Microbiome Modulation as a Therapeutic Approach in Chronic Skin Diseases

There is a growing quantity of evidence on how skin and gut microbiome composition impacts the course of various dermatological diseases. The strategies involving the modulation of bacterial composition are increasingly in the focus of research attention. The aim of the present review was to analyze the literature available in PubMed (MEDLINE) and EMBASE databases on the topic of microbiome modulation in skin diseases. The effects and possible mechanisms of action of probiotics, prebiotics and synbiotics in dermatological conditions including atopic dermatitis (AD), psoriasis, chronic ulcers, seborrheic dermatitis, burns and acne were analyzed. Due to the very limited number of studies available regarding the topic of microbiome modulation in all skin diseases except for AD, the authors decided to also include case reports and original studies concerning oral administration and topical application of the pro-, pre- and synbiotics in the final analysis. The evaluated studies mostly reported significant health benefits to the patients or show promising results in animal or ex vivo studies. However, due to a limited amount of research and unambiguous results, the topic of microbiome modulation as a therapeutic approach in skin diseases still warrants further investigation.


Introduction
In 1683, Antoni van Leuwenhoek made the first microscopic observation of bacteria colonizing the surface of the human skin [1]. Joshua Lederberg first suggested the term microbiome in 2000, meaning the collective genome of commensal, symbiotic and pathological bacteria, archaea and eukaryote of the human body [2].
The skin microbiome includes bacteria, fungi, viruses, micro-eukaryotes (mites), archaea, and phages [3]. They can be found not only on the surface of the epidermis, but also in sweat, sebaceous glands and associated hair follicles [4]. The composition of microbiome differs among different regions affected by numerous factors including age, gender, genetics, immunity, hormonal balance, sleep routine, stress, metabolic factors, hygiene and skin care routine, chemical or ultraviolet radiation exposure, physical activity, climate, environmental pollution and availability of nutrients [5]. The initial colonization of the skin depends on the delivery mode, with neonates delivered vaginally acquiring the species (spp.) present in the vaginal tract (e.g., Lactobacillus, Prevotella, Sneathia) in contrast to children delivered by Cesarean section, that acquire microbiome associated with the  [25] Pregnant women (n = 159) with a family histors of AD, continuing after delivery and their children (n = 132) Double-blind, randomised placebo-controlled trial Participants received two capsules of placebo (n = 95) or LGG (n = 64) daily for 2-4 weeks before expected delivery The frequency of AD was significantly reduced 2 Rautava et al.-2006 [26] Infants with 6 months of exclusive breast-feeding (n = 38) Double-blind placebo-controlled study Infant formula supplemented with either LGG and Bb-12 (n = 38) or placebo (microcrystalline cellulose) (n = 43) daily until the age of 12 months Supplementation of probiotics increased protective cow's milk-specific IgA responses. 13% of the infants receiving probiotics and 20% of those receiving placebo manifested with AD, cow's milk allergy was confirmed in none of the infants receiving probiotics and in 8% of the infants receiving placebo 3 Abrahamsson et al.-2007 [27] Pregnant women with a family history of at least 1 allergic disease (n = 188) and then their infants (n = 188) Prospective, double-blind, placebo-controlled, multicenter trial The mothers were taking L. reuteri (n = 95) or placebo (n = 93) 4 weeks before term and continued daily until delivery, after birth, the baby continued with the same product up to 12 months of age The cumulative incidence of AD was similar in the probiotic and the placebo groups (36% vs. 34%) 4 Taylor et al.-2007 [28] Infants with atopic mother (n = 178) Randomized, double-blind, placebo-controlled Newborns of women with allergy received either L. acidophilus (n = 89) or placebo (n = 89) daily for the first 6 months of life Not reduction in the risk of AD and increased allergen sensitization 5 Wickens et al.-2008 [29] Pregnant women (n = 474) and their infants (n = 474) Double-blind randomized placebo-controlled trial Daily supplementation with either HN001 (n = 157) or HN019 (n = 158) or placebo (n = 159) from 35 weeks gestation until birth, continuing to 6 months after birth in mothers if breastfeeding, and from birth till 2 years in all infants Prevention of the development of AD Pregnant women (n = 140) and infants (n = 138) Placebo-controlled prospective intervention study Oral administration of LGG and Bb-12 each day (n = 72/70), or placebo (microcrystalline cellulose and dextrose anhydrate) (n = 68). Atopic sensitization was at the age of 6 and 12 months and in mothers at third trimester of pregnancy There was no difference between infant sensitization in the probiotic and the placebo group 7 Kopp et al.