Abstract

The human skin harbours hundreds of species of commensal organisms, collectively known as the skin microbiota. The composition of the microbiota can be modified by various factors, such as host genotype, diet, antibiotics, hygiene, and pathogen infections, among others. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or a decrease in the number of beneficial bacteria. Dysbiosis has been implicated in some dermatological diseases. This mini-review aims to discuss the topic of the skin microbiota and its potential effects on various skin diseases.

Introduction

The microorganisms inhabiting the human body are collectively known as the microbiota. They colonize the most environmentally exposed surfaces such as the skin, mouth, gut and vagina immediately after birth [43]. Estimated at approximately 100 trillion organisms, most of which are bacteria, the microbiota numbers about 10 times the total cells of the human body [43]. The majority of microbes reside in the gastrointestinal tract, have a profound influence on human physiology and nutrition, and are crucial for human life [7,37]. The suggested total number of bacteria inhabiting a healthy human gut is approximately 1014 [11]. Their collective genome, referred to as the metagenome, is estimated to contain at least 100 times more unique genes than the human genome [43]. Of the 70 known bacterial divisions and the 13 divisions of Archaea that have been described to date, only two phyla predominate within the intestine: the Bacteroidetes (16.3%) and the Firmicutes (65.7%) [23,25]. The fact that the bacteria within the human intestine represent such a small fraction of the total bacteria found on the planet suggests that these bacteria are highly evolved and specialized to live within the mammalian intestine. Numerous studies have identified important roles for bacterial signals in promoting the optimal digestion of food [37], maintaining epithelial homeostasis [3], modulating fat metabolism [6], promoting angiogenesis [74], supporting resistance to infection [69], and promoting normal development and regulation of immune cell homeostasis [15], among others. The composition of the intestinal microbiota can be modified by various factors, such as host genotype, diet, antibiotic ingestion, pathogen infections and other life events [73]. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or a decrease in the number of beneficial bacteria [33]. Though it is widely accepted that shifts in the gut microbiota composition and density can affect local immune responses, it is becoming clear that these changes can also alter host immunity and inflammation in organs distal from the intestine [10]. Accumulating evidence indicates that dysbiosis is not only a marker of various inflammatory diseases but also a trigger, leading to altered immune responses that underlie these diseases [35,65]. Intestinal dysbiosis has been recently implicated in numerous inflammatory and autoimmune diseases, including inflammatory bowel diseases (IBD) [48], coeliac disease [70], rheumatoid arthritis [68], diabetes mellitus type I [84] and II [62], multiple sclerosis [55], and allergies [36], among others. A strong association with dysbiosis has also been found in obesity [76], metabolic syndrome [79], atherosclerosis [82], and cancer [49]. Despite our growing understanding of the roles that intestinal bacteria play in normal development and regulation of the human immune system, little is known about the microbiota inhabiting the skin, the largest organ of the body. This mini-review aims to discuss the topic of skin microbiota and their potential effects on various skin diseases.

Skin microbiota

The skin is an ecosystem composed of 1.8 m2 of diverse habitats with an abundance of folds, invaginations and specialized niches that support a wide range of microorganisms. The primary role of the skin is as a physical barrier, resisting penetration by microorganisms and potential toxins while retaining moisture and nutrients inside the body. The skin is also a primary interface with the outside environment and, as such, is colonized by a diverse group of microorganisms, including bacteria, fungi, viruses and mites.

Although human skin is a rather inhospitable environment, very poor in nutrients, acidic, desiccated, with continual shedding of superficial skin cells, it is inhabited by one billion bacteria per square centimetre on average [29]. The microbiota of the skin is characterized by the same four predominant phyla as in other body sites: Actinobacteria, Firmicutes, Proteobacteria, and Bacteroide tes [18,28]. The proportions, however, differ significantly: whereas Actinobacteria members are more abundant on skin, Firmicutes and Bacteroidetes members are more abundant in the gastrointestinal tract. A common feature of gut and skin microbial compositions is a low diversity at the phylum level, and a high diversity at the species level.

Additionally, microbial profiling has revealed that the relative distributions of bacterial phyla and families differ significantly among various skin sites [24]. These differences in microbial distribution reflect differences in skin temperature, humidity, glandular distribution, environmental exposure, etc [24]. Some regions of the skin, for instance, are partially occluded, such as the groin, axillary vault and toe web, and are higher in temperature and humidity. These regions are inhabited by microorganisms preferring moist conditions, such as Gram-negative bacilli, Corynebacterium spp. and Staphylococcus [63]. Other areas, characterized by a high density of sebaceous glands, including the face, chest and back, are preferentially inhabited by lipophilic microorganisms, such as Propionibacterium spp. and Malassezia spp. [63]. Arm and leg skin, due to the relative desiccation and fluctuations of surface temperature, harbour fewer organisms than other skin areas [63]. There are also various factors specific to the host (age, location and sex), as well as environmental factors (occupation, clothing choice, antibiotic use, hygiene, UV exposure, etc) that significantly affect the composition of skin microbial flora [30]. Despite bacterial diversity at different sites, skin microbial composition seems to be more similar between skin sites than among other body habitats.

