Team:Paris Bettencourt/SkinMicrobiome

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The skin is a complex surface and microbiomes are communities of microorganisms developing on living complex surfaces…

The Human Skin

As your primary barrier, your skin or the integumentary system, is an important organ which protects against external hazards such as pathogenic microorganisms, helps retain water and ions, protects your nutritive reserves such as glycogen, fat, and free amino acids from pretty much all the living organisms who would otherwise fester on it, protects your organs from moderate physical aggression, and helps regulate your body temperature. If you were to look at a cross section of your skin, there are three general layers we consider. From the deepest layer to the surface, we have the hypodermis (subcutaneous layer), dermis, and finally, the epidermis. Each layer is composed of specific cell types and structures, thus determining specialized functions. Starting from the bottom, the hypodermis is mostly made up of fat cells and connective tissue, this connects the skin to the deeper muscle fibers. The fat also plays a role in electrically and thermically insulating the body, protecting from physical shock and energy storage. The middle layer, or the dermis is the thick inner layer of the skin that contains nerves, connective tissue, blood vessels, lymph vessels, sebaceous glands and hair follicles. As we will see with some examples of physiopathology, this is the source of immune activity in the advent of infection. Finally, we have the upper layer, the epidermis. This layer of the skin is made up of different layers of cells which have various roles, including providing the material for hair formations, sensing and engulfing foreign pathogens and synthesizing melanin for UV protection (this molecule also gives us our pigment!).

Microbiomes: we may be alone in the universe but not within our own body

You might not feel it, but your body is an ecosystem for millions of microbes. In general, we call living organisms that are too small to see with the naked eye (microscopic), ‘microbes’ or ‘microorganisms. This can refer to fungi, bacteria, or viruses among others. There have been great technological advancements that help scientists study the microbiome and it’s been uncovered that it can play an important role in human health. As an example, the gut microbiome can influence cancer (in some cases by promoting a chronic hyper inflammation), autoimmune disorders (both calming it in some cases through immunosuppressive properties, and promoting in some cases through cross-reactions), certain medications (sometimes neutralizing some medications that are metabolized by some micro-organisms, sometimes activating some pro-drug, again through metabolization by come micro-organisms), and sometimes even being able to influence the behavior of its host, and per example its appetite to make him crave food that the microbes want. There’s a lot left to understand and discover about the entire human microbiome, but we know that we are not alone in our bodies, and that our roommates are important.

Skin microbiome: an ecosystem at the frontier between the human body and its environment

The Human Skin: a petri dish hidden in plain sight

The human skin is a 2m2 aerobic, acidic and dry media, host to a hidden yet manifold amount of life. The human gut microbiome is very well known, and the focus of a lot of attention, but the human skin microbiome is much lesser known but nonetheless key to human health. The human skin microbiome is the ensemble of all the microorganisms living on the human skin, therefore as crazy as it sounds, at the exterior surface of the human body. On which layers of the human skin exactly? Well… all of them! Therefore, you can find microbes throughout all these complex and interesting layers of cells and tissues!

It comprises a majority of bacteria, but also some yeasts, and by extent phages infecting them. The diversity seems to be mainly internal, with about a thousand different species of bacteria living on the skin of a given individual, but about the same overall species when looking at different people. The repartition of the species among a given skin is very heterogenous, in the same way we enjoy certain temperatures and environments, so do our microbes. The humidity, nutrient content and pH of regions are among a few important factors that dictate what kind of microbes we’ll find in different zones on the surface of the skin as well as within layers of the skin. Diversity is as diverse, with an average of about 44 different species on the forearm, but only 15 behind the ear, and so is density with about 107 bacteria / cm2 between toes and on armpits, for only about 102 bacteria/cm2 on forearms and torso. So the microbiome is a very riche and very diverse micro ecosystem of microbiomes that functions in a globally harmless way towards the hosts. But in some instances of skin disease, we can see a complete imbalance in the microbiome composition where certain species are overrepresented in the population than normal and the total diversity is decreased. This is called dysbiosis.

There are various ways to evaluate the kind of microbes that live in the skin. First one needs to take a sample which can be easily done with a swab or scraper for an epidermal sample, or with a biopsy to sample deeper layers. To detect what’s present in the samples, there are microbiological methods such as staining for particular types of microbes or even culturing samples. These are limited because one cannot always detect all the microbes present and because their precision is very, very limited and one cannot be certain to have a certain type or subtype of microorganism, because one cannot compare precisely microorganisms found at different places or different points in time. So, the most popular method that are currently widely used is partial or whole genome sequencing where one extracts the microbes from the samples, and then uses techniques and technology that allows for the reading of the microbial DNA and sometimes RNA. There are certain regions that are very specific to particular families of microbes, and regions who are used as some kind of an “ID card” because they are both different enough from one specie or even sub specie to another, and conserved enough to be able to be sure to find it and to be able to compare results easily. With all these techniques, one can get a good idea of the diversity present where the sample was taken. Using these methods researchers and physicians can associate different skin regions with particular microorganisms and learn more about the role this invisible ecosystem has in human health.

