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Keywords:

  • bioproducts;
  • lactic acid bacteria;
  • probiotics

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Probiotics have been extensively reviewed for decades, emphasizing on improving general gut health. Recently, more studies showed that probiotics may exert other health-promoting effects beyond gut well-being, attributed to the rise of the gut–brain axis correlations. Some of these new benefits include skin health such as improving atopic eczema, atopic dermatitis, healing of burn and scars, skin-rejuvenating properties and improving skin innate immunity. Increasing evidence has also showed that bacterial compounds such as cell wall fragments, their metabolites and dead bacteria can elicit certain immune responses on the skin and improve skin barrier functions. This review aimed to underline the mechanisms or the exact compounds underlying the benefits of bacterial extract on the skin based on evidences from in vivo and in vitro studies. This review could be of help in screening of probiotic strains with potential dermal enhancing properties for topical applications.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

The benefits of probiotics in regulating gut health have been explored and recognized for over a century. In 1974, probiotics were defined as ‘organisms or substances which contribute to intestinal microbial balance’ (Parker 1974). Since then, increasing interest on probiotics has mainly focused on improving general gut health. The definition of probiotics has been redefined throughout the years, and it was defined as ‘live microorganisms that confer a health effect on the host when consumed in adequate amounts’ (Guarner and Schaafsma 1998). A more recent definition has accepted the roles of probiotics without an administered oral route, where they are now defined as ‘live microorganisms which when administered in adequate amount confer a health benefit to the host’ (Rijkers et al. 2010).

A notable number of microbial species and genera have been known to exhibit functional characteristics typically associated with probiotic properties (Table 1). Although the definition ‘probiotics’ includes the term ‘live microorganisms’, there is increasing evidence suggesting that nonreplicating bacteria, extracts or bacterial cell wall components could also exert health potentials (Gueniche et al. 2010; Hoang et al. 2010).

Table 1. Micro-organisms associated with probiotic properties
LactobacillusBifidobacteriumEnterococcusStreptococcusLactococcus

Lact. acidophilus

Lact. brevis

Lact. casei

Lact. curvatus

Lact. fermentum

Lact. gasseri

Lact. johnsonii

Lact. reuteri

Lact. rhamnosus

Lact. salivarius

Bif. adolescentis

Bif. animalis

Bif. breve

Bif. infantis

Bif. longum

Bif. thermophilum

Ent. faecalis

Ent. faecium

Strep.  thermophilus

L. lactis subsp. cremoris

L. lactis subsp. lactis

PropionibacteriumYeastOthers
  1. Adapted from Caramia and Silvi (2011).

P. freudenreichii

P. freudenreichii subsp. shermanii

P. jensenii

Kluyveromyces lactis

Saccharomyces boulardii

Saccharomyces cerevisiae

Leuconostoc mesenteroides

Pediococcus acidilactici

Probiotics have been widely reported to alleviate lactose intolerance, suppress diarrhoea, reduce irritable bowel symptoms, prevent inflammatory bowel disease and exhibit anticolorectal cancer activities. Recently, clinical studies have reported that probiotics may exert other health-promoting effects beyond gut well-being. Probiotics have been documented to lower blood cholesterol levels (Ooi and Liong 2010), exert antihypertensive effects (Yeo and Liong 2010), treat urogenital infections (Abad and Safdar 2009), reduce allergic reactions (Michail 2009), prevent dental caries (Saha et al. 2012), reduce risks of cancers (Kumar et al. 2010), alleviate postmenopausal symptoms (de Vrese 2009) and exhibit immunomodulatory effects (Ruemmele et al. 2009). In addition, probiotics have also been documented to exert dermal potentials such as improving atopic eczema, atopic dermatitis, healing of burn and scars, skin-rejuvenating properties and also improving skin's innate immunity. The gut–brain–skin axis concept, as proposed by Arck et al. (2010) suggests that modulation of the microbiome by deployment of probiotics can exert profound beneficial effects, for example, on skin inflammation and skin homeostasis.