Generally, bacterial skin populations can be categorized as: i) transient (contaminant, non-reproducing), ii) temporary residents (not typically resident, yet can colonize), and iii) resident (growing and reproducing) flora [53]. The ‘normal’ resident skin flora includes Propionibacterium acnes, Staphylococcus epidermidis, Staphylococcus aureus, Corynebacterium diphtheria, Corynebacterium jeikeium and Pseudomonas aeruginosa. The roles of resident bacteria are highly varied and not fully understood.

Microbiota-cutaneous immune system interactions

In addition to being a physical barrier, the skin is an immunological barrier [12]. The skin immune response is crucial in infection and wounding, but also modulates the commensal microbiota residing on the skin. Keratinocytes continuously sample the microbial antigens through pattern recognition receptors (PRRs) capable of recognizing pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide, flagellin, nucleic acids from Gram-negative bacteria, mannan and zymosan from fungal cell walls, and peptidoglycan and lipoteichoic acid from Gram-positive bacteria. The key PRRs involved in recognition of these microbial components are Toll- -like receptors (TLR), nucleotide oligomerization domain receptors (NODs), and mannose receptors [60]. The activation of keratinocyte PRRs by PAMPs initiates the innate immune response, resulting in the secretion of cytokines, chemokines and antimicrobial peptides (AMPs), such as cathelicidins and β-defensins that altogether effect the adaptive immune response [14]. Secretion or release of AMPs provides innate antibiotic-like actions against infectious pathogens, and some of them, such as cathelicidin LL-37, also trigger inflammatory cell recruitment and cytokine release [52]. Keratinocytes, different immune cells and skin microorganisms are involved in a constant interplay modulated by a variety of signals of both host and microbial origin.

Despite being constantly exposed to large numbers of microorganisms, the skin can discriminate between harmless commensal microorganisms and harmful pathogens. The mechanism responsible for this discrimination is not fully understood, but involves the induction of tolerance by commensal microorganisms. In the steady state, both the skin Langerhans cells (LCs) and dermal dendritic cells (dDCs) maintain the tolerance through induction of FOXP3+ regulatory T cells, which can act in a bacteria-specific manner [78]. While LCs have been demonstrated to promote skin resident Treg cell proliferation [71], it seems that mainly dDCs present self-antigens in the skin draining lymph nodes [5,9]. Suboptimal DC activation and very low doses of antigens, or a combination of these factors, have been linked to the induction of bacteria-specific Treg cells [78]. Recently, numerous PAMPs of commensal origin have been identified capable of inducing Treg cells (Table 1). Markers typical for skin resident Treg cells are CD44 and CD103, indicating that the majority of skin Treg cells are of memory/effector type [22,67,75]. Skin Treg cells also express high levels of IL-10 and TGF-β, two potent immunoregulatory cytokines [75].

Accumulating evidence indicates that microorganisms are capable of modulating the host immune response. A large number of Gram positive bacteria such as Lactococcus, Streptococcus and Streptomyces species are able to produce factors that inhibit other bacteria [27]. Staphylococcus epidermidis, for instance, the dominant commensal bacterium, can selectively inhibit skin pathogens such as Staphylococcus aureus, group A Streptococcus and Escherichia coli by phenol-soluble modulins (PSM), such as PSMγ and PSMδ [17]. PSMs function in a similar mechanistic manner as various AMPs, creating pores and causing membrane leakage and membrane perturbation in bacteria. PSMs can also enhance the antimicrobial activity of the host AMPs [27]. It has been recently found that a small molecule of <10 kDa produced by Staphylococcus epidermidis can trigger keratinocyte expression of AMPs through a TLR2- -dependent mechanism [41]. Similarly, co-cultivation of differentiated human primary keratinocytes with live Staphylococcus epidermidis enhances production of various AMPs and RNases [27]. Moreover, keratinocytes pre-incubated with Staphylococcus epidermidis-conditioned media strongly enhanced AMP production by keratinocytes activated by Staphylococcus aureus [83]. This suggests that commensal bacteria are capable of sensitizing keratinocytes towards pathogenic bacteria and amplifying the innate immune response. It has also been demonstrated that lipoteichoic acid (LTA) produced by Staphylococcus epidermidis inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR2-dependent mechanism [42].

Dysbiosis and skin diseases

Various skin diseases, such as psoriasis and atopic dermatitis, are strongly associated with dysregulation of the skin immune response, which affects and/or results from the changes in the microbiota (Table 2). Atopic dermatitis is a chronic inflammatory and pruritic skin disease characterized by flares and remissions. Atopic dermatitis lesions are characterized by low levels of AMP production, despite the presence of skin inflammation, and are regularly infected with pathogens, including Staphylococcus aureus, which can be isolated from more than 90% of patients [19,57]. Interestingly, RNase7 and psoriasin are induced in atopic dermatitis skin and the AMP induction is upregulated by barrier disruption [32]. It is believed that the upregulation of Th2 cytokines in atopic dermatitis lesions at least partially accounts for the suppression of the innate immune response observed in AD [54]. Inhibited induction of some but not all AMPs is thought to contribute to the susceptibility of atopics to infection. Polymorphisms within genes encoding TLR2 and TLR9 have also been associated with atopic dermatitis [77].

