PracticalDermatology

Significant progress has been made in understanding how bacteria interact with their local environment and how that interplay factors into human health. Advances in the ability to decipher genomic information allow researchers for the first time to describe the functional role of microbes in maintaining health, controlling pathogenic species, and priming the immune system to respond to foreign microorganic species.

Implications for this new science are particularly relevant for dermatology. In contrast to the gut and other body sites, the microflora on the skin is highly diverse (Figure 1). In turn, that diversity confers an advantage for harnessing the inherent beneficial properties of the microflora to affect the health of the skin. According to the Shannon algorithm, which quantifies the stability of a given microenvironment based on the diversity of its species, lower biodiversity is associated with a lesser degree of stability—similar species competing for the same nutritional sources create the conditions for opportunistic foreign invaders to outcompete native species. A similar model can be constructed in skin impacted by atopic dermatitis (AD): unaffected skin has high biodiversity, whereas affected areas have low biodiversity. In this sense, a highly diverse microflora in unperturbed skin has protective benefits, and, intuitively, resetting the balance might restore the skin’s health. In psoriatic skin, on the other hand, unaffected and affected skin has similar Shannon diversity, because the integrity of the skin overall is diminished. In psoriasis, the active microorganism milieu is a consequence and not a cause of the skin condition. Resetting the normal state may still have benefit, as the unnatural microorganism culture is helping to potentiate the disease process.

Figure 1. Bacterial Community Variation in Human Body Habitats

Commensal Bacteria And Healthy Skin

Bacterial growth is highly dependent on its local environment. In this regard, the specific type of bacteria that thrives on human skin varies according to body site and differs individually. This is because pH and temperature, two factors that influence bacterial viability, differ according to body site and also change from person to person. These kinds of fluctuations are not found at other body habitats, which helps to explain the more homogenous species distribution among internal organs. Regardless, the implication of multiple micro-habitats on human skin is that while, generally speaking, the same dominant bacteria are present on skin between individuals, the representation of the remaining population of bacteria is highly variable.

Importantly there are no “good” or “bad” bacteria; in fact, they are biologically inert and only gain beneficial or harmful properties based on their interactions with their culture media—in this case, referring to the human skin and the context of other microorganisms. Bacteria are, for example, a major nutritional source for fungi. Thus, it is easy to appreciate that if certain bacteria are able to proliferate on the skin, and able to do so in sufficient quantity, they can be a veritable feeding trough for potentially harmful microorganisms.

Another way skin biome makeup becomes important relates specifically to barrier function. So-called healthy skin with a “normal” microbiota helps preserve the integrity of the skin. This has been described by some as almost a second skin. On the other hand, if certain bacteria are overabundant, they trigger biologic pathways leading to inflammation and/or others that impair important immune functions while also disrupting the barrier.

In a similar fashion, the ability of the skin to maintain the particular makeup of its biome—also known as its commensal bacteria—is consequential for adaptive immunity. Bacteria have a natural defense mechanism in the form of production of bacteriocin, proteins that inhibit the growth of a competing species. When native species bacteria produce these peptides, they are also recognized by keratinocytes, in essence educating the immune system. In the presence of non-native species (ie, potentially pathogenic bacteria), various toll-like receptors (TLR) in the keratinocytes become activated. Once conjugated, TLR transmembrane proteins share a common pathway, leading to upregulation of antimicrobial peptide (AMP) production.

Several studies have demonstrated the influence of commensal bacteria on skin pathogens. For example, it has been shown that Staphylococcus epidermidis induces expression of the antibiotic beta-defensin peptide family. Other studies show that S. epidermidis and S. aureus activate different pathways that influence the degree and type of AMP production.

Influencing Commensal Bacteria for Therapeutic Benefit

Based on these concepts, interest has turned to how restoring balance to the microbiota might confer benefits for the health of the skin. In one study, samples were acquired from affected areas and adjacent skin areas of patients with AD to assess the composition of the local microbiome. Assessments were taken at baseline and again after 84 days of treatment with Lipikar AP+, a product that contains prebiotics, or substances that encourage growth of beneficial microorganisms. Patients were a mean 12 ±9 years of age, and the mean SCORAD index was 33.

As shown in Figure 2, prior to treatment, the local microbiome differed in affected and unaffected skin areas; as well, both differed greatly from samples taken from healthy skin of patients with no known history or diagnosis of AD. Specifically, skin areas affected by AD demonstrated an overload of Fimicutes, which indicates a high level of Staphylococcus species—both S. epidermidis and S. aureus—and a low representation of actinobacteria (which has known antibacterial activity) and probiotics.

Figure 2. Healthy vs. Lesional vs. Non-lesional

A graphical representation of the post-treatment effect is shown in Figure 3. Notably, the microbial diversity in affected skin areas was similar to that of unaffected skin both before and after treatment. While there was a decline in Staphylococcus species overall, there was an increase of Stenotrophomonas. As are other members of the Xanthomonadaceae family, the latter is keratolytic, which has potential consequences for counteracting the hallmark keratinocyte hyperproliferation of AD.

Figure 3. Lipikar Balm AP+ Influences Skin Microbiata

The study supported the hypothesis that AD is associated with skin microbiome dysbiosis and that the microfloral balance can be restored without antibiotics. It also suggested that restoring barrier function may not be sufficient, whereas regulation of the bacteria population to restore homeostasis may be more meaningful. Further evidence to support the latter derives from a second protocol supported by La Roche-Posay in which water containing selenium and strontium, mannose, and a postbiotic product (Aqua Posae Filiformis [APF]) were added to the regimen. These additional measures have strong biologic rationale. For one, Gram-negative bacteria, which are more effective at priming the immune system than Gram-positive bacteria, are more hydrophilic than Gram-positive species. Second, S. aureus is more adapted to grow in dry environments compared to S. epidermidis. Third, mannose is a prebiotic food source for encouraging growth of beneficial bacteria. Fourth, the postbiotic compound, which is essentially an immobilized probiotic, supports bacterial growth and viability. At the end of the study, it was found that APF induced higher expression of human beta-defensin 2 (as noted above, a known antibiotic) and that APF and mannose combined to increase S100A7 expression, which is another keratinocyte-derived antimicrobial protein.

Conclusions

Of approximately 30,000 formally recognized bacterial species, only 20 genus have been identified to have pathogenic potential, though they are not disease causing on their own.

There are many examples of bacteria providing benefit to other species. The endosymbiotic theory states that mitochondria and chloroplasts are derived from primitive bacterial cells. More germane to the field of medicine, and to dermatology in particular, strong evidence from treatment trials suggests that harnessing the activity of the microbiome and resetting the natural order composition can have clear and positive benefits for health.

Richard Martin, PhD studies the relationship between skin disease and barrier function. He started research in this field in 2008 with Martin Blaser (NYC) and then Noah Fierrer (Denver) and for the past six years in France with INRA. He and his colleagues pioneered a holistic vision of skin microbiota when other researchers focused on gut bacteria.