There is increasing evidence that bacterial compounds such as cell wall fragments, their metabolites and dead bacteria can elicit certain immune responses on the skin and improve skin's barrier function. Cell-free cultures of lactic acid bacteria with probiotic potentials have been demonstrated to exert antimicrobial and immunomodulatory activities, suggesting the use of probiotic in nonviable forms (Iordache et al. 2012). Natural cell components and metabolites may be the preferred choice in cases where the delivery of live cells is not possible. Moreover, cell components and metabolites are more stable than viable cells at room temperature and are thus more suitable for topical applications. Human clinical studies have suggested that probiotic exert dermal benefits not only through the gastrointestinal route but also upon topical applications. Using in vitro study, Iordache et al. (2012) have demonstrated that cell-free cultures of lactic acid bacteria with probiotic potentials including Lactobacillus plantarum, Lactobacillus casei and Enterococcus faecium inhibited the expression of soluble virulence factors by opportunistic dermal pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa and decreased their adherence capacity to the cellular substrate represented by HeLa cells. Meanwhile, using ex vivo human skin explants model, Gueniche et al. (2010) found a statistically significant (P < 0·05) improvement following application of cell lysate from Bifidobacterium longum sp. versus placebo in various parameters associated with inflammation such as a decrease in vasodilation, oedema, TNF-alpha release and mast cell degranulation. The potentials of probiotics in dermal application have also been evaluated in several in vivo studies (Table 2).

Table 2. In vivo potential of probiotics in dermal applications
TreatmentStrains involvedExperimental designDose and durationEffectsReferences
Atopic eczema/dermatitisLactobacillus rhamnosus GG ATCC53103Randomized, double-blind, placebo-controlled clinical trial of 230 infants with atopic eczema/dermatitis syndromeAdministration of 5 × 109 CFU; twice daily for 4 weeksGreater reduction in Severity Scoring of Atopic Dermatitis (SCORAD) of IgE-sensitized infants as compared to the placeboViljanen et al. (2005)
Resistant childhood atopic eczemaLactobacillus rhamnosus TB

Open-label nonrandomized clinical

observation of 14 cases of paediatric patients (aged of 8–64 months)

Administration of cell lysate (300–500 mg daily) for 1 monthMarked improvements in eczema symptoms scores, daytime irritation and nighttime disturbances scoresHoang et al. (2010)
Sensitive skinBifidobacterium longum spRandomized, double-blind, placebo-controlled clinical trial of 66 female volunteers with reactive skinTopical application of cream containing 10% Cell lysate; twice a day for 2 months

Decrease skin sensitivity score

Strengthen skin's natural barrier

Gueniche et al. (2010)
Wound healingProbiotic mixture in kefirRandomized, double-blind, placebo-controlled clinical trial 56 male Wistar rats with burn wounds infected with Pseudomonas aeruginosa (ATCC 27853)Topical application of gel containing 50% kefir extract; twice a day for 1 week

No microbial contaminations were observed in the burn wounds;

Wound size significantly lowered (P < 0·05) as compared to base gel and untreated groups as well as silver sulfadiazine treated group

Heseini et al. (2012)

While many studies and patents have been published on the use of probiotic extracts for topical application on the skin, the mechanisms underlying or the exact compounds responsible for the benefits of bacterial extract on the skin, however, remain unclear. Increasing demand for probiotic dermal formulations further boosts the urge to understand the exact mechanisms of action. This review aimed to report on the bacterial compounds that lead to the beneficial dermal effects and some possible mechanisms of action (Fig. 1).

image

Figure 1. Bioactives from probiotics for dermal applications.

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Hyaluronic Acid

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Hyaluronic acid (HA) consists of a basic unit of two sugars, glucuronic acid and N-acetylglucosamine, polymerized into large macromolecules of 2000–25 000 repeating units (Chong et al. 2005). Depending on the source, molecular weight of HA could range between 104 and 107 Da. HA has been widely utilized in dermatology as a biomaterial for bioengineering purposes as well as for the stimulation of wound healing. In addition to being utilized in dermatology and cosmetic products, HA is also widely used in ophthalmology, rheumatology, pharmacology and drug delivery (Kogan et al. 2007).

Most of the mammalian HA are found in the skin where it serves as a matrix. HA is essential for maintaining the normal structure of the stratum corneum and conserve epidermal barrier functions. HA also plays a series of other important roles in the skin, for example, in immobilizing water in tissue, and influencing cell proliferation, differentiation and tissue repair. Due to a high water binding capacity, HA often contributes to the maintenance of the extracellular dermal matrix and facilitates the transport of water-soluble molecules and ion solutes. The highly osmotic nature of HA is likely to be relevant in controlling tissue hydration during inflammatory processes (Weindl et al. 2004). A study by Pavicic et al. (2011) involving 76 female subjects aged between 30 and 60 years showed significant (P < 0·05) improvement in skin hydration and elasticity upon topical application of 0·1% HA for 60 days. The authors also reported that application of low-molecular-weight HA resulted in a significant (P < 0·05) reduction in wrinkle depth, attributed to better penetration.