Psoriasis is a chronic inflammatory skin disease mediated by T cells, which trigger keratinocytes to hyperproliferate and perpetuate the disease. The disease has been strongly associated with Th1 and Th17 cytokine profiles. Psoriatic lesions are characterized by high production of cathelicidins and hBDs as well as by a strong innate immune response [19,31]. Keratinocytes from psoriatic plaques express high levels of TLRs 1 and 2 [77]. In psoriatic lesions, the representation of Propionibacterium and Actinobacteria species is lower than in normal skin, while Firmicutes species are overrepresented [28]. It seems, therefore, that psoriasis is, in part, associated with substantial alteration in the composition and representation of the cutaneous microflora; however, the disease has not been linked to any clear microbial component, although the guttate subset of psoriasis has been associated with streptococcal infections [58].

The commensal skin bacterium Propionibacterium acnes is associated with the common teenage malady acne, which is an inflammatory disorder of the pilosebaceous unit. Propionibacterium acnes and other lipophilic microorganisms secrete lipases, proteases and hyaluronidases that injure the tissue [20]. It has been found that Propionibacterium acnes is capable of activating classical and alternative complement pathways, leading to the formation of C5a, an anaphylatoxin that induces the secretion of proinflammatory cytokines, including TNF-α, IL-1β, and IL-8 by monocytes [77]. Propionibacterium acnes also produces low-molecular weight, serum-independent chemotactic factors that attract neutrophils through the epithelium wall, into the lumen of sebaceous follicles [30]. It has been shown that there is a positive correlation between the severity of acne lesions and the upregulation of TLR2 and TLR4 [40,77].

In rosacea, similarly to psoriasis, the upregulation of cathelicidin and TLRs has been observed, driving inflammation and abnormal blood vessel growth by mechanisms of cell activation [40,86,87]. These defects in innate immune mechanisms could impact the homeostasis of skin-resident microflora, which may disrupt the skin barrier and induce abnormal inflammatory responses. Although no specific pathogens have been isolated in the lesional skin of rosacea [47], the dysbiosis has been implied in the pathogenesis of the disease. The predominance of Staphylococcus epidermidis has been observed in the lesional skin, while other bacteria have been recorded at much lower levels compared to peripheral non -lesional skin [85]. In addition, studies have also revealed increased microbial loads or immune hyperactivity to the following microorganisms: Demodex folliculorum, Bacillus oleronius, Helicobacter pylori, and Chlamydophila pneumonia [34].

Conclusions

Recent studies have shown that skin microbiota contribute to the protection against pathogenic microorganisms as well as against overgrowth of opportunistic pathogens. A great example of such a role is provided by Staphylococcus epidermidis, the most common skin bacterium capable of inhibiting the colonization and biofilm formation by Staphylococcus aureus [39]. Staphylococcus epidermidis has been demonstrated to produce the glutamyl endopeptidase protein, which can synergize with the human AMP β-defensin 2, interfering with Staphylococcus aureus colonization. It has also been shown that cutaneous commensals exert their effect against pathogens by augmenting IL-1 signalling and amplifying the response in accordance with the local inflammatory milieu [51]. It is worth mentioning that the IL-1 pathway is an evolutionary conserved mechanism of the innate immune system that may have arisen as an early mediator of host skin-commensal cross talk, implying the possibility of coevolution. Therefore the maintenance of normal skin microflora may be crucial to maintain healthy skin. The composition of the skin microbiota, however, can be modified by various factors, such as diet, antibiotic ingestion, hygiene, pathogen infections, etc. Changes in these factors can cause dysbiosis, resulting in the outgrowth of potential pathogenic bacteria or a decrease in the number of beneficial bacteria, ultimately leading to induction and/or exacerbation of the disease.

The picture becomes even more complicated when taking into account the cross-talk between the skin and other organ systems that can be assumed based on the number of skin conditions that commonly co-manifest with non-cutaneous disorders [81]. The existence of a specific communication axis between the skin, the gut, and the brain has been recently postulated, since both the gut and skin exhibit similar neuronal and inflammatory activity [2]. Though currently it is widely accepted that shifts in the gut microbiota composition and density can affect local immune responses, it is becoming clear that these changes can also alter host immunity and inflammation in organs distal from the intestine [10]. There is convincing evidence indicating the association between gut dysbiosis and numerous inflammatory and autoimmune diseases, including dermatological diseases [16,61]. Current data suggest, for instance, that acne vulgaris has a strong gut microbial involvement [13]. The link between gut dysbiosis and psoriasis seems also plausible. First of all, there is a known association between psoriasis and Crohn’s disease (CD), a chronic inflammatory disease of the gastrointestinal tract resulting, at least partially, from a breakdown of immune tolerance to the gut microbiota [46]. CD patients are five times more likely to develop psoriasis compared with a control population [38,88]. Conversely, patients with psoriasis are at greater risk of developing CD than the general population [44]. Both diseases feature increased permeability of the intestine [56]. In addition to a similar peak age of onset, the two diseases show an overlap in their immunopathogenic pathways (Th23/Th22/Th17 axis), genetic mutations and response to biologic therapies, implying similar pathology [26].

