microbes at different skin microenvironments

The microbial inhabitants of the skin are often commensal, symbiotic, mutualistic, or pathogenic, and some organisms can vacillate between their roles intermittently. The different niches of the skin present varying ecological pressures e.g., humidity, pH, temperature, host-derived metabolites, and nutrients which largely influence the abundance and distribution of different microbes [9].

The skin microbiota is predominantly made up of bacteria and the distribution of skin resident bacteria can vary largely according to the skin topography. Sebaceous skin sites contain the lowest bacterial diversity while dry sites favor a wider diversity, indicating a presence of selection pressure. [10], [11].

In contrast to the rich diversity of the bacterial communities, the composition of the fungal population is relatively uniform across body sites, regardless of topological niche [9], [13]. 18S ribosomal DNA and internal transcribed spacer (ITS) region sequencing showed lower abundance of fungal genomes and metagenomics data aligned closely with culturomics information, identifying the strong dominance of Malassezia spp. [11], [13]. Malassezia yeast colonized almost all body sites with the exception of the feet, which displayed wider fungal diversity.

The benefits of diverse skin microbiota

The diversity profile of the human skin microbiota presents as an indicator of healthy skin or the onset of cutaneous conditions. The balanced relationships of the microorganism communities is intricately linked with skin health, and the physiological condition of the skin can be a core determinant of the structure and functionality of the skin microbiome [11]. It is believed that changes in skin microbiome are consequences of the altered skin environment, rather than the primary cause.

Much like the gut microbiota, many microorganisms on the skin confer beneficial properties. These include microbiome-derived metabolites and antibacterial peptides, which can guard against invasion by or overgrowth of opportunistic pathogens [1], [14]–[16]. As skin is constitutively colonized by its local microbiome, it harbors among the highest numbers of activated or memory T cell populations, much like the GI tract. The skin microbiome primes and trains the host immune system, especially in creating tolerance and active suppression towards commensals [17]. Furthermore, the skin microbiome can regulate the skin inflammatory environment and control the dermal T cells in producing inflammatory cytokines in a distinct and highly compartmentalized manner, preserving tissue homeostasis [17]–[19].

How the host genotype impacts the skin microbiome

Our understanding of the pressures exerted by external and internal factors in shaping the human skin microbiome far surpasses our knowledge of how the human immune system can impact skin-microbiome interactions. One study attempted to identify the effects of the host genotype on the skin microbiome. Through meta-analysis of genome-wide association studies (GWAS), the group narrowed down seven candidate gene functions involved in innate immune signaling, cell differentiation, cell proliferation, environmental sensing, and fibroblast activity that may have important roles in the disease progression of atopic dermatitis [27]. Despite deep combing through GWAS, it was difficult to identify the gene candidates and variants in the host genetics that may influence the skin microbiome.

Nonetheless, emerging evidence provides further insights into the connection between the skin microbiome and host immune response/function. In chronic or inflammatory skin conditions such as atopic dermatitis, mutations in filaggrin result in weakened skin barrier functions and are correlated to disease severity [28]. In AD skin, lower alpha diversity was observed compared to healthy skin in non-lesioned skin sites [29]. Atopic dermatitis flares may be associated with the dysbiosis of the microbiome by influencing the skin surface environment through the interactions with the host immune system. Enrichment of Staphylococci and the reduction of specific Malassezia species may invoke strong immune response in AD skin [30]. In diseased skin, immune response may be muted or the alterations in skin lipids, proteins, and AMPs may also allow uncontrolled growth of pathogens or opportunistic pathogens.

On the other hand, where there is over reactivity of the immune system, such as in psoriasis, pro-inflammatory cytokines IL-17 produced by dermal T cells may also induce abnormal response to skin commensals [31], [32]. Collectively, studies have indicated the dysbiosis in the cutaneous microbiota and a possible strong link between host genetics and the skin microbiome.

Skin aging and the microbiome

The composition of the skin microbiome can undergo restructuring at various stage of life. During puberty, as the skin shifts to become oily due to the increased levels of hormones and growth factors, the activity of sebaceous glands is stimulated and sebum secretion is ramped up. This, in turn, promotes the growth of lipophilic microbes e.g., Cutibacterium, Corynebacterium, and Malassezia [20].

