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Prebiotic Cosmetics

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Abstract

The microbiota of the human skin is characterized by a complex and filigrane network of interactions between the microbes and the skin surface cells. Most of the resident microbes on healthy skin can be regarded as being harmless or even beneficial to skin. The topical application of prebiotic and probiotic actives turns out to become a new and promising approach in therapy and cosmetics. In cosmetics, prebiotic actives with the ability to rebalance the skin microflora may be used. Probiotic approaches mainly consist of applying inactivated microbial biomass rather than live bacteria. Stimulating the expression of the skin’s own antimicrobial peptides provides another way of improving the skin microbiota. First examples are given for the treatment of mild to moderate microbial disorders on the skin of face and body, on the scalp, and in the oral cavity.

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References

  1. Akiyama, H., Yamasaki, O., Tada, J., Arata, J.: Adherence characteristics and susceptibility to antimicrobial agents of Staphylococcus aureus strains isolated from skin infections and atopic dermatitis. J. Dermatol. Sci. 23, 155–160 (2000)

    Article  CAS  PubMed  Google Scholar 

  2. Bek-Thomsen, M., Lomholt, H.B., Kilian, M.: Acne is not associated with yet-uncultured bacteria. J. Clin. Microbiol. 46, 3355–3360 (2008)

    Article  CAS  PubMed  Google Scholar 

  3. Bierbaum, G.: The biosynthesis of the lantibiotics epidermin gallidermin, Pep5 and epilancin K7. Antonie Leeuwenhoek 69, 119–127 (1996)

    Article  CAS  PubMed  Google Scholar 

  4. Bockmuehl, D.: Präbiotika für kosmetische Anwendungen. 130, 3–6 (2004)

    Google Scholar 

  5. Bockmuehl, D., Jassoy, C., Nieveler, S., Scholtyssek, R., Wadle, A., Waldmann-Laue, M.: Prebiotic cosmetics: an alternative to antibacterial products. Int. J. Cosmet. Sci. 9, 1–5 (2006)

    Google Scholar 

  6. Bojar, R.A., Holland, K.T.: Review: the human cutaneous microflora and factors controlling colonisation. World J. Microbiol. Biotechnol. 18, 889–903 (2002)

    Article  CAS  Google Scholar 

  7. Braat, H., Rottiers, P., Hommes, D.W., Huyghebaert, N., Remaut, E., Remon, J., van Deventer, S.J.H., Neirynck, S., Peppelenbosch, M.P., Steidler, L.: A Phase I trial with transgenic bacteria expressing Interleukin-10 in Crohn’s disease. Clin. Gastroenterol. Hepatol. 4, 754–759 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. Braff, M.H., Gallo, R.L.: Antimicrobial peptides: an essential component of the skin defensive barrier. Curr. Top. Microbiol. Immunol. 306, 91–110 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. Braff, M.H., Bardan, A., Nizet, V., Gallo, R.L.: Cutaneous defense mechanisms by antimicrobial peptides. J. Invest. Dermatol. 125, 9–13 (2005)

    Article  CAS  PubMed  Google Scholar 

  10. Burton, J.P., Chilcott, C.N., Moore, C.J., Speiser, G., Tagg, J.R.: A preliminary study of the effect of probiotic Streptococcus salivarius K12 on oral malodour parameters. J. Appl. Microbiol. 100, 754–764 (2006)

    Article  CAS  PubMed  Google Scholar 

  11. Çaglar, E., Sandalli, N., Twetman, S., Kavaloglu, S., Ergeneli, S., Selvi, S.: Effect of yogurt with Bifidobacterium DN-173 010 on salivary mutans streptococci and lactobacilli in young adults. Acta Odontol. Scand. 320, 317–320 (2005)

    Article  Google Scholar 

  12. Carolan, H., Watkins, S., Bradshaw, D.: The prebiotic concept-a novel aproach for skin health. Euro Cosmetics 7(8), 22–27 (2008)