It also seems that any deviations from the normal microbiota during childhood may alter the outcome of immune development and potentially predispose individuals to various inflammatory and autoimmune diseases later in life. It has been observed, for instance, that normally, intestinal colonization of neonates is dominated by transmission of bacteria from the maternal vaginal flora [21]. However, infants born by Caesarean section are initially colonized more by bacterial species of epidermal origin, and are predisposed to development of allergies and asthma later in life [8]. Recent studies have also demonstrated the association between Caesarean section and low intestinal microbial diversity in infants and subsequent development of atopic dermatitis [1,59]. In conclusion, accumulating evidence indicates that resident commensals are necessary for optimal host skin immune fitness. Still, much has to be learnt about the interactions between skin commensals and the cutaneous immune system. Understanding the role of microbiota in maintaining skin homeostasis is not only of prime importance for human health, but might also help to develop new therapeutic strategies.

References

• 1. Abrahamsson T.R., Jakobsson H.E., Andersson A.F., Björkstén B.,Engstrand L., Jenmalm M.C.: Low diversity of the gut microbiotain infants with atopic eczema. J. Allergy Clin. Immunol., 2012; 129:434-440
  Google Scholar
• 2. Arck P., Handjiski B., Hagen E., Pincus M., Bruenahl C., BienenstockJ., Paus R.: Is there a ‘gut-brain-skin axis’? Exp. Dermatol.,2010; 19: 401-405
  Google Scholar
• 3. Artis D.: Epithelial-cell recognition of commensal bacteria andmaintenance of immune homeostasis in the gut. Nat. Rev. Immunol.,2008; 8: 411-420
  Google Scholar
• 4. Atarashi K., Tanoue T., Oshima K., Suda W., Nagano Y., NishikawaH., Fukuda S., Saito T., Narushima S., Hase K., Kim S., Fritz J.V., WilmesP., Ueha S., Matsushima K. et al.: Treg induction by a rationallyselected mixture of Clostridia strains from the human microbiota.Nature, 2013; 500: 232-236
  Google Scholar
• 5. Azukizawa H., Döhler A., Kanazawa N., Nayak A., Lipp M., MalissenB., Autenrieth I., Katayama I., Riemann M., Weih F., Berberich–Siebelt F., Lutz M.B.: Steady state migratory RelB+ langerin+ dermaldendritic cells mediate peripheral induction of antigen-specific CD4+CD25+ Foxp3+ regulatory T cells. Eur. J. Immunol., 2011; 41: 1420-1434
  Google Scholar
• 6. Bäckhed F., Ding H., Wang T., Hooper L.V., Koh G.Y., Nagy A., SemenkovichC.F., Gordon J.I.: The gut microbiota as an environmentalfactor that regulates fat storage. Proc. Natl. Acad. Sci. USA, 2004;101: 15718-15723
  Google Scholar
• 7. Bäckhed F., Ley R.E., Sonnenburg J.L., Peterson D.A., Gordon J.I.:Host-bacterial mutualism in the human intestine. Science, 2005;307: 1915-1920
  Google Scholar
• 8. Bager P., Wohlfahrt J., Westergaard T.: Caesarean delivery andrisk of atopy and allergic disease: meta-analyses. Clin. Exp. Allergy,2008; 38: 634-642
  Google Scholar
• 9. Bedoui S., Whitney P.G., Waithman J., Eidsmo L., Wakim L., CaminschiI., Allan R.S., Wojtasiak M., Shortman K., Carbone F.R., BrooksA.G., Heath W.R.: Cross-presentation of viral and self antigens byskin-derived CD103+ dendritic cells. Nat. Immunol., 2009; 10: 488-495
  Google Scholar
• 10. Belkaid Y., Naik S.: Compartmentalized and systemic control oftissue immunity by commensals. Nat. Immunol., 2013; 14: 646-653
  Google Scholar
• 11. Berg R.D.: The indigenous gastrointestinal microflora. TrendsMicrobiol., 1996; 4: 430-435
  Google Scholar
• 12. Borkowski A.W., Gallo R.L.: The coordinated response of thephysical and antimicrobial peptide barriers of the skin. J. Invest.Dermatol., 2011; 131: 285-287
  Google Scholar
• 13. Bowe W., Patel N.B., Logan A.C.: Acne vulgaris, probiotics andthe gut-brain-skin axis: from anecdote to translational medicine.Benef. Microbes, 2014; 5: 185-199
  Google Scholar
• 14. Braff M.H., Gallo R.L.: Antimicrobial peptides: an essential componentof the skin defensive barrier. Curr. Top. Microbiol. Immunol.,2006; 306: 91-110