In aging skin, physiological changes in skin texture, topography, lowered sebaceous gland activity and increased transepidermal water loss (TEWL) can alter the skin barrier function and ecological niches of the skin-resident microbes [21]. Numerous studies have described changes in microbiome composition with greater alpha diversity in aged skin. Notably, cohort studies in Caucasian and Asian subjects show an uptick of Corynebacterium but reduction of Acinetobacter and Cutibacterium in older adults [21]–[25]. The different profile of aged skin may also include lowered secretion of sebum and varied classes of lipids, which could further support Corynebacterium growth [26], allowing it to outcompete other microorganisms. One research study corroborates earlier findings that while physical changes in the host’s skin can impact the microbiome structure, such as the higher abundance of Cornyebacterium in the skin of older subjects [33], the skin microbiota can also similarly exert influences on the physiological processes in skin aging. The research highlighted that bacterial metabolic pathways could generate ceramides, pigmentation, and fatty acid reactants or metabolites that may contribute to protein glycation, impacting aging of the skin [33]. The study draws attention to the possible association between microbial metabolism and aging skin although more research is required to validate if a causal and functional relationship is present.

A focus on fungi

Similar observations are also made regarding the eukaryotic community. Many fungal secreted factors are widely regarded as virulence effectors and secreted proteases are well recognized as pathogenic agents in mycoses and varied atopic skin disorders [34]–[36].

Malassezia has always been thought to be an opportunistic pathobiont, closely associated with seborrheic dermatitis and atopic dermatitis. Interestingly, earlier work demonstrated that a secreted aspartyl protease, known as MGSAP1, detected from Malassezia globosa, which is readily detectable on healthy human skin, can confer a protective role in inhibiting biofilm formation from S. aureus biofilm through specifically targeting S. aureus major surface proteins known as Protein A (SpA) [37]. SpA molecules are secreted and anchored to peptidoglycan on the cell wall of multiplying staphylococci to allow the bacterial cells to adeptly adhere to surfaces [38].

MGSAP1 demonstrated strong degradation of SpA and S. aureus biofilm under physiological conditions and high proteolytic activity even when the ratio of MGSAP1 was 200 times less abundant than the substrates [37]. This strongly suggests that MGSAP1 may possess a competitive role in inhibiting colonization from invading microbes especially when both M. globosa and S. aureus coinhabit various skin sites at the same time. It is plausible that Malassezia proteolytic properties can help to deter competition and colonization from the skin microbiota communities, and simultaneously promote host tissue invasion.

The incidental impact of the skin microbiota

The possible altruistic and mutualistic relationships microorganisms can have with a host may result from metabolic processes that have functional relevance to the host, but they can also be due to by-products of the microbe’s cellular metabolism.

One study examining the functional roles of Malassezia furfur proteolytic enzymes showed that a group of secreted aspartyl proteases, known as MFSAP1,can directly modulate the external environment through cleaving host- and other microbial-derived extracellular proteins [39]. However, the de facto functions of MFSAP1 may be more largely involved in controlling Malassezia cell adhesion by secreting hydrolytic enzymes to modify cell surface properties in releasing yeast cells from its own biofilm, transiting from sessile to planktonic phase [39]. MFSAP1 may help to improve the commensal’s colonization on the harsh conditions of skin.

While MFSAP1 does not cause any observable effects on healthy skin, it can induce and exacerbate inflammation, aggravating clinical symptoms of atopic dermatitis in animal models [39]. The study also suggests that secretory hydrolase is not directly involved in driving pathogenesis, but the enzymatic expression is likely to be affected by the abnormal skin environment or stratum corneum. The altered epidermal barrier properties [40] could additionally make the skin more susceptible to penetration and sensitive to microbial enzymes.

It’s in the balance

Our knowledge of the skin microbiota has evolved beyond the archaic categorization of microbes as just beneficial or harmful. The advancement of sequencing technologies and functional studies has allowed us to better describe the functions and roles resident microbes may contribute to healthy or diseased skin.

However, it is imperative to consider the complexities of studying the skin microbiome. While we know that a balanced ecosystem is critical in maintaining homeostasis between the host and microbes, many of the underlying nuances and mechanisms remain to be elucidated. The high interpersonal variability and temporal stability of microbiota composition are further complicated by the dynamic interactions of the skin with the external environment, host factors, as well as the interplay of the mind-gut-skin axis.


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