Your microbiome and you (part II): Skin

by Jim Caryl

This post was chosen as an Editor's Selection for ResearchBlogging.orgTHIS is the second of two posts featuring studies on the human microbiome. In part I we looked at your gut, the relative merits of probiotics, and several studies from the lab of Jeffrey Gordon looking at how the gut microbiome changes in obesity. In this post I will look at some very recent studies that, rather than looking at a whole community of bacteria, focus on one bacterium that is resident on our skin.

This is perhaps seemingly at odds with the message that I conveyed in part I, which focussed on large, diverse communities; and in which I was sceptical of the real benefit of taking a monoculture as an aid to health. However, in this post we’ll look at what has been learned about the interaction of this single resident species with our skin, how it may help to control your skin’s response to injury, and in fact may even join forces with your body to fight off pathogenic, disease-causing, bacteria. This has potential implications for therapies that destroy the skin microbiome, and for the employment of fastidiously over-hygienic practises that restrict the development of a healthy microbiome.


Upper layer of epidermis made of dead skin cells that slough off to be replaced by the living cells beneath.

Our skin, just like the gut, is home to an abundance of microbial communities that differ in composition depending upon location. One of the more prevalent of these residents (also known as commensals) is a bacterium called Staphylococcus epidermidis, an otherwise innocuous coloniser of healthy skin.

The surface of our skin, the epidermis, represents our largest physical barrier against the environment, and plays a delicate balancing act between initiating an inflammatory immune response to invading pathogenic bacteria, or injury, whilst also tolerating the resident bacteria on its surface. Inflammation is an undesirable yet necessary protective response that activates several defensive strategies, from the production of antimicrobial peptides that actively kill bacteria, to directing the secondary ‘adaptive’ immune response, and tissue repair. However, persistent inflammation in the absence of infection leads to poor healing and dysfunctional healing 1.

Two recent studies from the lab of Richard Gallo, at University of California San Diego Medical School, provide a tantalising case for the benefits we may receive from components of our skin microbiome, such as S. epidermidis. In the first of these studies 2, Yuping Lai and co-workers tested the hypothesis that the microbiome may ‘serve to protect the host from unintended inflammatory diseases’. They demonstrate how a product of staphylococci, lipotechoic acid (LTA), suppresses skin inflammation during wound repair, thus preventing a normal inflammatory response from becoming excessive.

Epidermis-dermisIt is well known that certain receptors on the surface of keratinocytes, the cells that make up your skin, are able to detect the products of  bacteria; these receptors, known as toll-like receptors (TLRs), signal other cells using small molecules called cytokines, which in turn initiate a cascade of events that result in an inflammatory response. Yet commensal species such as S. epidermidis, which live on keratinocytes, do not initiate inflammation. The hypothesis was that S. epidermidis must be able to interfere with the signalling of TLRs, and in doing so it seems it is not only able to evade being recognised as an enemy, but it can also help decrease the magnitude of inflammation associated with skin injury.

When your skin is injured, dead cells release their contents, and these act as potent signals to surrounding cells that something is wrong. The researchers knew that a particular type of TLR, TLR-3, has been identified as a means by which cells on the surface of the gut detect cell death. It was previously thought that the main role for TLR-3 was in the recognition of viruses, by way of the particular type of nucleic acid coding material that some viruses carry, RNA. The researchers show for the first time that in fact the RNA released from necrotic human cells triggers TLR-3 on neighbouring healthy keratinocytes, and these in turn, stimulate a proinflammatory response via production of cytokines.

It therefore follows that if S. epidermidis wants to maintain a quiet life, it is in their own interest to help control excessive inflammation that may expose them to the full force of the immune system, which is unlikely to look on their presence so kindly. So it is that the lipotechoic acid (LTA) S. epidermidis produces triggers another type of TLR, TLR-2, on the surface of keratinocytes. Thus, just as TLR-3-triggered cells would begin to kick-off a proinflammatory response, the LTA-TLR2 interaction triggers the production of a protein called N-TRAF1 that then inhibits TLR-3, so reducing the degree of inflammation in response to injury.

This is a previously unknown mechanism by which a staphylococcal product suppresses inflammation. It is worth remembering however that whilst LTA has this unique interaction with keratinocytes, should they be detected by cells of the immune system, or deeper tissue, it would have the opposite effect. Cells that are not exposed to the microbiome would recognise all such signals as foreign, and mount a defence accordingly.

The authors finish by suggesting a therapeutic implication:

“Local modulation of the inflammatory response by products of bacterial commensals at the site of such an injury might be a beneficial therapeutic strategy for management of wound healing complicated by excessive inflammation or control of other inflammatory skin disorders. The trick will be to evoke a reduction in the detrimental aspects of inflammation without increasing the risk of wound infection.”

plosoneIn the second of the two studies from the Gallo lab, Anna Cogen and co-workers turn their attention to antimicrobial peptides (AMPs) 3. These are small strings of amino acids that are produced by most organisms, in one form or another. In humans they are produced by several different cell types, including keratinocytes. Here they form an important component of our innate immune defence in which they regulate the occupation of our skin by microorganisms, and are produced at the site of a skin wound where they help dispatch invading bacteria, and mediate in triggering wound healing and adaptive immune response.