  Google Scholar
• 15. Cebra J.J.: Influences of microbiota on intestinal immune systemdevelopment. Am. J. Clin. Nutr., 1999; 69: 1046S-1051S
  Google Scholar
• 16. Cho I., Blaser M.J.: The human microbiome: at the interface ofhealth and disease. Nat. Rev. Genet., 2012; 13: 260-270
  Google Scholar
• 17. Cogen A.L., Yamasaki K., Sanchez K.M., Dorschner R.A., Lai Y.,MacLeod D.T., Torpey J.W., Otto M., Nizet V., Kim J.E., Gallo R.L.: Selectiveantimicrobial action is provided by phenol-soluble modulinsderived from Staphylococcus epidermidis, a normal resident of the skin.J. Invest. Dermatol., 2010; 130: 192-200
  Google Scholar
• 18. Costello E.K., Lauber C.L., Hamady M., Fierer N., Gordon J.I.,Knight R.: Bacterial community variation in human body habitatsacross space and time. Science, 2009; 326: 1694-1697
  Google Scholar
• 19. de Jongh G.J., Zeeuwen P.L., Kucharekova M., Pfundt R., van derValk P.G., Blokx W., Dogan A., Hiemstra P.S., van de Kerkhof P.C.,Schalkwijk J.: High expression levels of keratinocyte antimicrobialproteins in psoriasis compared with atopic dermatitis. J. Invest.Dermatol., 2005; 125: 1163-1173
  Google Scholar
• 20. Dessinioti C., Katsambas A.D.: The role of Propionibacterium acnesin acne pathogenesis: facts and controversies. Clin. Dermatol.,2010; 28: 2-7
  Google Scholar
• 21. Dominguez-Bello M.G., Costello E.K., Contreras M., Magris M.,Hidalgo G., Fierer N., Knight R.: Delivery mode shapes the acquisitionand structure of the initial microbiota across multiple body habitatsin newborns. Proc. Natl. Acad. Sci. USA, 2010; 107: 11971-11975
  Google Scholar
• 22. Dudda J.C., Perdue N., Bachtanian E., Campbell D.J.: Foxp3+ regulatoryT cells maintain immune homeostasis in the skin. J. Exp.Med., 2008; 205: 1559-1565
  Google Scholar
• 23. Eckburg P.B., Bik E.M., Bernstein C.N., Purdom E., Dethlefsen L.,Sargent M., Gill S.R., Nelson K.E., Relman D.A.: Diversity of the humanintestinal microbial flora. Science, 2005; 308: 1635-1638
  Google Scholar
• 24. Findley K., Oh J., Yang J., Conlan S., Deming C., Meyer J.A., SchoenfeldD., Nomicos E., Park M., NIH Intramural Sequencing CenterComparative Sequencing Program, Kong H.H., Segre J.A.: Topographicdiversity of fungal and bacterial communities in human skin.Nature, 2013; 498: 367-370
  Google Scholar
• 25. Friswell M.K., Gika H., Stratford I.J., Theodoridis G., Telfer B.,Wilson I.D., McBain A.J.: Site and strain-specific variation in gutmicrobiota profiles and metabolism in experimental mice. PLoSOne, 2010; 5: e8584
  Google Scholar
• 26. Fry L., Baker B.S., Powles A.V., Fahlen A., Engstrand L.: Is chronicplaque psoriasis triggered by microbiota in the skin? Br. J. Dermatol.,2013; 169: 47-52
  Google Scholar
• 27. Gallo R.L., Nakatsuji T.: Microbial symbiosis with the innateimmune defense system of the skin. J. Invest. Dermatol., 2011; 131:1974-1980
  Google Scholar
• 28. Gao Z., Tseng C.H., Strober B.E., Pei Z., Blaser M.J.: Substantialalterations of the cutaneous bacterial biota in psoriatic lesions. PLoSOne, 2008; 3: e2719
  Google Scholar
• 29. Grice E.A., Kong H.H., Renaud G., Young A.C.; NISC ComparativeSequencing Program; 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., 2008; 18: 1043-1050
  Google Scholar
• 30. Grice E.A., Segre J.A.: The skin microbiome. Nat. Rev. Microbiol.,2011; 9: 244-253
  Google Scholar
• 31. Gudjonsson J.E., Ding J., Li X., Nair R.P., Tejasvi T., Qin Z.S., GhoshD., Aphale A., Gumucio D.L., Voorhees J.J., Abecasis G.R., Elder J.T.:Global gene expression analysis reveals evidence for decreased lipidbiosynthesis and increased innate immunity in uninvolved psoriaticskin. J. Invest. Dermatol., 2009; 129: 2795-2804
  Google Scholar
• 32. Harder J., Dressel S., Wittersheim M., Cordes J., Meyer-Hoffert U.,Mrowietz U., Fölster-Holst R., Proksch E., Schröder J.M., Schwarz T.,Gläser R.: Enhanced expression and secretion of antimicrobial peptidesin atopic dermatitis and after superficial skin injury. J. Invest.Dermatol., 2010; 130: 1355-1364