Low-molecular-weight HA has also been reported to increase epithelial defence by inducing β-defensin-2 via Toll-like receptors (TLR) (Gariboldi et al. 2008). β-Defensins are one of the most common types of antimicrobial peptides participating in the host response against bacterial infections and are expressed in multiple tissues in the body, most notably in leucocytes and epithelial surfaces (Menendez and Brett Finlay 2007). It has also been reported that treatment for murine skin by the low-molecular-weight HA induced the release of mouse β-defensin-2 in all layers of the epidermal compartment (Gariboldi et al. 2008).

It has been shown that HA fragments are released following injury, leading to increased expression of chemokine IL-8 in endothelial cells, thus stimulating the endothelium to recognize injury and initiate wound repair (Taylor et al. 2004), while the antioxidant properties of HA prevented oxygen free radical damage on granulation tissue during wound repair (Trabucchi et al. 2002). In addition, the supportive role of exogenous HA in wound healing has been reported to be attributed to its ability to retain moisture, thus supporting various processes such as proteolytic degradation of provisional matrix to promote epithelial migration, regeneration and remodelling (Anilkumar et al. 2011). An in vitro study was used to demonstrate the anti-inflammatory effects of HA in ethanol-induced damage in skin cells by regulating excessive production of pro-inflammatory cytokines (Neuman et al. 2011). In the study, human A431 epidermoid skin cells and mouse fibroblasts were treated with 100 mmol l−1 ethanol for 24 h to induce damage, while control cells were exposed only to plain medium for 24 h. Treatment for the ethanol-induced damage skin cells with HA at concentration of 4% significantly (P < 0·05) reduced the concentration of pro-inflammatory cytokine TNF-α released from mouse fibroblasts (26·6 ± 2·0–18·0 ± 2·0 pg ml−1) and A431 epidermoid skin cells (38·6 ± 1·2–16·0 ± 1·2 pg ml−1). The authors also reported that HA treatment significantly (P < 0·05) reduced cytotoxicity of the mouse fibroblast from 24 ± 7·2 to 14 ± 4% and on A431 epidermoid skin cells from 18 ± 2·5 to 8 ± 2%.

Hyaluronic acid is obtained commercially from rooster combs and certain attenuated strains of group C Streptococcus which synthesize this compound naturally as part of their capsule. A comprehensive overview of the sources from which HA can be isolated has been documented (Shiedlin et al. 2004). It has been reported that preparation of HA from bacterial source contains lower amounts of contaminating protein, endotoxin and nucleotides than those of animal source (Shiedlin et al. 2004). To date, only a few bacterial species are known to produce HA: group A and group C streptococci (Gram positive) and Pasteurella multocida (Gram negative). It was reported for the first time in 2009 that HA is produced in milk broth through fermentation by a putative probiotic strain Streptococcus thermophilus YIT2084 (Izawa et al. 2009). It has also been reported that fermentations by Streptococcus zooepidemicus can produce low-molecular-weight HA (<200 kDa) upon optimized fermentation conditions (Liu et al. 2009). Recently, there has been an emerging alternative in producing higher yield of HA through fermentation of recombinant generally recognized as safe (GRAS) microbial strains. HA was successfully produced in recombinant Bacillus subtilis 168 by overexpressing both Streptococcus equisimilis hasA gene and endogeneous tuaD gene (Widner et al. 2005). Meanwhile, HA-producing recombinant Lactococcus lactis LL-NAB was constructed by coexpressing hasA and hasB gene of Strep. equisimilis subsp. zooepidemicus in a nisin-controlled expression system (Chien and Lee 2007). Recently, Streptococcus thermophillus YIT2084 strains have been transformed to produce more than 1 g l−1 HA by overexpressing endogenous hasA, hasB and glmU derived from nonpathogenic bacteria (Izawa et al. 2011). In our recent study, we have demonstrated that certain strains of lactobacilli such as Lactobacillus rhamnosus FTDC 8313 and Lactobacillus gasseri FTDC 8131 were also capable of producing HA at concentrations exceeding 1 g l−1 when cultivated in skimmed milk, thus suggesting its dermatological potentials (Lew et al. 2012).

Sphingomyelinase

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Sphingomyelinase (SMase) is an enzyme that generates a family of ceramides and phosphorylcholine from glucosylceramide and sphingomyelin precursors for the development of extracellular lipid bilayers in the stratum corneum (Jensen et al. 2005). SMase activity has been demonstrated to be important for skin barrier function (Choi and Maibach 2003). A decrease in ceramide in the stratum corneum causes water loss and barrier dysfunction in the epidermis, including a loss of protection against antigens and bacteria (Mizutani et al. 2009). In addition, the reduction in the stratum corneum ceramide levels has been proposed as a possible aetiological factor in atopic dermatitis, psoriasis, contact dermatitis and irritant dermatitis (Motta et al. 1994; Murata et al. 1996; Berardesca et al. 2001).