So the human skin is a petri dish fostering many microorganisms, with a considerable diversity, very complex organization, and many implications for the health of its host.

The skin microbiome: a web of interaction hidden in plain sight

Such quantity and diversity of life constitutes a mini ecosystem, which means a considerable amount of very complex interactions. Most of the microorganisms of the skin microbiome have a symbiotic or commensal relationship with the human owner of the skin, but nevertheless some are opportunistic pathogens, able to spearhead infections when able to enter the body, and for example access the bloodstream. Even when they are not pathogenic for the human hosts, as said before the microorganisms of the skin microbiome are involved in a lot of interactions, sometimes involving mild or moderate consequences for the host, sometimes involving straight out pathologies. This eco-system is so vast and so complex that microorganisms can indirectly be involved in pathologies by per example having a metabolism that generates byproducts that are key to the development of a pathogen nearby, or inversely, indirectly stop the growth of a pathogen through complex metabolic interactions. This in addition to the many very direct interactions between pathogens and other microorganisms. The “main systems” interacting with the skin microbiome are the skin as a surface through epithelial skin cells, the outside environment through air, everything floating in the air, as well as by definition everything that comes to contact with the human skin, the human body as a circulation system through the blood and lymphatic vessels, and the human body as an eco-system of cells with destruction and neutralization potential through the cells and secreted molecules of the immune system. The skin microbiome is involved in two main types of interactions, external and internal.

External Interactions

The skin microbiome has two main types of “outside” interactions, with the environment and with the human body. With the human body it consists in taking supplies, from the blood stream and from some substances the body produce such as sebum, sometimes at the source from the glands producing it, being on the lookout for opportunities to enter, like openings in barriers such as the skin, and a fine-tuned equilibrium with the immune system. The immune system regulates the growth of bacteria, who themselves tend to modulate its activation, sometimes calming it, sometimes activating it. With the environment it is mainly departure/arrivals of microorganisms, some detaching from the skin, some new attaching, with sometimes other types of interactions such as emission/reception of secreted molecules such as toxins, or communication molecules such as Quorum Sensing/ Quorum Quenching molecules, or straight out macro physical interactions such as mechanic shock, bathing in liquids, or contact with high/low temperature, fire, electricity, etc.

Internal Interactions

As far as interactions between microorganisms of the skin microbiome, they are many, complex, and diverse, ranging from symbiose to predation, with also cooperation or straight up indifference. At the molecular level, those interaction can happen directly, or within specialized structures such as biofilms. Biofilms are medium composed of molecules secreted by microorganisms specifically for this purpose such as Exo Poly Saccharide. They can extend on considerable surfaces, and are the host of many micro organisms who possess specific structures to attach to it and interact inside of it. In some biofilms, micro-organisms of many different species are well organized, changing their metabolisms to make them complementary, and sharing some functions benefiting to many such as antibiotics chemical inactivation by exporting enzymes performing it outside the bacteria to put them inside the media of the biofilm. Cooperation, both metabolic or in other areas, can of course also happen outside biofilms. Key to the regulation of both interactions between micro organisms and the development of biofilms, is the phenomenon of Quorum Sensing. It consists on some micro organisms producing and secreting signaling molecules, and at the same time being able to perceive the concentration in the environment of those molecules. It allows them to have an approximative idea of how many of them are present, and to “make decisions” on many areas such as growth, metabolism, and the production or not of biofilms, based on this. Some type of this communication are species or even sub species specific, some are broader, some microorganisms being able to perceive the Quorum Sensing of other species precisely to have an idea of their presence, their quantity, etc… Competition or even predation consists mainly in the injection (via one of the many very advanced secretion systems possessed by bacteria) or secretion of toxins who can damage or kill the bacteria, through interference with Quorum Sensing via phenomenon such as Quorum Quenching (which is mainly either overproduction of the Quorum Sensing molecules of one species by other species to fool this species into thinking she is more numerous than she is, or on the opposite degradation of Quorum Sensing molecules to hide to a species how numerous she is). Finally it can even be metabolic parasitism, with for example bacteria producing the receptor of metal harvesting proteins such as transferrin without producing the protein, hence parasiting the bacteria spending energy producing the transferrin.

Skin microbiome: symbiotic friend or pathological foe?

Microbiome with Benefits

The human skin microbiome brings to the epithelial table a lot of benefits for its host. Maybe the simplest is that by being non pathogenic and occupying space on the skin, it prevents pathological bacteria from installing there, both by physically occupying the space, but also by occupying the ecological niche and consuming the nutriments. It also physically blocks a certain number of harmful rays from reaching the skin, such as UVs, will contribute to the regulation of skin pH through its mainly acidic metabolism, and produce some metabolites that are useful for the host. Finally, one key, and very complex benefit is the way it both trains and grooms the immune system by cross reaction between harmless skin microbiome bacteria and pathogens, and the way it at the same time modulates it, sometimes training it to not react to harmless bacteria, calming down inflammation, sometimes activating it early when pathogens are present.