    Google Scholar 

  13. Cogen, A.L., Nizet, V., Gallo, R.L.: Skin microbiota: a source of disease or defence? Br. J. Dermatol. 158, 442–455 (2008)

    Article  CAS  PubMed  Google Scholar 

  14. Comelli, E.M., Guggenheim, B., Stingele, F., Neeser, J.R.: Selection of dairy bacterial strains as probiotics for oral health. Eur. J. Oral Sci. 110, 218–224 (2002)

    Article  PubMed  Google Scholar 

  15. Cosseau, C., Devine, D.A., Dullaghan, E., Gardy, J.L., Chikatamarla, A., Gellatly, S., Yu, L.L., Pistolic, J., Falsafi, R., Tagg, J., Hancock, R.E.W.: The commensal Streptococcus salivarius K12 downregulates the innate immune responses of human epithelial cells and promotes host–microbe homeostasis. Infect. Immun. 76, 4163–4175 (2008)

    Article  CAS  PubMed  Google Scholar 

  16. Dekio, I., Hayashi, H., Sakamoto, M., Kitahara, M., Nishikawa, T., Suematsu, M., Benno, Y.: Detection of potentially novel bacterial components of the human skin microbiota using culture-independent molecular profiling. J. Med. Microbiol. 54, 1231–1238 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Donnarumma, G., Paoletti, I., Buommino, E., Orlando, M., Tufano, M.A., Baroni, A.: Malassezia furfur induces the expression of β-defensin-2 in human keratinocytes in a protein kinase C-dependent manner. Arch. Dermatol. Res. 295, 474–481 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Donnarumma, G., Buommino, E., Baroni, A., Auricchio, L., Filippis, A.D., Cozza, V., Msika, P., Piccardi, N., Tufano, M.A.: Effects of AV119, a natural sugar from avocado, on Malassezia furfur invasiveness and on the expression of HBD-2 and cytokines in human keratinocytes. Exp. Dermatol. 16, 912–919 (2007)

    Article  CAS  PubMed  Google Scholar 

  19. Fierer, N., Hamady, M., Lauber, C.L., Knight, R.: The influence of sex, handedness, and washing on the diversity of hand surface bacteria. Proc. Natl. Acad. Sci. USA 105, 17994–17999 (2008)

    Article  CAS  PubMed  Google Scholar 

  20. Finlay, B.B., Hancock, R.E.W.: Can innate immunity be enhanced to treat microbial infections? Nat. Rev. Microbiol. 2, 497–504 (2004)

    Article  CAS  PubMed  Google Scholar 

  21. Fredricks, D.N.: Microbial ecology of human skin in health and disease. J. Investig. Dermatol. Symp. Proc. 6, 167–169 (2001)

    Article  CAS  PubMed  Google Scholar 

  22. Frohm, M., Agerberth, B., Ahangari, G., Ståhle-Bäckdahl, M., Lidén, S., Wigzell, H., Gudmundsson, G.H.: The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272, 15258–15263 (1997)

    Article  CAS  PubMed  Google Scholar 

  23. Gao, Z., Tseng, C.-, Pei, Z., Blaser, M.J.: Molecular analysis of human forearm superficial skin bacterial biota. Proc. Natl. Acad. Sci. USA 104, 2927–2932 (2007)

    Article  CAS  PubMed  Google Scholar 

  24. Garciéa, J.R., Krause, A., Schulz, S., Rodriéguez-Jiménez, F.J., Klüver, E., Adermann, K., Forssmann, U., Frimpong-Boateng, A., Bals, R., Forssmann, W.G.: Human beta-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity. FASEB J. 15, 1819–1821 (2001)

    Google Scholar 

  25. Gibson, G.R., Roberfroid, M.B.: Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J. Nutr. 125, 1401–1412 (1995)

    CAS  PubMed  Google Scholar 

  26. Grice, E.A., Kong, H.H., Renaud, G., Young, A.C., Bouffard, G.G., Blakesley, R.W., Wolfsberg, T.G., Turner, M.L., Segre, J.A.: A diversity profile of the human skin microbiota. Genome Res. 18, 1043–1050 (2008)