Sphingomyelinase is localized in the epidermal lamellar bodies and stratum corneum interstices and has been classified as acid, alkaline and neutral SMase based on their pH optima. Acid SMase is a soluble glycoprotein with an optimum activity at pH 5. The absence of this enzyme in humans is known to lead to neurological disorder Niemann–Pick syndrome. It has been reported that patients with Niemann–Pick syndrome also displayed an abnormality in skin permeability barrier homeostasis with delayed recovery kinetics following acute barrier disruption (Schmuth et al. 2000). Considering that acid SMase is located in the outer epidermis, it is thus responsible for the generation of ceramides for basal permeability barrier functions (Jensen et al. 2005). In addition, a decrease in inner epidermal acid SMase has been associated with skin ageing (Jensen et al. 2005). Neutral SMase on the other hand is cell membrane associated and is important for cell signalling during permeability barrier repair via enhanced accumulation of ceramide (Kreder et al. 1999). Decreased neutral SMase activity in the outer as well as in the inner epidermal layers has been found in aged skin (Jensen et al. 2005), possibly attributed to reduced proliferation rate, leading to reduced capacity for barrier repair. Mice defective in TNF-induced neutral SMase activation showed reduced capacity of barrier repair and smaller increase in epidermal proliferation upon barrier disruption (Kreder et al. 1999). Neutral SMase activity was also reported to be reduced in lesional and nonlesional atopic dermatitis skin, correlating with impaired expression of cornified envelope proteins and keratins, which is important for skin barrier functions (Jensen et al. 2004).

Sphingomyelinase is detected in bacteria, yeast and mammalian cells, with great variations in SMase activity among different bacterial strains (Di Marzio et al. 2001). While mammalian neutral SMase is a membrane-bound protein, bacterial SMase is a secretory protein released from cells into the media (Titball 1993). In an in vitro study by Di Marzio et al. (1999), ceramide reportedly increased in human keratinocytes cell line HaCat that was cocultured with sonicated cells of Streptococcus thermophilus. Ceramide levels in treated keratinocytes were reported to increase 50–60-fold after 18 h with respect to the basal value while control group showed only 12–14-fold increase in ceramide level. It has been suggested that the increased level of ceramide was attributed to SMase (>0·1 mU ml−1) obtained from sonicated cells of Strep. thermophilus (Di Marzio et al. 1999). These results were then confirmed using in vivo test on 17 healthy Caucasian volunteers aged between 24 and 47 years. 0·5 g of cream containing sonicated Strep. thermophilus was applied twice daily on the volar surface of the forearms while base cream (control) was applied to the contralateral forearm. Results from this randomized, double-blind, paired-comparison design showed that cream containing sonicated Strep. thermophilus induced a very significant (P < 0·05) increase in ceramide levels after 7 days of topical treatment (639 ± 136·21 pmol ceramides per μg protein) as compared to controls (136 ± 25 pmol ceramides per μg protein). An increase in ceramide content was reported in the stratum corneum of all subjects upon topical application of cream containing lysed Strep. thermophilus as well as cream containing SMase (4 ng per 50 μl PBS per ml base cream) (Di Marzio et al. 1999). The effects of the Strep. thermophilus-containing cream on atopic dermatitis patients were further corroborated by Di Marzio et al. (2003). Following observation from a clinical trial, the authors reported an improvement in symptoms such as erythema, scaling and pruritus upon 2-week application of the cream in the forearms of 11 patients. We have recently documented that both acid and neutral SMase could be produced by strains of lactobacilli and bifidobacteria at concentrations sufficient to promote ceramide production in skin cells with the possibility to improve skin barrier properties (Lew et al. 2012). Also, the production of SMase by lactobacilli can be enhanced via the supplementation of divalent metal ions into the growth medium, due to improved binding affinity between the SMase and sphingomyelin as well as improved interaction distances between the important catalytic residues Glu53 and His296 with phosphate head group of sphingomyelin (Fig. 2) (Lew and Liong 2012).

image

Figure 2. Diagrams of sphingomyelin and the putative key interaction distances (dotted lines) with catalytic residues Glu53 and His296 of sphingomyelinase (a) without ion, (b) with manganese ion. Free energy of binding of (a) −4·13 kcal mol−1, (b) −2·44 kcal mol−1.

