Introduction

Prebiotics have been defined as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one, or a limiting number of, bacteria in the colon”. This concept has originally been developed for the gut, but in principle can be applied to modulate the composition of any microbial community including the skin microflora to achieve beneficial effects.

Scientific interest in the composition and function of the skin’s microflora (=the skin’s microbiota) is currently experiencing a revival, and in fact, has become one of the most exciting and rapidly developing areas in cutaneous biology. A major driving force for this development has been the discovery that epidermal keratinocytes have the potential to affect the cutaneous microflora by producing antimicrobial peptides. Also, recent research efforts to understand the control of skin barrier functions unambiguously point to a close link between physical, immunological and cell biological properties of the skin and its microflora. Manipulation of the composition and/or function of the skin microflora by prebiotic strategies, which, in contrast to antibiotics, may allow selective inhibition of detrimental and at the same time preservation and/or stimulation of beneficial bacteria, is therefore of obvious interest in dermatology.

In contrast to prebiotics, probiotics are based on the use of living organisms which upon ingestion in certain numbers exert health beneficial effects beyond inherent general nutrition. Probiotics have been widely used for the treatment/prevention of gastrointestinal disorders, but a growing number of clinical studies suggest that probiotic strategies induce systemic effects which extend beyond the gut and may even affect selected functions of the skin. Accordingly, modulation of the gut’s microflora through probiotics appears to cause beneficial effects in healthy as well as diseased human skin.

This article briefly summarizes the scientific basis for such strategies and provides a critical overview about the currently available studies on the use of pre- and/or probiotica in clinical dermatology and cosmetics.

Microflora of human skin

The normal human skin microflora is composed of a limited number of microbial types, as outlined below. This is a direct consequence of the unique environmental conditions the skin offers to microbes, which markedly differ from those found at mucosal surfaces. In other words only a limited number of microbial types (mainly Gram-positive species) have evolved to take advantage of the harsh environmental conditions that are being offered by the skin.

In general, resident and transient microbial species are present on the skin. The term resident refers to viable, reproducing populations, whereas transient species are defined as contaminants with little or no capacity for sustained growth and reproduction in the cutaneous environment. Resident microbial species include Proprionibacteria ( P acnes , P avidum and P granulosum ), Coagulase-negative Staphylococci ( Staphylococcus epidermidis ), Micrococci , Corynebacteria and Acinetobacter . In addition, there are Malassezia yeast species and a variety of bacteriophage species. Common transient species are Staphylococcus aureus , Escherichia coli , Pseudomonas aeroguinosa and Bacillus species. It should be emphasized that the above said represents the “textbook” knowledge on the skin’s microflora, which is limited to culture-dependent assays, although it is estimated that less than 1% of harvested species can be cultivated. More recent studies employing 16SrRNA gene survey strategies indicate that the human skin microbiota is far more complex and in fact comprises 113 phylotypes that belong to six bacterial divisions. Among these, Proteobacteria dominate the skin microbiota. In contrast, 16 SrRNA sequences that closely match S epidermidis and P acnes consisted of less than 6% of the captured microbiota. This is in clear contrast to the commonly held notion that S epidermidis is the dominant aerobic bacteria resident in skin.

The resident microflora fills a niche that could otherwise be colonized by pathogenic microorganisms that are aggressive and cause infection, either at the skin site or by transfer to other sites. Also, if the skin could be colonized by pathogens adopted for other sites (eg, mucous membranes), this could facilitate the spread of pathogens by offering them more dispersed routes.

This is, however, not the only positive function of the resident microflora. Accordingly, Propionibacteria have been shown to have adjuvant and antitumor activities and to contribute to a more efficient immunological response to general infections. On the other hand, the same species are of pathogenic relevance in acne and folliculitis. In aggregate, preservation of the resident microflora is thought to be an effective way to achieve maintenance of healthy “normal” skin functions. It is only when the host becomes compromised by trauma, injury or changes in the immune defense that the resident microflora displays pathogenic potential. Under such circumstances, pathogenic effects not only are restricted to S epidermidis , but may also be observed with Propionibacterium species. Thus, the resident microflora may be regarded as “beneficial” to the “normal, healthy” host, but may become dangerous to the host with disturbed skin integrity.