    Article  CAS  PubMed  Google Scholar 

  27. Gueniche, A., Knaudt, B., Schuck, E., Volz, T., Bastien, P., Martin, R., Röcken, M., Breton, L., Biedermann, T.: Effects of nonpathogenic gram-negative bacterium Vitreoscilla filiformis lysate on atopic dermatitis: A prospective, randomized, double-blind, placebo-controlled clinical study. Br. J. Dermatol. 159, 1357–1363 (2008)

    Article  CAS  PubMed  Google Scholar 

  28. Guéniche, A., Cathelineau, A.-, Bastien, P., Esdaile, J., Martin, R., Queille Roussel, C., Breton, L.: Vitreoscilla filiformis biomass improves seborrheic dermatitis. J. Eur. Acad. Dermatol. Venereol. 22, 1014–1015 (2008)

    Article  PubMed  Google Scholar 

  29. Guggenheim, M., Shapiro, S., Gmür, R., Guggenheim, B.: Spatial arrangements and associative behavior of species in an in vitro oral biofilm model. Appl. Environ. Microbiol. 67, 1343–1350 (2001)

    Article  CAS  PubMed  Google Scholar 

  30. Haffajee, A.D., Socransky, S.S.: Microbial etiological agents of destructive periodontal diseases. Periodontol. 2000 5, 78–111 (1994)

    Article  CAS  PubMed  Google Scholar 

  31. Haraszthy, V.I., Zambon, J.J., Sreenivasan, P.K., Zambon, M.M., Gerber, D., Rego, R., Parker, C.: Identification of oral bacterial species associated with halitosis. J. Am. Dent. Assoc. 138, 1113–1120 (2007)

    PubMed  Google Scholar 

  32. Harder, J., Schröder, J.: RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin. J. Biol. Chem. 277, 46779–46784 (2002)

    Article  CAS  PubMed  Google Scholar 

  33. Harder, J., Bartels, J., Christophers, E., Schroöder, J.: Isolation and characterization of human β-Defensin-3, a novel human inducible peptide antibiotic. J. Biol. Chem. 276, 5707–5713 (2001)

    Article  CAS  PubMed  Google Scholar 

  34. Hartley, G., McKenzie, C., Greenman, J., El-Maaytah, M.A., Scully, C., Porter, S.: Tongue microbiota and malodour: effects of metronidazole mouthrinse on tongue microbiota and breath odour. Microb. Ecol. Health Dis. 11, 226–233 (1999)

    Article  CAS  Google Scholar 

  35. Haukioja, A., Loimaranta, V., Tenovuo, J.: Probiotic bacteria affect the composition of salivary pellicle and streptococcal adhesion in vitro. Oral Microbiol. Immunol. 23, 336–343 (2008)

    Article  CAS  PubMed  Google Scholar 

  36. Heldermann, M., Van der Hoeven, H.: Probiotic active for the skin – helps your skin stay in balance. Household and Personal Care Today 1, 8–9 (2007)

    Google Scholar 

  37. Hillman, J.D., Brooks, T.A., Michalek, S.M., Harmon, C.C., Snoep, J.L., Van Der Weijden, C.C.: Construction and characterization of an effector strain of Streptococcus mutans for replacement therapy of dental caries. Infect. Immun. 68, 543–549 (2000)

    Article  CAS  PubMed  Google Scholar 

  38. Holland, K.T., Bojar, R.A.: Cosmetics: what is their influence on the skin microflora? Am. J. Clin. Dermatol. 3, 445–449 (2002)

    Article  PubMed  Google Scholar 

  39. Iovieno, A., Lambiase, A., Sacchetti, M., Stampachiacchiere, B., Micera, A., Bonini, S.: Preliminary evidence of the efficacy of probiotic eye-drop treatment in patients with vernal keratoconjunctivitis. Graefes Arch. Clin. Exp. Ophthalmol. 246, 435–441 (2008)