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Lipoteichoic Acid

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Lipoteichoic acid (LTA) is a structural component of the cell walls of Gram-positive bacteria and plays a vital role in the growth and physiology of the bacteria. LTA has been reported as one of the immune-stimulating component of both pathogenic and nonpathogenic Gram-positive bacteria (Kim et al. 2008). Previous studies showed that LTA can function as an important pathogen-associated molecular pattern, leading to production of proinflammatory cytokines, nitric oxide, activation of nuclear transcription factor NF-ĸB and other proinflammatory mediators (Lebeer et al. 2012). Inflammatory response is an attempt by the host's body to restore and maintain homeostasis following an infection or injury. LTA from pathogenic Gram-positive bacteria such as Staphylococcus aureus can, however, cause excessive inflammation, leading to the development of systemic inflammatory response syndrome such as septic shock (De Kimpe et al. 1995). Although most LTA molecules have a similar basic structure, structure–activity relationship studies showed that important strain-specific differences can occur. Unlike LTA from pathogenic bacteria such as Staph. aureus, Kim et al. (2008) reported that LTA isolated from beneficial probiotics such as Lactobacillus plantarum KCTC10887BP (pLTA) induced tolerances by protecting against the overproduction of proinflammatory cytokines associated with sepsis such as TNF-α. The authors reported a significant reduction (P < 0·001) in TNF-α production in THP-1 cells that were pretreated with pLTA (100 μg ml−1) for 18 h followed by restimulation with LPS (0·5 μg ml−1) for 4 h. The inhibitory effects of pLTA were further confirmed via in vivo test on LPS-induced endotoxin shock BALB/c mice, and the results showed that when mice were preinjected with pLTA for 24 h before injection of LPS (45 mg kg−1), the survival rate increased significantly (P < 0·05) in a dose-dependent manner.

Upon topical application, LTA has been found to stimulate skin defence against microbial threats via induction of toll-like-receptor (TLR) (Sumikawa et al. 2006). Activation of TLR in the cutaneous pathogen recognition system triggers the release of soluble effectors such as the antimicrobial peptides that maintain sterility in the dermis (Schauber and Gallo 2008). The most common types of antimicrobial peptides participating in the host response against skin bacterial infections are human β-defensins (hBD) and cathelicidins. Menzies and Kenoyer (2005) have demonstrated that LTA treatment on Ca2+-differentiated keratinocytes for 5 h significantly (P < 0·05) stimulated hBD2 transcripts in a concentration-dependent manner when compared to untreated cells. Meanwhile, Nell et al. (2004) showed that LTA stimulation for 2 weeks at concentration of 100 ng ml−1 significantly increased (P < 0·05) the expression of human cathelicidin hCAP-18/LL-37 in air-exposed cultured sphenoid epithelial tissue. We have recently documented that lactobacilli and bifidobacteria contained sufficient amounts of LTA to increase dermal cellular defence against bacterial infection (Lew et al. 2012).

The resulting local accumulation of antimicrobial proteins offers a fast and very efficient way to prevent establishment of microbial infections (Harder and Schroder 2005). The importance of antimicrobial peptides was further corroborated by Niyonsaba and Ogawa (2005) who found that a diminished expression of antimicrobial peptides such as hBD2 has been associated with reoccurrence of skin infections induced by Staph. aureus in patients with atopic dermatitis. In addition to the antimicrobial properties, LTA, through stimulation of hBD, also contributed to cutaneous wound healing and performed a series of immunomodulatory functions, thus acting not only as proinflammatory agents but also as a key link between the innate and the adaptive immune system (Niyonsaba et al. 2007). More recently, Wang et al. (2012) have demonstrated that exposure of LTA from nonpathogenic commensal bacteria at the epithelial surface increased skin mast cells antimicrobial activity against vaccinia viruses via activation of TLR2, thus suggesting the potential new roles of LTA in antiviral therapy.

Peptidoglycan

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Peptidoglycan (PG) is the major structural component of bacterial cell wall and is responsible for maintaining the shape and protection against osmotic lysis. It is a polymer of β(1–4)-linked N-acetylglucosamine and N-acetylmuramic acids, crosslinked by short peptides containing alternating l- and d-amino acids (Dziarski 2003). PG is especially abundant in Gram-positive bacteria, in which it accounts for approximately 90% of the weight of the cell wall and thickness up to 80 nm (Cabeen and Jacobs-Wagner 2005). In Gram-negative bacteria, a relatively thin PG layer with thickness <10 nm surrounds the cytoplasmic membrane underneath the lipopolysaccharide-containing outer membrane. Although the structure and biosynthesis of PG are remarkably conserved across bacterial species, the chain lengths have been found to depend on the bacterial species as well as the growth conditions. Chains from different species were found to average between 10 and 65 disaccharide units (Ghuysen 1968).