-2008 [31] Pregnant women (n = 105) with a family history of at least one allergic disease and their children (n = 96) Double-blind, placebo-controlled prospective trial Administration of either the probiotic LGG (n = 54) twice daily or placebo (n = 51) 4-6 weeks before expected delivery, followed by a postnatal period of 6 months After a 2 year follow-up, administration of probiotic did not reduce the incidence nor altered the severity of AD 8 West et al.-2009 [32] Healthy infants with birth weight >2500 g who were vaginally delivered (n = 89) Double-blind, placebo-controlled randomized intervention trial Daily intake of cereals supplemented with LF19 (n = 89) or identical cereals without LF19 supplementation (n = 90) from 4 to 13 months of age Decreased cumulative incidence of AD 9 Niers et al.-2009 [33] Pregnant women (156) and then their infants with a positive family history of allergic disease (n = 156) Double-blind, randomized, placebo-controlled trial Probiotic bacteria were prenatally administered to pregnant mothers (n = 78) during the last 6 weeks of pregnancy and postnatally for 12 months to their infants (n = 78); the intervention group received once daily B. bifidum W23, B. lactis W52, and L. lactis W58) in a freeze dried powder Decreased incidence of AD 10 Soh et al.-2009 [34] Infants with a positive family history of allergic disease (n = 253) Double-blind, placebo-controlled randomized clinical trial Infants (n = 127) received commercially available cow's milk formula with probiotic supplementation of BL999 and L. rhamnosus daily for the first 6 months. Infants in the control group (n = 126) received milk without probiotics No effect on the prevention of AD or allergen sensitization Pregnant women with a family history of allergic diseases (n = 112), continuing after delivery and their infants (n = 68) Double-blind, randomized, placebo-controlled trial Pregnant woman received supplement of B. bifidum BGN4, B. lactis AD011 and L. acidophilus AD03 (n = 33) or placebo (n = 35), starting at 4-8 weeks before delivery and continuing until 6 months after delivery. Infants were exclusively breastfed during the first 3 months, and were fed with breastmilk or cow's milk formula from 4 to 6 months of age The prevalence of AD in the first year of life was significantly lower in the probiotic group.     Infants with AD, mean age of 4.6 months (n = 27) Randomized double-blind placebo-controlled study Probiotic-supplemented, Bb-12 (n = 9) or LGG ATCC 53103 (n = 9), extensively hydrolysed whey formulas or to the same formula without probiotics (n = 9) First clinical demonstration of specific probiotic strains modifying AD 3 Kirjavainen et al.-2003 [59] Infants with AD, mean age was 5.5 months (n = 43)

Randomized double-blind manner
Infants were randomly assigned into placebo (n = 10), viable LGG (n = 17), or heat-inactivated LGG groups (n = 16) and extensively hydrolyzed whey formula or the same formula supplemented with viable or heat-inactivated LGG Supplementation of infant formulas with viable but not heat-inactivated probiotic was effective for the management of AD and cow's milk allergy  Infants were randomized to daily supplements containing L. paracasei or B. lactis (n = 137) or placebo (n = 71) for a 3-month period, while receiving extensively hydrolysed whey-formula (dairy-free diet) No benefit in the treatment of eczema and no effect on the progression of allergic disease   Children aged 1 to 13 years with AD (n = 43) Double-blind, placebo-controlled, crossover study The patients were randomized in two groups to receive either placebo followed by active treatment or active treatment followed by placebo. 2 probiotic lyophilized L. rhamnosus 19070-2 and L. reuteri DSM 122460 were given in combination for 6 weeks Combination of probiotics was significantly effective in the management of AD Double-blind prospective randomized study L. rhamnosus Lcr35 plus prebiotic preparation (n = 24) or prebiotic preparation alone (n = 24) was given three times a day for 3 months Both synbiotics and prebiotics used alone seem able to significantly improve the manifestations of AD Children suffering from a moderate-to-severe AD, 1-13 years of age (n = 40) Double-blind, randomized, placebo-controlled study The probiotic group (n = 20) was administered with a probiotic complex containing B. bifidum, L. acidophilus, L. casei, and L. salivarius for 8 weeks. The placebo group (n = 20) was administered skim milk powder and dextrose Probiotics to be effective in reducing SCORAD index, serum IL-5, IL-6, IFN-γ, and total serum IgE levels but not effective in reducing serum IL-2, IL-4, IL-10, ECP, or TNF-α levels   