The limited number of microbial species that colonize human skin is determined by a variety of physical and biochemical factors. The physical factors are mainly defined by the host environment and include the number and size of follicles and glands, gland function, the flow of secretions, the integrity of barrier function, skin pH and osmotic potential. A slightly acidic pH, eg, favors Proprionibacterium spp., whereas neutral and alkaline pH favors most other resident bacteria. Also, high hydration is associated with higher pH, which is again associated with high microbial population density, eg, in the foot. Biochemical factors include chemical compounds such as soluble micronutrients derived from sebum (lipids and aminoacids) and sweat (vitamins, lactate and amino acids) as well as biochemical molecules which are produced as a consequence of the metabolic activity of microorganisms on the skin and which in turn function to influence colonization. Examples of microbial metabolites controlling other residents are lantibiotics produced by Staphylococcus spp. Other factors are methantiol, bacteriocins, organic acids and lytic enzymes, including those produced by bacteriophages. Also, bacterial metabolism affects pH and osmotic potential.

Another level of complexity is provided by the interplay between skin microorganisms and the skin immune system. The skin possesses the capacity to mount both, adaptive and non-adaptive immune responses. Non-adaptive (=innate) immune responses are immediate and non-specific, whereas adaptive immune responses are secondary and selective in nature.

There is currently no evidence to suggest that adaptive immune responses of the skin influence the normal skin microflora. There is, however, some evidence that the skin microflora activates the adaptive immune system. Accordingly, microorganisms on the skin have been shown to be coated with immunoglobulins which are most likely derived from eccrine gland secretions. Also, numerous reports have described humoral and cell-mediated immune responses in the peripheral blood against skin microbials (eg, ). These studies did not clarify, however, whether stimulation of the adaptive immune system occurred via the skin or at a different site where the same or related species of microorganisms reside. In favor of first possibility is the observation that in pityriaisis versicolor, seborrheic dermatitis and dandruff, the immune response to Malassezia species is maintained at higher levels as compared to healthy control subjects. Similar observations have also been made in acne patients for immune response against P acnes .

In marked contrast to adaptive immune responses, non-adaptive, innate immune responses of the skin are clearly involved in the control of microbial colonization. Accordingly, upon activation by microorganisms, epidermal keratinocytes have the capacity to produce all four known β-defensins as well as cathelicidin hCAP-18 and by producing these antimicrobial peptides inhibit growth or kill microorganisms, i.e. bacteria and also viruses.

A detailed review of the relative importance of these factors and their complex interplay can be found in Reference. In the context of this review it is important to state that skin microflora, skin barrier function and the skin immune system are closely linked to each other and appear to form a complex and highly regulated network that controls a variety of fundamental skin functions. It is therefore no surprise that attempts have been made beyond antibiotica to selectively manipulate this system in order to achieve beneficial effects for human skin.

Microflora of human skin

The normal human skin microflora is composed of a limited number of microbial types, as outlined below. This is a direct consequence of the unique environmental conditions the skin offers to microbes, which markedly differ from those found at mucosal surfaces. In other words only a limited number of microbial types (mainly Gram-positive species) have evolved to take advantage of the harsh environmental conditions that are being offered by the skin.

In general, resident and transient microbial species are present on the skin. The term resident refers to viable, reproducing populations, whereas transient species are defined as contaminants with little or no capacity for sustained growth and reproduction in the cutaneous environment. Resident microbial species include Proprionibacteria ( P acnes , P avidum and P granulosum ), Coagulase-negative Staphylococci ( Staphylococcus epidermidis ), Micrococci , Corynebacteria and Acinetobacter . In addition, there are Malassezia yeast species and a variety of bacteriophage species. Common transient species are Staphylococcus aureus , Escherichia coli , Pseudomonas aeroguinosa and Bacillus species. It should be emphasized that the above said represents the “textbook” knowledge on the skin’s microflora, which is limited to culture-dependent assays, although it is estimated that less than 1% of harvested species can be cultivated. More recent studies employing 16SrRNA gene survey strategies indicate that the human skin microbiota is far more complex and in fact comprises 113 phylotypes that belong to six bacterial divisions. Among these, Proteobacteria dominate the skin microbiota. In contrast, 16 SrRNA sequences that closely match S epidermidis and P acnes consisted of less than 6% of the captured microbiota. This is in clear contrast to the commonly held notion that S epidermidis is the dominant aerobic bacteria resident in skin.