Peptidoglycan plays an important role in skin defence against pathogens by stimulating the innate immunity system via Toll-like receptor-2 (TLR2), leading to secretion of a variety of cytokines and chemokines that are involved in immune responses (Niebuhr et al. 2010). PG has also been demonstrated to activate nuclear factor kB and induce abundantly IL-8 production from keratinocytes, suggesting that PG plays major roles in the production of cytokines and chemokines from keratinocytes (Matsubara et al. 2004). PG is also recognized by several other PG recognition molecules, including CD14, nucleotide oligomerization domain–containing proteins (Kumar et al. 2010), a family of PG recognition proteins (PGRPs) and PG-lytic enzymes (lysozyme and amidase) (Dziarski 2003). These molecules induce host responses to micro-organisms, degrade PG or mediate the release of antimicrobial peptides and chemokines that recruit phagocytic cells to the site of infection (Dziarski and Gupta 2005). It has been reported that microbe-derived molecules including PG were capable of inducing or increasing the expression of hBD in keratinocytes of whole human skin, leading to activation of host innate immunity (Sorensen et al. 2005). In addition, it has been shown in vitro that treatment for HaCaT keratinocytes with Staphylococcus aureus PG (10 μg ml−1) for 24 h significantly increased (P < 0·05) the expression of cathelicidin LL37, another major family of antimicrobial peptides with potential importance in human skin defence (Ruiz-Gonzalez et al. 2009). PG from lactobacilli were demonstrated to stimulate innate immune response via TLR2 and also to induce the production of IL-12 and other regulatory factors by macrophages, thus contributing to skin protection (Sun et al. 2005; Paradis-Bleau et al. 2007; Shida et al. 2009). We have recently demonstrated that lactobacilli and bifidobacteria contained total PG amounting up to 0·425 μg ml−1 (Lew et al. 2012). It has been reported that PG in the range of 10–100 μg ml−1 is necessary to stimulate cellular responses (Fournier and Philpott 2005); however, PG has also been reported to be effective at lower concentrations, via synergism with LTA (Yang et al. 2001).

Lactic Acid

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Lactic acid, categorized as one of the α-hydroxy acids (AHAs), is an organic acid with one hydroxyl group attached to the alpha position of the acid. Lactic acid can be produced by either microbial fermentation or chemical synthesis. Chemically synthesized lactic acid often consists of racemic dl-lactic acid, while an optically pure l(+)- or d(−)-lactic acid can be obtained by microbial fermentation using appropriate micro-organisms (Wee et al. 2006). Lactobacilli metabolize carbohydrates either homofermentatively or heterofermentatively to produce lactic acid as predominant end products, with at least 50–85% lactic acid (Yeo and Liong 2010). We have previously demonstrated that strains of lactobacilli could produce lactic acid at concentrations sufficient to exhibit antibacterial activity against most dermal pathogenic bacteria (Lew et al. 2012). Lactic acid has been widely used for many years in cosmetic regiments and skin care products such as moisturizers, exfoliants and emollients (Smith 1996). One of the reasons AHAs such as lactic acid are widely used as exfoliator and chemical peeling agent is its profound effect on desquamation of the skin. Desquamation is due to the dissociation of the cellular adhesions, which occurs as a result of reduced calcium ion concentration in the epidermis by chelating action of AHAs (Wang 2008). The decreased level of calcium ion in the epidermis also tends to promote cell growth and retard cell differentiation, thus giving rise to a younger-looking skin (Wang 2008).

In addition, lactic acid has potentials in skin applications attributed to its ability to improve the stratum corneum barrier function and enhance the production of ceramides by keratinocytes. Rawlings et al. (1996) evaluated the effects of lactic acid on keratinocyte ceramide synthesis, stratum corneum lipid levels and barrier function. The authors reported that exposure of l-lactic acid (20 mmol l−1) to keratinocytes in vitro for 24 h significantly increased (P < 0·05) ceramide levels up to 300% as compared to control, whereas, in vivo, 4% l-lactic acid treatment for 1 month resulted in a 38% increase (P < 0·05) in stratum corneum ceramide levels when compared with vehicle-treated skin. This trial involved a double-blind paired-comparison study with treatment assignments randomized and balanced to 24 male and female subjects aged from 23 to 54 years. The authors also showed that lactic acid not only increased the production of ceramide in the stratum corneum, but also appeared to improve the ratio of ceramide 1-linoleate to oleate as compared to vehicle following 1-month topical application of 4% l-lactic acid. The increased ratio of ceramide 1-linoleate to oleate has been suggested to play an important role in increasing skin barrier function (Yamamoto et al. 2006).

