Commensal skin bacteria as the probiotic of the cutaneous immune response

The skin is the primary interface between the host and environmental microorganisms. An immune response to these diverse microorganisms and other environmental dangers is crucial to survival, but controlling the extent and duration of this response is equally important for health. Recent studies have discovered that common skin commensal bacteria play an important role in balancing the immune response, and likely act in a previously unsuspected manner to benefit the tissue that provides a niche for their growth. Therefore, it is time to reconsider our model for the human skin immune system to begin to recognize that skin commensals participate in our protection and provide essential elements that protect us from infection and uncontrolled inflammation.

Skin microbiota: friend or foe?

Since microorganisms were first shown to cause disease in humans in the 1800s, scientific investigations of the microbial world have been overwhelmingly focused on microbial pathogenesis and on immune responses to organisms. Development of this ‘germ theory’ of human disease has led to millions of lives being saved through improving social hygiene conditions and developing vaccines and antibiotics. However, the vast majority of microorganisms, such as commensals inhabiting on human beings, do not result in disease. These microorganisms typically have benign relationships with their hosts, and a variety of observational studies have suggested a role in development, physiological function and health maintenance, ranging from directing metabolic activity to immune homeostasis [1–3]. The best evidence for the beneficial effects of commensal microbes has been exemplified by observations of indigenous bacteria in the mammalian gut. These bacteria have long been appreciated for potential benefits to the host by providing essential nutrients, metabolism of indigestible compounds, defense against colonization by opportunistic pathogens and contributions to the development of the intestinal architecture [4,5]. However, while the beneficial roles of the gut microbial community have been extensively researched, both theoretically and empirically, for decades, the study of the resident cutaneous microflora in skin health is surprisingly rare. To date, most studies on skin microbes have been conducted to analyze the type and diversity of microbes present on the skin, with a focus on understanding their pathogenic roles in infections. When either characterized by classic culture techniques, or identified by more recent sequencing surveys of 16S rRNA, sparse attention has been paid to the function of these microbes that inhabit our skin. Therefore, we have asked the questions: can skin microbiota benefit its host? And how might this occur? Our results suggest that the most common culturable bacterium on normal human skin, Staphylococcus epidermidis, helps us to balance inflammatory responses after skin injury and increases the ability of the epidermis to mount an effective antimicrobial defense against infections. Thus, drawing an analogy to the role of beneficial microorganisms in the gut, bacteria such as S. epidermidis likely represent the probiotic of the skin.

Staphylococcus epidermidis balances the inflammatory response after skin injury

As mentioned previously, S. epidermidis is the most commonly isolated bacterial species from healthy human skin, and generally has a benign relationship with its host [6–8]. Despite its generally innocuous nature, over the past 20 years the research on S. epidermidis has been focused on its action as an opportunistic pathogen, and the identification of factors contributing to the conversion of S. epidermidis from a member of the resident microflora to an infectious agent. Our recent study has revolutionarily broken this traditional concept and reveals that S. epidermidis controls skin homeostasis via suppressing unwanted inflammatory cytokine production after injury [9]. Importantly, and in contrast to most other probiotics, in addition to observing beneficial actions for S. epidermidis, a specific set of molecular events have been defined to explain the mechanism of action of this organism.

In skin injury, tissue damage results in cellular necrosis, which initiates an inflammatory response that is in part dependent on the capacity of Toll-like receptor (TLR)-3 to recognize the release of self-nucleic acids. Despite the importance of this inflammatory response to normal wound repair, excessive inflammation during wound repair is undesirable in the absence of infection and may cause dysfunction during healing. Therefore, normal immune defense requires that a balance is maintained to minimize unnecessary inflammation yet recruit an appropriate leukocyte response to stimulate wound repair or fight infection. A product of S. epidermidis, lipoteichoic acid, participates in regulating this inflammatory event by the activation of TLR2 signaling, thus triggering expression of the regulatory factor TRAF1, and this subsequently suppresses the extent and duration of TLR3-induced cutaneous inflammation [9]. The action of S. epidermidis is specific to the surface cells of the skin, the keratinocytes, where it maximizes anti-inflammatory action. However, circulating immune surveillance cells, such as monocytes and macrophages that normally exist in a sterile environment, react in an opposite manner to S. epidermidis. Therefore, it appears that an elegant system of coevolution has occurred whereby S. epidermidis benefits the host by dampening unwanted inflammation when it is confined to the epidermis, but is still recognized as a potential pathogen when it penetrates beyond the skin. Unfortunately, this ‘treaty’ between host and the commensal may have been exploited by other pathogenic species of Staphylococci, such as Staphylococcus aureus, as a mechanism of virulence. It is currently not clear how we manipulate this beneficial/pathogenic role during wound healing. One may speculate that the abundance of S. epidermidis surrounding the wound and the specific structure of lipoteichoic acid produced by these species of Staphylococci may be intimately linked to the proper functioning of the immune system, and maintains a capacity to be recognized differently than S. aureus. This hypothesis requires further investigation.