  Google Scholar
• 33. Hill D.A., Artis D.: Intestinal bacteria and the regulation of immunecell homeostasis. Ann. Rev. Immunol., 2010; 28: 623-667
  Google Scholar
• 34. Holmes A.D.: Potential role of microorganisms in the pathogenesisof rosacea. J. Am. Acad. Dermatol., 2013; 69: 1025-1032
  Google Scholar
• 35. Honda K., Littman D.R.: The microbiome in infectious diseaseand inflammation. Annu. Rev. Immunol., 2012; 30: 759-795
  Google Scholar
• 36. Hong P.Y., Lee B.W., Aw M., Shek L.P., Yap G.C., Chua K.Y., LiuW.T.: Comparative analysis of fecal microbiota in infants with andwithout eczema. PLoS One, 2010; 5: e9964
  Google Scholar
• 37. Hooper L.V., Midtvedt T., Gordon J.I.: How host-microbial interactionsshape the nutrient environment of the mammalian intestine.Annu. Rev. Nutr., 2002; 22: 283-307
  Google Scholar
• 38. Hughes S., Williams S.E., Turnberg R.A.: Crohn’s disease andpsoriasis. N. Engl. J. Med., 1983; 308: 101
  Google Scholar
• 39. Iwase T., Uehara Y., Shinji H., Tajima A., Seo H., Takada K., AgataT., Mizunoe Y.: Staphylococcus epidermidis Esp inhibits Staphylococcusaureus biofilm formation and nasal colonization. Nature, 2010;465: 346-349
  Google Scholar
• 40. Jugeau S., Tenaud I., Knol A.C., Jarrousse V., Quereux G., KhammariA., Dreno B.: Induction of toll-like receptors by Propionibacteriumacnes. Br. J. Dermatol., 2005; 153: 1105-1113
  Google Scholar
• 41. Lai Y., Cogen A.L., Radek K.A., Park H.J., Macleod D.T., LeichtleA., Ryan A.F., Di Nardo A., Gallo R.L.: Activation of TLR2 by a smallmolecule produced by Staphylococcus epidermidis increases antimicrobialdefense against bacterial skin infections. J. Invest. Dermatol.,2010; 130: 2211-2221
  Google Scholar
• 42. Lai Y., Di Nardo A., Nakatsuji T., Leichtle A., Yang Y., Cogen A.L.,Wu Z.R., Hooper L.V., Schmidt R.R., von Aulock S., Radek K.A., Huang C.M., Ryan A.F., Gallo R.L.: Commensal bacteria regulate Toll-likereceptor 3-dependent inflammation after skin injury. Nat. Med.,2009; 15: 1377-1382
  Google Scholar
• 43. Ley R.E., Peterson D.A., Gordon J.I.: Ecological and evolutionaryforces shaping microbial diversity in the human intestine. Cell,2006; 124: 837-848
  Google Scholar
• 44. Li W.Q., Han J.L., Chan A.T., Qureshi A.A.: Psoriasis, psoriatic arthritisand increased risk of incident Crohn’s disease in US women.Ann. Rheum. Dis., 2013; 72: 1200-1205
  Google Scholar
• 45. Maintz L., Novak N.: Modifications of the innate immune systemin atopic dermatitis. J. Innate Immun., 2011; 3: 131-141
  Google Scholar
• 46. Manichanh C., Borruel N., Casellas F., Guarner F.: The gut microbiotain IBD. Nat. Rev. Gastroenterol. Hepatol., 2012; 9: 599-608
  Google Scholar
• 47. Marks R.: Concepts in the pathogenesis of rosacea. Br. J. Dermatol.,1968; 80: 170-177
  Google Scholar
• 48. Melgar S., Shanahan F.: Inflammatory bowel disease – from mechanismsto treatment strategies. Autoimmunity, 2010; 43: 463-477
  Google Scholar
• 49. Moore W.E., Moore L.H.: Intestinal floras of populations thathave a high risk of colon cancer. Appl. Environ. Microbiol., 1995;61: 3202-3207
  Google Scholar
• 50. Nagano Y., Itoh K., Honda K.: The induction of Treg cells bygut-indigenous Clostridium. Curr. Opin. Immunol., 2012; 24: 392-397
  Google Scholar
• 51. Naik S., Bouladoux N., Wilhelm C., Molloy M.J., Salcedo R., KastenmullerW., Deming C., Quinones M., Koo L., Conlan S., SpencerS., Hall J.A., Dzutsev A., Kong H., Campbell D.J., Trinchieri G., SegreJ.A., Belkaid Y.: Compartmentalized control of skin immunity byresident commensals. Science, 2012; 337: 1115-1119
  Google Scholar
• 52. Nijnik A., Hancock R.E.: The roles of cathelicidin LL-37 in immunedefences and novel clinical applications. Curr. Opin. Hematol.,2009; 16: 41-47
  Google Scholar
• 53. Noble W.C., Somerville D.A.: Microbiology of Human Skin. London:W.B. Saunders, 1974
  Google Scholar