    Article  CAS  PubMed  Google Scholar 

  40. Janssen, F., Waldmann-Laue, M.: Efficacy of a prebiotic product combination against skin impurities. IFSCC Congress poster presentation at the IFSCC Congress in (2008)

    Google Scholar 

  41. Jenkinson, H.F., Lamont, R.J.: Oral microbial communities in sickness and in health. Trends Microbiol. 13, 589–595 (2005)

    Article  CAS  PubMed  Google Scholar 

  42. Katsuyama, M., Wachi, Y., Ikezawa, Z., Kitamura, K., Suga, C., Ohnuma, S.: Correlation between the population of Staphylococcus aureus on the skin and severity of a score of dry type atopic dermatitis conditions. Nippon Hifuka Gakkai Zasshi 107, 1103–1111 (1997)

    Google Scholar 

  43. Kõll, P., Mändar, R., Marcotte, H., Leibur, E., Mikelsaar, M., Hammarström, L.: Characterization of oral lactobacilli as potential probiotics for oral health. Oral Microbiol. Immunol. 23, 139–147 (2008)

    Article  PubMed  Google Scholar 

  44. Kozuka, T.: Patch testing to exclude allergic contact dermatitis caused by povidone-iodine. Dermatology 204, 96–98 (2002)

    Article  CAS  PubMed  Google Scholar 

  45. Kroes, I., Lepp, P.W., Relman, D.A.: Bacterial diversity within the human subgingival crevice. Proc. Natl. Acad. Sci. USA 96, 14547–14552 (1999)

    Article  CAS  PubMed  Google Scholar 

  46. Krutmann, J.: Pre- and probiotics for human skin. J. Dermatol. Sci. 54, 1–5 (2009)

    Article  PubMed  Google Scholar 

  47. Lang, C., Veen, M., Budde, E., Böttner, M., Reindl, A., Knöll, R.: Microorganisms inhibiting the formation of axillary malodor. US patent WO 2007/031300 (2007)

    Google Scholar 

  48. Lang, C., Heilmann, A., Veen, M., Budde, E., Böttner, M., Reindl, A., Knöll, R.: Methods and means for protecting the skin against pathogenic bacteria. US patent WO 2006/136420 A2 (2006)

    Google Scholar 

  49. Larson, E.L., Gomez-Duarte, C., Lee, L.V., Della-Latta, P., Kain, D.J., Keswick, B.H.: Microbial flora of hands of homemakers. Am. J. Infect. Control 31, 72–79 (2003)

    Article  PubMed  Google Scholar 

  50. Leyden, J.J., McGinley, K.J., Holzle, E.: The microbiology of the human axilla and its relationship to axillary odor. J. Invest. Dermatol. 77, 413–416 (1981)

    Article  CAS  PubMed  Google Scholar 

  51. Leyden, J.J., McGinley, K.J., Nordstrom, K.M., Webster, G.F.: Skin microflora. J. Invest. Dermatol. 88, 65–72 (1987)

    Article  Google Scholar 

  52. Masako, K., Hideyuki, I., Shigeyuki, O., Zenro, I.: A novel method to control the balance of skin microflora: Part 1. Attack on biofilm of Staphylococcus aureus without antibiotics. J. Dermatol. Sci. 38, 197–205 (2005)

    Article  CAS  PubMed  Google Scholar 

  53. Masako, K., Yusuke, K., Hideyuki, I., Atsuko, M., Yoshiki, M., Kayoko, M., Makoto, K.: A novel method to control the balance of skin microflora: Part 2. A study to assess the effect of a cream containing farnesol and xylitol on atopic dry skin. J. Dermatol. Sci. 38, 207–213 (2005)