Significant inhibition of imiquimod-induced skin inflammation   New Zealand white rabbit (n = 4) Animal study The wounds were treated with control or gNO-producing patches designed to produce gNO levels. Wounds are not infected (1. and 2. rabbit) or infected (3. and 4. rabbit). Wounds are treated with placebo (1. and 3. rabbit) or with gNO producing patches (2. and 4. rabbit) Histological analysis showed improved wound healing in gNO-producing patch-treated rabbits Rats were wounded and divided intor 6 groups (n = 6/group); (1) a control group over 3 days, (2) a group that used distilled water over 7 days, (3) a group that underwent topical treatment over 3 days, (4) a group that used probiotic (L. casei) administered topically over 7 days, (5) a group that underwent systemic treatment over 3 days (6) a group that took oral probiotics for the traumatic ulcers over 7 days Significant differences were observed in the number of fibroblasts and blood vessels   Less than 22 years old acutely burned patients, and were admitted/consented within 10 days of burn injury (n = 20)

IN VITRO STUDIES-PROBIOTICS APPLICATION
Randomized, double-blind, placebo-controlled The treatment group received LGG (n = 10). The control group received placebo (n = 10). Investigational products were administered via nasoduodenal feeding tube twice daily Improved gastrointestinal outcomes and reduced time to wound healing Thermally-injured pediatric patients with total body surface burns between 20-50% and depth between 5-10% (n = 40) The rats were divided into groups: burn model group (n = 15)-normal saline; glutamine treatment group (n = 15)-glutamine + normal saline; probiotics treatment group (n = 15)-probiotic + normal saline; glutamine and probiotics combined treatment group (n = 15)-lutamine + normal saline. All were administered once daily for 7 days Glutamine and probiotics together significantly inhibited nitric oxide (NO) content and reduced levels of the inflammatory factors  [121] Male Wistar rats (n = 25) Animal study

Atopic Dermatitis
AD is a common, chronic inflammatory skin disease, affecting almost 3% of adults and up to 10-20% of the child population, with an increasing prevalence. The onset usually occurs during the first year of life. AD is characterized by dry skin, pruritus and recurrent eczematous lesions. The severity of AD may be assessed by SCORAD (scoring atopic dermatitis) severity score [137]. AD is often associated with other atopic diseases: allergic rhinitis and asthma [138]. The skin and gut microbiome in adult AD patients is affected among others by maternal diet during pregnancy, the mode of delivery, antibiotics taken during pregnancy and in infancy, chronic exposure to allergens [139]. It is estimated that in over 90% of cases both lesional and non-lesional skin of the patients is colonised with S. aureus in AD, compared with less than 5% of healthy individuals. Moreover, in the affected areas, the abundance of S. aureus was associated with disease severity [140]. Increase in fungal diversity and the presence of unique anaerobic bacterial species such as Clostridium and Serratia spp. was also found on the skin of AD patients [13].
Prevention of the development of atopic dermatitis using probiotics. Eight out of 21 studies reported a decreased occurrence of AD in the probiotics group. Most studies investigated L. rhamnosus GG (LGG). The positive impact of probiotics has been proven by Kalliomaki [25]. Wickens et al. in their study examined the L. rhamnosus HN001 (HN001) and HN019 influence on AD, founding the probiotic group with significantly lower cumulative prevalence of eczema and skin prick test sensitization [29]. Another study by Wickens et al. proved that mother and child intervention with HN001 probiotic supplementation was associated with a reduction in eczema and SCORAD. Note that maternal-only HN001 supplementation did not significantly reduce the prevalence of eczema in the infant by 12 months [43].  [38]. Schmidt et al. carried out another study involving the supplementation of LGG and Bb-12, resulting in lower incidence of AD (4.2%) in the probiotic versus placebo group (11.5%) [45] Kim et al. proved that in the probiotic group the occurrence of AD was significantly reduced compared to the placebo group at 12 months of age (36.4% vs. 62.9%) [141]. Lau et al. showed that Escherichia coli and Enterococcus faecalis significantly reduced the incidence of AD development in the subgroup of high risk infants. Ten percent (15/154) of infants in the active group developed AD compared to 19% in the placebo group. This was more pronounced in the group of infants with paternal heredity for atopy (11% vs. 32%) [40]. The study of West et al. investigated the use of L. paracasei F-19 and found that the cumulative incidence of eczema at 13 months of age was 9/84 in the probiotic and 19/87 in the placebo groups [32].