Cogen and co-workers build on their previous observations that S. epidermidis also produces AMPs on our skin, which may act as an additional antimicrobial shield. Remarkably, they have now identified one such S. epidermidis AMP, called PSMγ, that cooperates with our own AMPs to kill Group A Streptococcus, the causative bacterium of several unpleasant diseases: impetigo, strep throat, scarlet fever and necrotising fasciitis.

From: Gallo & Huttner (1998) Journal of Investigative Dermatology 111, 739–743In humans, several AMPs have been characterised and given singularly memorable names, some of which include: LL-37, and CRAMP, both of which are referred to as cathelicidins, also hBD2 and hBD3, which are β-defensins. So how do our AMPs work? Well there are several mechanisms, LL-37 for example is a pore-former that functions by coalescing with other molecules of LL-37 on the bacterial cell surface, and so destabilising it to form a hole (see figure – left). Bacteria don’t respond well to having holes poked in them, and tend to die as a result.

LL-37 and other human AMPs can be found in keratinocytes at sites of inflammation, and thus are typically produced in regions of psoriasis and other skin inflammatory disorders. They can also be found in a particular cell type that moves to the site of open wounds, called neutrophils. Neutrophils are cells that form part of the innate immune system, and which are ultimately the major constituent of pus; they help stimulate further inflammation, but also directly attack bacteria in three ways: phagocytosis (ingestion), release of AMPs, and generation of neutrophil extracellular traps (NETs) – sticky webs that ensnare pathogens and any toxins they may secrete, and help deliver AMPs.

It is not unusual for different human AMPs to act alongside each other in a synergistic manner, i.e. having an effect greater than the sum of their parts, which is often the case when they are glued up in the sticky NET of neutrophils. The researchers decided to investigate whether S. epidermidis PSMγ could join the party and similarly interact with our AMPs to improve the overall bacterial inhibition and innate immune response.

Having identified that PSMγ is detectable on human epidermis and hair follicles, the researchers then looked to sites of injury where, as I mentioned, we expect to see a high number of neutrophils. S. epidermidis PSMγ is able to both stimulate the production of and bind to the sticky NETs. Furthermore, the researchers show for the first time that it is able to physically bind with each human AMP (LL-37, CRAMP, hBD1 and hBD2) enhancing the individual abilities of these AMPs to kill Group A Streptococcus in whole blood, and in a mouse wound that has been pretreated with PSMγ.

“Here, we suggest that S. epidermidis benefits the host and provides an additional layer of protection against skin pathogens. S. epidermidis rather than acting alone, is able to kill pathogens by complementing the host’s innate immune system.”

We can envisage that following a skin injury S. epidermidis will, to a certain degree, suppress excessive inflammation. Furthermore, the AMP S. epidermidis produces is readily found on our skin, providing an additional shield of antimicrobial protection. Any injury would likely bring S. epidermidis, and its products, into the wound where it will encounter other cells of the innate immune system, where it may increase production of antimicrobial NETs.

These studies also perhaps provide a molecular basis for the ‘hygiene hypothesis’, namely, that the lack of exposure to ‘dirt’ in early childhood increases that child’s later susceptibility to disease; this may in part be due to the poor education of their immune system and lack of recognition, or tolerance, of their own microbiome. The type of treatment we seek for inflammatory skin disorders or infections should also take into account the role of our skin microbiome.

We should seek to preserve the human microbiome where possible, and try to anticipate the effect that of a course of antibiotics could have on the various microbiome communities. However, as with all things, seemingly mutualistic arrangements with microorganisms represent a double-edged sword. Otherwise innocuous commensals, including S. epidermidis, are well capable of causing disease in people with failing immune systems, especially when they can gain access to the deeper layers of skin via catheters and shunts. Commensals also act as reservoirs of antibiotic resistance, by dint of their more or less permanent colonisation of our bodies. This exemplifies the issues with using broad-spectrum antibiotics, with the development of resistance that can be passed from harmless microbiomal species to visiting pathogens.


While we’re on the subject of skin, another notable paper hit the news during the week focussed on effect of circumcision on the penis microbiome. The work is potentially quite important, but in an inherently controversial field of discussion. Jonathan Eisen over at the Tree of Life blog has a good researchblogging write up of that article.

1. Gallo, R.L. and Nizet, V. (2008) Innate barriers against infection and associated disorders. Drug Discov Today Dis Mech. 5: 145–152.

2. Lai, Y., Di Nardo, A., Nakatsuji, T., Leichtle, A., Yang, Y., Cogen, A., Wu, Z., Hooper, L., Schmidt, R., von Aulock, S., Radek, K., Huang, C., Ryan, A., & Gallo, R. (2009). Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury Nature Medicine, 15 (12), 1377-1382 DOI: 10.1038/nm.2062

3. Cogen, A., Yamasaki, K., Muto, J., Sanchez, K., Crotty Alexander, L., Tanios, J., Lai, Y., Kim, J., Nizet, V., & Gallo, R. (2010). Staphylococcus epidermidis Antimicrobial δ-Toxin (Phenol-Soluble Modulin-γ) Cooperates with Host Antimicrobial Peptides to Kill Group A Streptococcus PLoS ONE, 5 (1) DOI: 10.1371/journal.pone.0008557