Lactic acid has also been applied for the treatment for photoageing and hyperkeratotic skin disorders, including ichthyosis, acne and dry skin (Rendl et al. 2001). It has been suggested that AHAs reduced the overall severity of photodamaged skin by improving the surface roughness, dyspigmentation and mild wrinkling (Van Scott et al. 1996). Meanwhile, clinical, histological and ultrastructural study showed that treatment with lotion containing 25% lactic acid to photoaged skin resulted in reversal of epidermal and dermal markers of photoageing (Ditre et al. 1996). The study involved a randomized, double-blind and placebo-controlled clinical trial of 17 subjects (aged from 52 to 83 with moderate-to-severe photoaged skin) for an average of 6 months. Results from the study demonstrated a significant increase (P < 0·0001) in skin thickness in forearms treated with 25% AHAs when compared to vehicle treatment. The mechanisms responsible for the effects of AHAs have been considered to be the remodelling of epidermal and dermal cells and tissues, resulting in an increase in the viable epidermal thickness and quick pigment dispersion (Yamamoto et al. 2006). Immunohistochemical analysis showed that treatment with lactic acids decreased melanin deposits and upregulated collagen-I and procollagen-I levels in the skin (Yamamoto et al. 2006). Application of lactic acid has also been shown to modulate angiogenin, vascular endothelial growth factor and cytokines secretion by keratinocytes (Rendl et al. 2001). Regulation of keratinocytes-derived growth factors and cytokines has been reported to play an important role in contributing to the therapeutic effects of AHAs on skin disorders such as photoageing (Rendl et al. 2001).

Lactic acid has been documented as part of the natural moisturizing factor (NMF) that retains moisture in the skin and plays important roles in the physical properties of the stratum corneum (Nakagawa et al. 2004). Using corneum obtained from the rear footpads of guinea pigs, Middleton (1974) showed that immersion in a 10% solution of lactic acid for 30 min significantly increased (P < 0·05) water-holding capacity and skin extensibility as compared to immersion in water. The results were further corroborated using a randomized, double-blind and placebo-controlled designed human trial study involving 406 female subjects for a period of 2 weeks. Results from the study showed that topical application of hand lotions containing 10% lactic acid adjusted to pH 4 significantly improved (P < 0·05) skin dryness and flaking as compared to control lotion.

Antimicrobial activity of lactic acid against dermal pathogens such as Staphylococcus aureus, beta haemolytic Streptococci, Proteus species, Escherichia coli and Pseudomonas aeruginosa has also been reported (Pasricha et al. 1979). In addition to its antimicrobial activity, long-term topical application of lactic acid lotion has been recommended as a preventive treatment for acne vulgaris due to the nontoxic and nonsensitizing properties. In an open clinical study involving 22 subjects having acne vulgaris, Garg et al. (2002) showed that topical application of 5% lactate lotion on face twice a day for 1 year significantly reduced (P < 0·05) the lesion counts, in which 40·9% subjects achieved 90–100% reduction in the inflammatory lesions and 22·7% subjects in noninflammatory lesions.

Acetic Acid

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Acetic acid is produced industrially both synthetically and by bacterial fermentation. Acetic acid has also been reported to be produced by heterofermentative lactic acid bacteria via the hexosemonophosphate or pentose pathway (Yeo and Liong 2010). We have previously reported that strains of lactobacilli and bifidobacteria were able to produce acetic acid in concentrations up to 3·32 mg ml−1 during fermentation (Lew et al. 2012). The use of acetic acid has been reported from time to time as a topical agent for the treatment of bacterial infections and in most reports has been used for burns and superficial infection. It has been suggested as the best alternative when infection is caused by multiple antibiotic-resistant strains and where there is shortage of therapeutic options (Nagoba et al. 2008).