The resident microflora fills a niche that could otherwise be colonized by pathogenic microorganisms that are aggressive and cause infection, either at the skin site or by transfer to other sites. Also, if the skin could be colonized by pathogens adopted for other sites (eg, mucous membranes), this could facilitate the spread of pathogens by offering them more dispersed routes.

This is, however, not the only positive function of the resident microflora. Accordingly, Propionibacteria have been shown to have adjuvant and antitumor activities and to contribute to a more efficient immunological response to general infections. On the other hand, the same species are of pathogenic relevance in acne and folliculitis. In aggregate, preservation of the resident microflora is thought to be an effective way to achieve maintenance of healthy “normal” skin functions. It is only when the host becomes compromised by trauma, injury or changes in the immune defense that the resident microflora displays pathogenic potential. Under such circumstances, pathogenic effects not only are restricted to S epidermidis , but may also be observed with Propionibacterium species. Thus, the resident microflora may be regarded as “beneficial” to the “normal, healthy” host, but may become dangerous to the host with disturbed skin integrity.

The limited number of microbial species that colonize human skin is determined by a variety of physical and biochemical factors. The physical factors are mainly defined by the host environment and include the number and size of follicles and glands, gland function, the flow of secretions, the integrity of barrier function, skin pH and osmotic potential. A slightly acidic pH, eg, favors Proprionibacterium spp., whereas neutral and alkaline pH favors most other resident bacteria. Also, high hydration is associated with higher pH, which is again associated with high microbial population density, eg, in the foot. Biochemical factors include chemical compounds such as soluble micronutrients derived from sebum (lipids and aminoacids) and sweat (vitamins, lactate and amino acids) as well as biochemical molecules which are produced as a consequence of the metabolic activity of microorganisms on the skin and which in turn function to influence colonization. Examples of microbial metabolites controlling other residents are lantibiotics produced by Staphylococcus spp. Other factors are methantiol, bacteriocins, organic acids and lytic enzymes, including those produced by bacteriophages. Also, bacterial metabolism affects pH and osmotic potential.

Another level of complexity is provided by the interplay between skin microorganisms and the skin immune system. The skin possesses the capacity to mount both, adaptive and non-adaptive immune responses. Non-adaptive (=innate) immune responses are immediate and non-specific, whereas adaptive immune responses are secondary and selective in nature.

There is currently no evidence to suggest that adaptive immune responses of the skin influence the normal skin microflora. There is, however, some evidence that the skin microflora activates the adaptive immune system. Accordingly, microorganisms on the skin have been shown to be coated with immunoglobulins which are most likely derived from eccrine gland secretions. Also, numerous reports have described humoral and cell-mediated immune responses in the peripheral blood against skin microbials (eg, ). These studies did not clarify, however, whether stimulation of the adaptive immune system occurred via the skin or at a different site where the same or related species of microorganisms reside. In favor of first possibility is the observation that in pityriaisis versicolor, seborrheic dermatitis and dandruff, the immune response to Malassezia species is maintained at higher levels as compared to healthy control subjects. Similar observations have also been made in acne patients for immune response against P acnes .

In marked contrast to adaptive immune responses, non-adaptive, innate immune responses of the skin are clearly involved in the control of microbial colonization. Accordingly, upon activation by microorganisms, epidermal keratinocytes have the capacity to produce all four known β-defensins as well as cathelicidin hCAP-18 and by producing these antimicrobial peptides inhibit growth or kill microorganisms, i.e. bacteria and also viruses.

A detailed review of the relative importance of these factors and their complex interplay can be found in Reference. In the context of this review it is important to state that skin microflora, skin barrier function and the skin immune system are closely linked to each other and appear to form a complex and highly regulated network that controls a variety of fundamental skin functions. It is therefore no surprise that attempts have been made beyond antibiotica to selectively manipulate this system in order to achieve beneficial effects for human skin.