• 54. Nomura I., Goleva E., Howell M.D., Hamid Q.A., Ong P.Y., HallC.F., Darst M.A., Gao B., Boguniewicz M., Travers J.B., Leung D.Y.:Cytokine milieu of atopic dermatitis, as compared to psoriasis, skinprevents induction of innate immune response genes. J. Immunol.,2003; 171: 3262-3269
  Google Scholar
• 55. Ochoa-Repáraz J., Mielcarz D.W., Begum-Haque S., Kasper L.H.:Gut, bugs, and brain: role of commensal bacteria in the control ofcentral nervous system disease. Ann. Neurol., 2011; 69: 240-247
  Google Scholar
• 56. Ojetti V., De Simone C., Aguilar Sanchez J., Capizzi R., MignecoA., Guerriero C., Cazzato A., Gasbarrini G., Amerio P., Gasbarrini A.:Malabsorption in psoriatic patients: cause or consequence? Scand.J. Gastroenterol., 2006; 41: 1267-1271
  Google Scholar
• 57. Ong P.Y., Ohtake T., Brandt C., Strickland I., Boguniewicz M., GanzT., Gallo R.L., Leung D.Y.: Endogenous antimicrobial peptides and skininfections in atopic dermatitis. N. Engl. J. Med., 2002; 347: 1151-1160
  Google Scholar
• 58. Owen C.M., Chalmers R.J., O’Sullivan T., Griffiths C.E.: A systematicreview of antistreptococcal interventions for guttate and chronicplaque psoriasis. Br. J. Dermatol., 2001; 145: 886-890
  Google Scholar
• 59. Penders J., Gerhold K., Stobberingh E.E., Thijs C., ZimmermannK., Lau S., Hamelmann E.: Establishment of the intestinal microbiotaand its role for atopic dermatitis in early childhood. J. Allergy Clin.Immunol. 2013; 132: 601-607.e8
  Google Scholar
• 60. Pivarcsi A., Kemény L., Dobozy A.: Innate immune functionsof the keratinocytes. A review. Acta Microbiol. Immunol. Hung.,2004; 51: 303-310
  Google Scholar
• 61. Proal A.D., Albert P.J., Marshall T.G.: The human microbiome andautoimmunity. Curr. Opin. Rheumatol., 2013; 25: 234-240
  Google Scholar
• 62. Qin J., Li Y., Cai Z., Li S., Zhu J., Zhang F., Liang S., Zhang W., GuanY., Shen D., Peng Y., Zhang D., Jie Z., Wu W., Qin Y. et al.: A metagenome-wideassociation study of gut microbiota in type 2 diabetes.Nature, 2012; 490: 55-60
  Google Scholar
• 63. Roth R.R., James W.D.: Microbial ecology of the skin. Annu. Rev.Microbiol., 1988; 42: 441-464
  Google Scholar
• 64. Round J.L., Lee S.M., Li J., Tran G., Jabri B., Chatila T.A., MazmanianS.K.: The Toll-like receptor 2 pathway establishes colonizationby a commensal of the human microbiota. Science, 2011; 332: 974-977
  Google Scholar
• 65. Round J.L., Mazmanian S.K.: The gut microbiota shapes intestinalimmune responses during health and disease. Nat. Rev. Immunol.,2009; 9: 313-323
  Google Scholar
• 66. Round J.L., Mazmanian S.K.: Inducible Foxp3+ regulatory T-celldevelopment by a commensal bacterium of the intestinal microbiota.Proc. Natl. Acad. Sci. USA, 2010; 107: 12204-11209
  Google Scholar
• 67. Sather B.D., Treuting P., Perdue N., Miazgowicz M., FontenotJ.D., Rudensky A.Y., Campbell D.J.: Altering the distribution of Foxp3+regulatory T cells results in tissue-specific inflammatory disease. J.Exp. Med., 2007; 204: 1335-1347
  Google Scholar
• 68. Scher J.U., Abramson S.B.: The microbiome and rheumatoidarthritis. Nat. Rev. Rheumatol., 2011; 7: 569-578
  Google Scholar
• 69. Sekirov I., Tam N.M., Jogova M., Robertson M.L., Li Y., Lupp C.,Finlay B.B.: Antibiotic-induced perturbations of the intestinal microbiotaalter host susceptibility to enteric infection. Infect. Immun.,2008; 76: 4726-4736
  Google Scholar
• 70. Sellitto M., Bai G., Serena G., Fricke W.F., Sturgeon C., Gajer P.,White J.R., Koenig S.S., Sakamoto J., Boothe D., Gicquelais R., KryszakD., Puppa E., Catassi C., Ravel J., Fasano A.: Proof of conceptof microbiome-metabolome analysis and delayed gluten exposureon celiac disease autoimmunity in genetically at-risk infants. PLoSOne, 2012; 7: e33387
  Google Scholar
• 71. Seneschal J., Clark R.A., Gehad A., Baecher-Allan C.M., KupperT.S.: Human epidermal Langerhans cells maintain immune homeostasisin skin by activating skin resident regulatory T cells. Immunity,2012; 36: 873-884
  Google Scholar
• 72. Smith P.M., Howitt M.R., Panikov N., Michaud M., Gallini C.A.,Bohlooly-Y M., Glickman J.N., Garrett W.S.: The microbial metabolites,short-chain fatty acids, regulate colonic Treg cell homeostasis.Science, 2013; 341: 569-573