Staphylococcus epidermidis increases antimicrobial defense against skin infections

Besides the regulation of inflammation in skin injury, S. epidermidis produces some antimicrobial molecules to benefit cutaneous immune defense by selectively inhibiting the survival of skin pathogens while maintaining the normal skin microbiome. S. epidermidis produces phenol soluble modulins γ and δ, lantibiotics and bacteriocins (such as epidermin, epilancin K7, epilancin 15X, Pep5 and staphylococcin 1580) [10] to inhibit the growth of S. aureus and group A Streptococcus (or S. pyogenes), thereby reducing the survival of group A Streptococcus, but not S. epidermidis, on skin [7]. By contrast, phenol soluble modulins from S. aureus have been labeled as virulence factors [11].

Furthermore, recent data suggest that S. epidermidis plays an additional protective role by stimulating the production of antimicrobial molecules from keratinocytes. S. epidermidis activates TLR2 signaling of keratinocytes to induce the production of β-defensins, thus enabling the skin to mount an enhanced response to pathogens. Through this direction by the microbe, keratinocytes are thereby able to respond more effectively and efficiently to pathogenic insults, thus playing an important role in defense against both bacterial and viral infections.

Improved hygiene: good or bad?

Observations that a skin commensal can benefit the host suggest that the preservation of these commensals on skin may be an effective way to achieve maintenance of healthy ‘normal’ skin functions. It is only when the host becomes immunodeficient that these microbes will display pathogenic potential. Thus, commensals may be regarded as ‘beneficial’ to the ‘normal, healthy’ host, but can become dangerous to the host with immunodeficiency or disturbed skin integrity. The use of topical and systemic antibiotics that deplete microflora from skin is beneficial when removing pathogens, or in situations where normal host immune defense is compromised, but also has negative consequences under other conditions where the normal immune defense is present and the beneficial effects of the normal microflora can be appreciated. One such situation where the normal microflora may be particularly missed is in atopic eczema. Here, both uncontrolled inflammation and the increased growth of pathogenic bacteria are characteristic of the disease. It is tempting to speculate that the association of improvements in personal hygiene with an increased risk of allergic and autoimmune disease [12] could be due in part to the indiscriminate depletion of the normal skin flora in such environments. This concept is supported by epidemiological and clinical reports documenting increased incidence of ulcerative colitis, Crohn’s diseases, colon cancer, asthma and multiple allergies in societies with improved medical care and hygiene [13]. It is thereby a new challenge for the traditional concept of good hygiene.

Implications & perspectives

Commensals have a bidirectional relationship with their host between symbionts and opportunistic pathogens. How do keratinocytes sense skin microflora and mediate immune responses to discriminate commensals from symbionts and pathogens? TLRs are the best-studied pattern recognition receptors in keratinocytes. The ligation of TLRs by pathogen-associated molecule patterns leads to the activation of host cell signaling pathways and subsequent innate and adaptive immune responses. The abundance or specific structure of pathogen-associated molecule patterns from symbionts or pathogens might dictate this different recognition, but further investigation is needed. Furthermore, it has recently been proposed that the total information encoded by the mammalian genome is not sufficient to carry out all functions that are required to maintain health, and that products of our microbiome are crucial for protection from various diseases [14]. If commensal bacteria are actively shaping a healthy immune system, does the absence of commensals or alteration of the composition of the microbiota on the skin surface lead to disease? The study of germ-free mice at the tissue, cellular and molecular levels might help to address this question.

Taken together, a beneficial partnership has evolved between skin commensals and the host immune system. Harnessing the immunomodulatory capacity of symbiotic factors from commensal bacteria has a potential therapeutic role in human inflammatory diseases or infections, and may provide the basis for the development of therapeutic strategies for the treatment of skin disease with known deficiencies in barrier function and innate immunity, such as atopic eczema [15].

Financial & competing interests disclosure

This work was supported by NIH grants NIH R01AR052728, NIH R01AI052453, NIH R01AI083358 and a VA Merit Award to Richard L Gallo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.