    Article  CAS  PubMed  Google Scholar 

  54. Midorikawa, K., Ouhara, K., Komatsuzawa, H., Kawai, T., Yamada, S., Fujiwara, T., Yamazaki, K., Sayama, K., Taubman, M.A., Kurihara, H., Hashimoto, K., Sugai, M.: Staphylococcus aureus susceptibility to innate antimicrobial peptides, β-defensins and CAP18, expressed by human keratinocytes. Infect. Immun. 71, 3730–3739 (2003)

    Article  CAS  PubMed  Google Scholar 

  55. Nomura, I., Gao, B., Boguniewicz, M., Darst, M.A., Travers, J.B., Leung, D.Y.M.: Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J. Allergy Clin. Immunol. 112, 1195–1202 (2003)

    Article  CAS  PubMed  Google Scholar 

  56. Offenbacher, S., Katz, V., Fertik, G., Collins, J., Boyd, D., Maynor, G., McKaig, R., Beck, J.: Periodontal infection as a possible risk factor for preterm low birth weight. J. Periodontol. 67, 1103–1113 (1996)

    CAS  PubMed  Google Scholar 

  57. Ogawa, T., Katsuoka, K., Kawano, K., Nishiyama, S.: Comparative study of staphylococcal flora on the skin surface of atopic dermatitis patients and healthy subjects. J. Dermatol. 21, 453–460 (1994)

    CAS  PubMed  Google Scholar 

  58. Ong, P.Y., Ohtake, T., Brandt, C., Strickland, I., Boguniewicz, M., Ganz, T., Gallo, R.L., Leung, D.Y.M.: Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002)

    Article  CAS  PubMed  Google Scholar 

  59. Ouwehand, A.C., Båtsman, A., Salminen, S.: Probiotics for the skin: a new area of potential application? Lett. Appl. Microbiol. 36, 327–331 (2003)

    Article  CAS  PubMed  Google Scholar 

  60. Pancholi, P., Healy, M., Bittner, T., Webb, R., Wu, F., Aiello, A., Larson, E., Della Latta, P.: Molecular characterization of hand flora and environmental isolates in a community setting. J. Clin. Microbiol. 43, 5202–5207 (2005)

    Article  CAS  PubMed  Google Scholar 

  61. Paster, B.J., Boches, S.K., Galvin, J.L., Ericson, R.E., Lau, C.N., Levanos, V.A., Sahasrabudhe, A., Dewhirst, F.E.: Bacterial diversity in human subgingival plaque. J. Bacteriol. 183, 3770–3783 (2001)

    Article  CAS  PubMed  Google Scholar 

  62. Pernet, I., Reymermier, C., Guezennec, A., Viac, J., Guesnet, J., Perrier, E.: An optimized method for intensive screening of molecules that stimulate β-defensin 2 or 3 (hBD2 or hBD3) expression in cultured normal human keratinocytes. Int. J. Cosmet. Sci. 27, 161–170 (2005)

    Article  CAS  PubMed  Google Scholar 

  63. Pham, L.C., van Spanning, R.J.M., Röling, W.F.M., Prosperi, A.C., Terefework, Z., ten Cate, J.M., Crielaard, W., Zaura, E.: Effects of probiotic Lactobacillus salivarius W24 on the compositional stability of oral microbial communities. Arch. Oral. Biol. 54, 132–137 (2009)

    Article  CAS  PubMed  Google Scholar 

  64. Philpott, M.P.: Defensins and acne. Mol. Immunol. 40, 457–462 (2003)

    Article  CAS  PubMed  Google Scholar 

  65. Roberfroid, M.B.: Inulin-type fructans: functional food ingredients. J. Nutr. 137, 2493S–2502S (2007)

    CAS  PubMed  Google Scholar 

  66. Rogers, K.L., Rupp, M.E., Fey, P.D.: The presence of icaABCDis detrimental to the colonization of human skin by Staphylococcus epidermidis. Appl. Environ. Microbiol. 74, 6155–6157 (2008)

    Article  CAS  PubMed  Google Scholar 

  67. Roth, R.R., James, W.D.: Microbiology of the skin: resident flora, ecology, infection. J. Am. Acad. Dermatol. 20, 367–390 (1989)

