Skin Microecology: Title and subTitle BreakThe Old and the New

Interest in the ecology of skin bacteria and the skin as a habitat has waxed and waned over the past 30 or so years. The past few years have been a particularly active time as were the 1970s. Thirty years ago, a wealth of research demonstrated that different regions of the skin have distinct and reproducible bacterial populations that are determined by the cutaneous anatomy.¹

Three major factors were shown to determine the skin habitats: moisture, lipids, and the ability to maintain a reduced environment. Sebum is the most potent determinant of skin flora. Prior to the pubertal surge in testosterone, sebaceous glands are inactive and the skin microflora is greatly reduced. After puberty, in areas where sebum is plentiful, such as the head and upper trunk, there is a stable population of lipophilic organisms numbering in the tens of millions. The anaerobic propionibacteria dominate the region by virtue of an extracellular lipase that liberates glycerol from sebaceous triglycerides, which is then used as a carbon source. The fatty acids are unused by the bacteria and remain in sebum. The sebaceous gland provides a second ecological determinant, an enclosed relatively anoxic crypt where facultative anaerobes like propionibacteria can survive in the depths and lipophilic aerobes such as yeast of the Malassezia genus occupy the acroinfundibulum.^{1 - 3}

The presence of triglycerides in sebum is a characteristic unique to humans, as is the presence of a stable microflora.^{1 ,4} Animal sebum does not contain lipids that can be used metabolically by bacteria, and hence the presence of sebum does not provide a selective advantage for lipophilic organisms.⁴

In nonsebaceous regions, the major ecological factor is the availability of water. Areas that have numerous sweat glands and restricted airflow, such as the axilla, groin, and toe web, support large populations of “hydrophilic” bacteria, most notably gram-negative rods and Staphylococcus aureus.^{5 - 6} Occlusion of dry areas such as the forearm with a wound dressing mimic this anatomy and reproduce the hydrophilic flora.⁶ When the scalp, a sebaceous area, is occluded, there is no change in flora, pointing to the potency of sebum as an ecological determinant.⁶

The resident flora may provide protection against invasion by pathogens. Fatty acids cleaved from sebaceous triglycerides and those produced as metabolic byproduct may have benefit for both the resident bacteria and their host because sebaceous fatty acids have been shown to inhibit staphylococci and streptococci.^{7 - 8} Interestingly, puberty seems to lower the risk of facial impetigo, which is perhaps a reflection of sebaceous fatty acids inhibiting streptococcal colonization. Similarly, it has been shown that as many as 20% of skin resident bacteria produce compounds that are inhibitory to colonization by invading pathogens.⁹ Taken together with the observation that eradicating the resident skin flora aids colonization with Staphylococcus aureus, these findings may explain the ease with which neonates (who are virtually sterile at birth) acquire staphylococci infections.

After two and a half decades of minimal interest, there has been a resurgence in research on factors influencing the skin flora. Three areas have received particular attention: components of the innate immune system in the skin, the effect of antibiotics on skin bacteria and the acquisition of resistance, and the effect of bacterial products designed to evade immune defenses.

There is some confusion in the literature about the nature of microbial biofilms. As usually defined, a biofilm is the product(s) of bacteria that allows them to control their environment and interact with their host. When the term is used in a way consistent with its use in scientific literature, the skin does not have a biofilm of its own.

Skin bacteria do produce true biofilms. One of the first reported examples was the extracellular polysaccharide produced by certain strains of Staphylococcus epidermidis that cause miliaria rubra.¹⁰ When normally dry skin is kept hot and moist, the bacteria proliferate and the polysaccharide physically plugs the sweat gland resulting in an inflammatory papule. A similar exopolysaccharide has been shown to allow S epidermidis strains to evade phagocytosis by neutrophils.¹¹ Aureus produces an extracellular glycocalyx that, in combination with coagulase-mediated conversion of fibrinogen to a fibrin, results in an adhesive matrix that both anchors the bacteria on the skin and isolates it from phagocytes and other elements of innate immunity. Strains isolated from impetigo and furunculosis have been shown to have an enhanced production of this glycocalyx, suggesting that it is a bona fide pathogenic factor.^{12 - 13} Potential applications of this observation include dressings for indwelling catheters that release compounds inhibitory to glycocalyx production and dressings for chronic wounds that minimize the effect of bacterially produced biofilms.

A relatively recent discovery is the presence of families of small peptides (including defensins, cathelicidins, psoriasins, and dermcidins) in the skin and other organs that are inhibitory to bacteria. In general, the antimicrobial peptides are cleaved from larger precursor molecules by proteases including cathepsins and metalloproteinases. Dermcidins are produced constitutively in eccrine sweat, while defensins and cathelicidins are induced by damage to the skin.^{14 - 16} The exact role of the various peptides in host defense is still being worked out, but there is evidence that in patients with atopic dermatitis, those who are readily colonized by S aureus are deficient in cathelicidin and dermcidin.^{17 - 18} It would be interesting to examine whether the gram-negative strains that survive on moist sweaty skin or the staphylococci that produce miliaria are resistant to these dermcidins. Likewise, it is tempting to speculate that antimicrobial peptides might have therapeutic potential in skin infections or acne. However, despite many attempts, there have been no successful peptide drugs developed for these indications. The reasons for this failure are not clear. Potential explanations include an inability to deliver the peptides where they are needed (eg, an impacted sebaceous follicle), the possibility that special vehicles are needed to deliver an active peptide, and degradation of the molecules by skin and bacterial proteases. It is also possible that the majority of patients have a superabundance of antibacterial peptides so that adding exogenous peptide is of no benefit. Specialized patient populations, such as atopics deficient in cathelicidin, may have to be identified before antimicrobial peptide drugs can be effective.

Long-term treatment with antibiotics is common in the treatment of acne and rosacea. Since the introduction of topical macrolides in the late 1970s, there has been a progressive increase in the incidence of resistant P acnes as well as other resistant organisms such as methicillinresistant S aureus.^{19 - 20} While dermatologists are not the only cause of the problem, the discipline has been increasingly interested in documenting the effects of long-term antibiotic use as well as minimizing the overuse of antibiotics.

The decreased susceptibility of P acnes to commonly used antibiotics has been well documented. Less well known are the effects of acne therapy on other pathogens. Levy and colleagues²¹ have clearly shown that patients with acne treated with tetracycline harbor group A streptococci in greater numbers and that many of those strains are resistant to tetracycline. The cause of the tetracycline resistance is easily understood: tetracycline acts as a selective pressure for resistant strains. What is less clear is why tetracycline therapy should increase the incidence of streptococcal colonization at all. Potential explanations include decreased normal flora competition allowing the streptococci to gain a foothold. Another explanation might well involve tetracycline (which is also a protease inhibitor) inhibiting the production of the antimicrobial peptides involved in streptococci defense. A similar situation might explain the truly surprising finding that acne therapy with antibiotics seems to increase the incidence of upper respiratory tract viral infections.²² Perhaps some of these same peptides are also involved in viral defense and might be stimulated as a means of reducing the infectivity of rhinoviruses.

Correspondence: Dr Webster, 720 Yorklyn Rd, Suite 10, Hockessin, DE 19707 (gfweb@earthlink.net).

Financial Disclosure: None reported.