Involvement in disease
A reservoir of opportunists

The skin microbiome can be involved in disease in various ways, both in its “normal” state and when it is dysregulated. The most direct way is by fostering opportunist pathogens who can stay at the skin surface and thus be “on the first-row seats for an opportunity to enter the human body” and to become pathogenic. These opportunities can be a dysregulation of the skin microbiome, for example with the decrease in quantity of a specie that usually decrease the quantity of a pathogenic specie, thus allowing it to grow enough to become pathogenic, or a lesion of a skin that allow a specie that is harmless at the surface to enter inside the body and become pathogenic. Another direct way is by provoking an aberrant reaction by the immune system, per example an inadequate immunosuppression that allows an opportunist infection or an overreaction that triggers pathogenic inflammation.

Examples or more complex physiopathology

However, most of the skin microbiome related pathologies would not be related to opportunistic infections. Here are a few examples of those skin microbiome related diseases with a more complex physiopathology

Propionibacterium acnes is a bacterium that thrives on sebum, taking nutriments and amino acids in these cellular debris. In some circumstances, this bacterium would overgrow inside sebum producing follicles, attracted by the sebum gradient. This overgrowth would provoke many physical damages to the human cells nearby, and combined with the cellular debris of the bacteria as well as the cellular debris of the sebum itself, trigger an over inflammation that would lead to the pathology of acnes.

S. aureus is a bacterium that is pathogenic in a lot of contexts but is also very prevalent in the skin microbiome without leading to disease… mainly because it is present in a small amount. In the context of dermatitis, S. aureus would overgrow, and trigger an overinflammation ( by various ways, including its super antigen, a very potent virulence factor able to cross link and activate many TCRs). Along with the inflammation, another manifestation of this disease would be a drop in the overall diversity of the skin microbiome due to the invasive nature of S. aureus.

S. epidermidis: the inside way to the stakes of the skin microbiome

What about S. epidermidis?

S. epidermidis represents approximatively 90% of the aerobic skin flora, and about the 5% of overall skin microbiome species. It is a bacterium that behaves mainly in a mutualistic way, but who can also be an opportunistic pathogen. It is a non-motile gram-positive coccus, who possess ferritin receptors, and who is facultative anaerobic which means that it thrives on growing using respiration but that it can also use fermentation if required. As far as other characteristic features who are very useful when trying to detect and characterize it, it is catalase positive, and coagulase negative, which means that when grown on a medium with blood it doesn’t coalesce it. S. epidermidis also has a strong capacity and tendency to produce biofilms, which can be a huge virulence factor by reducing the ability of antibiotics to diffuse, and because it reduces the metabolism of the bacteria when they are inside the biofilm, preventing the conversion of prodrugs.

S. epidermidis: weaver of biofilms on the medical materiel

As previously said, S. epidermidis has a remarkable ability to produce biofilms. It does so in a variety of environments, but one with critical implications is at the surface of medical devices that will be implanted inside the human body. Having colonized the surface of the device, they enter the body when the device is implanted, and because of their increased resistance in biofilms, they can lead to problematic diseases. Thus, in addition to a broad range of opportunistic diseases, S. epi is one of the most common causes of nosocomial infections via medical devices, such as per example cardiac shafts and IV. It is sensitives to phages, and it led to phase II clinical trials trying to use them to cure osteoarticular infections. However, overall, its pathogenicity remains pretty low and it is considered a class 1 microorganisms, non-pathogenic for the user.

S. epidermidis: a key player in skin microbiome related diseases

S. epidermidis is believed to be involved in the physiopathology of many skin microbiome related diseases, playing a role that seems to be beneficial but who depends on the context, and that could be stabilized and enhanced.

Per example in acnes, S. epi would be involved, with a causality link concerning whether S. epi becomes involved once the disease is developed or if it plays the role in the development of the disease not yet entirely clear. What is now hypothesized is that S. epi would start to grow inside the most damaged sebum producing follicles, and produce succinic acid, which would inhibit the growth of P. acnes, the bacterium responsible for the disease. Thus, even though the complex interactions between the bacteria need to be further explored, S. epi is a very promising therapeutic perspective for acnes.

In dermatis, the outgrowth of S. aureus would provoke in response a growth of S. epi, who could be designed to regulate the growth of S. aureus. Once again, more needs to be explored on the chronology of the interaction between the two bacteria, but this make S. aureus a potential very promising treatment.

Working on S. epidermidis

Working on S. epidermidis brings about a lot of opportunities, in many different ways. First of all, S. epi being a very common and harmless member of the human skin microbiome, it could be a very good “way in” the microbiome, for example to introduce new molecules, or to introduce sensors. Then because of its involvement in many diseases, having tools to work on S. epidermidis could help to elucidate some of the complex physiopathology mecanisms involving it, and then help develop potential therapies, both in contexts when S. epi is the pathogen, and those are many, the nosocomial infections involving medical devices or opportunistic nosocomial infections who touch many in the world every year and will become an increasing challenge with the rise in antibiotic resistance to only name a few, and in context when S. epi seems to be helping, to enhance those beneficial behaviors.

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