  Google Scholar
• 73. Spor A., Koren O., Ley R.: Unravelling the effects of the environmentand host genotype on the gut microbiome. Nat. Rev. Microbiol.,2011; 9: 279-290
  Google Scholar
• 74. Stappenbeck T.S., Hooper L.V., Gordon J.I.: Developmental regulationof intestinal angiogenesis by indigenous microbes via Panethcells. Proc. Natl. Acad. Sci. USA, 2002; 99: 15451-15455
  Google Scholar
• 75. Tomura M., Honda T., Tanizaki H., Otsuka A., Egawa G., TokuraY., Waldmann H., Hori S., Cyster J.G., Watanabe T., Miyachi Y., KanagawaO., Kabashima K.: Activated regulatory T cells are the majorT cell type emigrating from the skin during a cutaneous immuneresponse in mice. J. Clin. Invest., 2010; 120: 883-893
  Google Scholar
• 76. Turnbaugh P.J., Ley R.E., Mahowald M.A., Magrini V., Mardis E.R.,Gordon J.I.: An obesity-associated gut microbiome with increasedcapacity for energy harvest. Nature, 2006; 444: 1027-1031
  Google Scholar
• 77. Valins W., Amini S., Berman B.: The expression of Toll-like receptorsin dermatological diseases and the therapeutic effect ofcurrent and newer topical Toll-like receptor modulators. J. Clin.Aesthet. Dermatol., 2010; 3: 20-29
  Google Scholar
• 78. van der Aar A.M., Picavet D.I., Muller F.J., de Boer L., van CapelT.M., Zaat S.A., Bos J.D., Janssen H., George T.C., Kapsenberg M.L.,van Ham S.M., Teunissen M.B., de Jong E.C.: Langerhans cells favorskin flora tolerance through limited presentation of bacterial antigensand induction of regulatory T cells. J. Invest. Dermatol., 2013;133: 1240-1249
  Google Scholar
• 79. Vijay-Kumar M., Aitken J.D., Carvalho F.A., Cullender T.C., MwangiS., Srinivasan S., Sitaraman S.V., Knight R., Ley R.E., Gewirtz A.T.:Metabolic syndrome and altered gut microbiota in mice lackingToll-like receptor 5. Science, 2010; 328: 228-231
  Google Scholar
• 80. Volz T., Skabytska Y., Guenova E., Chen K.M., Frick J.S., KirschningC.J., Kaesler S., Röcken M., Biedermann T.: Nonpathogenic bacteriaalleviating atopic dermatitis inflammation induce IL-10-producingdendritic cells and regulatory Tr1 cells. J. Invest. Dermatol., 2014;134: 96-104
  Google Scholar
• 81. Wakkee M., Nijsten T.: Comorbidities in dermatology. Dermatol.Clin., 2009; 27: 137-147
  Google Scholar
• 82. Wang Z., Klipfell E., Bennett B.J., Koeth R., Levison B.S., Dugar B.,Feldstein A.E., Britt E.B., Fu X., Chung Y.M., Wu Y., Schauer P., SmithJ.D., Allayee H., Tang W.H., DiDonato J.A., Lusis A.J., Hazen S.L.: Gutflora metabolism of phosphatidylcholine promotes cardiovasculardisease. Nature, 2011; 472: 57-63
  Google Scholar
• 83. Wanke I., Steffen H., Christ C., Krismer B., Götz F., Peschel A.,Schaller M., Schittek B.: Skin commensals amplify the innate immuneresponse to pathogens by activation of distinct signaling pathways.J. Invest. Dermatol., 2011; 131: 382-390
  Google Scholar
• 84. Wen L., Ley R.E., Volchkov P.Y., Stranges P.B., Avanesyan L., StonebrakerA.C., Hu C., Wong F.S., Szot G.L., Bluestone J.A., Gordon J.I.,Chervonsky A.V.: Innate immunity and intestinal microbiota in thedevelopment of type 1 diabetes. Nature, 2008; 455: 1109-1113
  Google Scholar
• 85. Whitfeld M., Gunasingam N., Leow L.J., Shirato K., Preda V.: Staphylococcusepidermidis: a possible role in the pustules of rosacea.J. Am. Acad. Dermatol., 2011; 64: 49-52
  Google Scholar
• 86. Yamasaki K., Gallo R.L.: Antimicrobial peptides in human skindisease. Eur. J. Dermatol., 2008; 18: 11-21
  Google Scholar
• 87. Yamasaki K., Kanada K., Macleod D.T., Borkowski A.W., MorizaneS., Nakatsuji T., Cogen A.L., Gallo R.L.: TLR2 expression is increasedin rosacea and stimulates enhanced serine protease production bykeratinocytes. J. Invest. Dermatol., 2011; 131: 688-697
  Google Scholar
• 88. Yates V.M., Watkinson G., Kelman A.: Further evidence for anassociation between psoriasis, Crohn’s disease and ulcerative colitis.Br. J. Dermatol., 1982; 106: 323-330
  Google Scholar

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