Acetic acid has been shown to exert antibacterial effects on different bacterial species, including staphylococci (Eifert et al. 1997; Russell and Diez-Gonzalez 1998), and eradicated Staphylococcus aureus and Pseudomonas aeruginosa cells from superficial wounds (Hansson and Faergemann 1995). In a study evaluating the effect of various antiseptic solutions on micro-organisms in venous leg ulcers, Hansson and Faergemann (1995) reported that after 15-min treatment with gauze dressings containing 0·25% acetic acid solution to 45 venous leg ulcers, the mean number of both Staph. aureus and Gram-negative rods per ulcer reduced significantly (P < 0·05) as compared to the controls. In another study, Nagoba et al. (2008) evaluated the antibacterial effect of acetic acid against multiple antibiotic-resistant strains of Ps. aeruginosa isolated from nosocomial wound infections of seven hospitalized patients not responding to traditional therapy. These pseudomonal isolates were found to be inhibited by 3% acetic acid in vitro upon exposure for 15 min. Similarly, Sloss et al. (1993) reported that topical application of acetic acid in concentrations between 0·5 and 5% for 15 min twice daily successfully eliminated Ps. aeruginosa from the burns and soft tissue wounds of 14 of the 16 patients within treatment of 2 weeks. Meanwhile, Ryssel et al. (2009) reported that acetic acid exhibited excellent bactericidal effect in vitro, particularly with problematic Gram-negative bacteria such as Proteus vulgaris, Ps. aeruginosa and Acinetobacter baumannii. Results from the study showed complete elimination of Pr. vulgaris, Ps. aeruginosa and Ac. baumannii after 5 min of incubation in 3% acetic acid solution, while growth of Staphylococcus epidermidis and Staph. aureus was completely inhibited after 30 min. Escherichia coli, Enterococcus faecalis and methicillin-resistant Staph. aureus were completely eliminated after 60 min of incubation in 3% acetic acid solution. It has been suggested that the bactericidal effects of acetic acid were due to its pH lowering capability, thereby making an environment unsuitable for growth of pathogens (Nagoba et al. 2008). However, Akiyama et al. (1999) demonstrated that colony counts of Staph. aureus cells in tryptic soy broth containing acetic acid (pH 3·6) were significantly lower (P < 0·01) than those tryptic soy broth containing hydrochloric acid (pH 3·6), thus suggesting that the bactericidal effects were not considered to be solely due to its low pH but rather the chemical action of acetic acid itself.

Diacetyl

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

Diacetyl, also known as 2,3-butanedione, is produced by some species of the genera Leuconostoc, Streptococcus, Lactobacillus and Pediococcus. Strains of lactobacilli and bifidobacteria could produce diacetyl in concentrations up to 30 mg ml−1 suggesting its potential to exhibit dermal antimicrobial activities (Lew et al. 2012), with greater sensitivity against Gram-negative bacteria and fungi as compared to Gram-positive bacteria (Jay 1982). While most Gram-negative bacteria such as Pseudomonas aeruginosa, Pasteurella multocida, Borrelia burgdorferi, Salmonella typhi, Bartonella sp., Klebsiella rhinoscleromatis, Vibrio vulnificus and Helicobacter pylori are not typical resident of the skin microflora, they have been reported to cause cutaneous infections (Pivarcsi et al. 2005). Diacetyl has been shown to be bactericidal against Escherichia coli and Staphylococcus aureus at a concentration as low as 100 ppm (Lanciotti et al. 2003). Staphylococcus aureus is a bacterial pathogen that has emerged as a leading cause of skin and soft tissue infections, including impetigo, folliculitis and cellulitis (Daum 2007; Jones et al. 2007), while E. coli is one of the most frequent skin pathogens (Doern et al. 1999). The antimicrobial activity of diacetyl has been well documented; however, research on topical application of diacetyl is scarcely available, and much research is needed to determine its effects on the skin.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

This review reported on the potential of cellular components or metabolites from probiotics that could benefits skin health and dermatological advancement, based on recent in vivo and in vitro studies. Although many of these studies have suggested positive potentials on skin health, we foresee that such a dermal health claim is still at its infancy, with the final topical applications requiring more comprehensive and well-designed human trials, to justify the exact doses needed, host dependency, possible side effects, safety and regulatory compliances, and, more importantly, the exact mechanisms for both direct and indirect actions of the compounds and/or live cells.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References

This work was financially supported by the Science Fund Grant (305/PTEKIND/613222) provided by the Malaysian Ministry of Science, Technology and Innovation (MOSTI), the FRGS grant (203/PTEKIND/6711239) provided by the Malaysian Ministry of Higher Education (MOHE), the RUI grant (Development of bioactive films from LAB for dermal diseases) and USM Fellowship provided by Universiti Sains Malaysia.

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  2. Summary
  3. Introduction
  4. Hyaluronic Acid
  5. Sphingomyelinase
  6. Lipoteichoic Acid
  7. Peptidoglycan
  8. Lactic Acid
  9. Acetic Acid
  10. Diacetyl
  11. Conclusions
  12. Acknowledgements
  13. References
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