    Article  CAS  PubMed  Google Scholar 

  68. Schauber, J., Gallo, R.L.: Antimicrobial peptides and the skin immune defense system. J. Allergy Clin. Immunol. 122, 261–266 (2008)

    Article  CAS  PubMed  Google Scholar 

  69. Schröder, J., Harder, J.: Human beta-defensin-2. Int. J. Biochem. Cell Biol. 31, 645–651 (1999)

    Article  PubMed  Google Scholar 

  70. Shelley, W.B., Hurley, H.J., Nichols, A.C.: Axillary odor. Arch. Dermatol. Syphilol. 68, 430–446 (1953)

    CAS  Google Scholar 

  71. Smiricky-Tjardes, M.R., Flickinger, E.A., Grieshop, C.M., Bauer, L.L., Murphy, M.R., Fahey Jr., G.C.: In vitro fermentation characteristics of selected oligosaccharides by swine fecal microflora. J. Anim. Sci. 81, 2505–2514 (2003)

    CAS  PubMed  Google Scholar 

  72. Steidler, L., Vandenbroucke, K.: Genetically modified Lactococcus lactis: Novel tools for drug delivery. Int. J. Dairy Technol. 59, 140–146 (2006)

    Article  CAS  Google Scholar 

  73. Tagg, J.R.: Prevention of streptococcal pharyngitis by anti-Streptococcus pyogenes bacteriocin-like inhibitory substances (BLIS) produced by Streptococcus salivarius. Indian J. Med. Res. 119, 13–16 (2004)

    CAS  PubMed  Google Scholar 

  74. Teughels, W., Van Essche, M., Sliepen, I., Quirynen, M.: Probiotics and oral healthcare. Periodontol. 2000 48, 111–147 (2008)

    Article  PubMed  Google Scholar 

  75. Trebesius, K., Banowski, B., Beimfohr, C., Bergmaier, I., Jassoy, C., Sättler, A., Scholtyssek, R., Simmering, R., Bockmuehl, D.: Gender-specific composition of the human axillary microbiota. Biospektrum Sonderausgabe VAAM-Jahrestagung 2006, 75 (2006)

    Google Scholar 

  76. Van Winkelhoff, A.J., Loos, B.G., Van Der Reijden, W.A., Van Der Velden, U.: Porphyromonas gingivalis, Bacteroides forsythus and other putative periodontal pathogens in subjects with and without periodontal destruction. J. Clin. Periodontol. 29, 1023–1028 (2002)

    Article  PubMed  Google Scholar 

  77. Washio, J., Sato, T., Koseki, T., Takahashi, N.: Hydrogen sulfide-producing bacteria in tongue biofilm and their relationship with oral malodour. J. Med. Microbiol. 54, 889–895 (2005)

    Article  CAS  PubMed  Google Scholar 

  78. Williams, R.E.A., Gibson, A.G., Aitchison, T.C., Lever, R., Mackie, R.M.: Assessment of a contact-plate sampling technique and subsequent quantitative bacterial studies in atopic dermatitis. Br. J. Dermatol. 123, 493–501 (1990)

    Article  CAS  PubMed  Google Scholar 

  79. Zambon, J.J.: Periodontal diseases: microbial factors. Ann. Periodontol. 1, 879–925 (1996)

    Article  CAS  PubMed  Google Scholar 

  80. Ziebuhr, W., Hennig, S., Eckart, M., Kränzler, H., Batzilla, C., Kozitskaya, S.: Nosocomial infections by Staphylococcus epidermidis: how a commensal bacterium turns into a pathogen. Int. J. Antimicrob. Agents 28, 14–20 (2006)

    Article  Google Scholar 

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Simmering, R., Breves, R. (2010). Prebiotic Cosmetics. In: Krutmann, J., Humbert, P. (eds) Nutrition for Healthy Skin. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12264-4_13

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