However, 13 out of 21 trials showed that the administration of probiotics had no impact on prevalence of AD. Studies by Allen et al., Dotterud et al., Huurre et al. and Plummer et al. showed that a mix of bacterial strains was given and revealed a similar frequency of diagnosed AD both in the study and control groups. They also showed no effect of the use of probiotics in pregnant mother and infants to avoid the development of AD [30,36,41,44]. The study by Niers et al. provided interesting results in which parental-reported eczema during the first three months of life was significantly lower in the intervention group compared with placebo, 6/50 vs. 15/52. After three months, the incidence of AD was similar in both groups [33]. The use of probiotic (L. reuteri) in the group of pregnant women and infants was evaluated by Abrahamsson et al. Despite the cumulative incidence of AD was similar in the L. reuteri and the placebo groups (36% vs. 34%), IgE-associated eczema was less common in the L. reuteri group, although the difference was only statistically significant during the second year of life (8% vs. 20%) [27]. Conclusions from the studies by Boyle et al., Cabana et al., Kopp et al. and Ou et al. evaluating the effect of LGG on pregnant mothers showed that there was no difference between the probiotic group and placebo in the appearance of AD among the infants [31,37,39,42]. Soh et al. examined the incidence of AD in infants receiving probiotics (B. longi and L. rhamnosus). The incidence of eczema in the probiotic group was similar to that in the placebo group (22% vs. 25%). The median SCORAD at 12 months was 17.10 in the probiotic group and 11.60 in the placebo group [34]. Investigating the effects of L. acidophilus in their study, Taylor et al. showed no difference in the probiotic (n = 23/89; 25.8%) and placebo (n = 20/88; 22.7%) groups [28].
Prebiotics in the prevention of atopic dermatitis. The number of studies on prebiotics in the prevention of AD is limited and they present inconsistent results. Studies investigated only a few prebiotic compounds: combination of galacto-oligosaccharide (GOS) and fructo-oligosahccaride (FOS), acidic oligosaccharides, polydextrose (PDX), different content of lactose, oligofructose plus inulin. Among the nine studies included in this review, five have shown the positive effect of prebiotics in the prevention of the development of eczema. The rest of the studies showed no significant differences in group of infants fed with or without prebiotics.
Positive effects of the administration of prebiotics has been shown by Ziegler et al., who investigated the administration of a GOS and PDX mix and found a statistical difference in the occurrence of eczema (prebiotics vs. control: 18 vs. 7%) [47]. The same combination was used by Pontes et al. in their study, who reported a lower number of allergic diseases including AD in the analyzed group receiving prebiotics [53]. Three trials investigating the relationship between GOS supplementation and preventing eczema shown a decreased risk of developing AD [46,48,49]. However, Grüber et al. found that a formula containing a mixture of neutral oligosaccharides can be also effective in prevention of AD [50]. Wopereis et al. also presented a beneficial impact in the prevention of AD and modulation of gut microbiota by using a partially hydrolyzed formula containing short-chain GOS and long-chain FOS and pectin-derived acidic oligosaccharides [56]. No differences between prebiotic groups and control groups have been found in four studies. Two of them investigated a mix of FOS and GOS [51,52]. Ranucci et al. used a mixture of GOS and PDX in their trial. There were no significant differences in the cumulative incidence, intensity and duration of AD among the investigated groups of patients [55]. A study by Boyle et al. on prebiotic containing FOS has shown that prebiotics did not prevent AD in high-risk infants during the first 12 months of life [54].
Role of probiotics and prebiotics in AD treatment. 20 of 27 studies on probiotics revealed improving SCORAD in AD patients compared to placebo. One of the first studies on probiotic treatment in AD, that found using probiotics may have positive impact on the course of AD, was the study by Isolauri et al. The aim of their study was to evaluate the effects of probiotics use with Bb-12 or LGG on infants with AD. The results showed that by using probiotics, the skin condition improves. SCORAD decreased in the Bb-12 group to 0, and in the LGG group to 1 versus the SCORAD of 13.4 in the placebo group [58]. Drago et al. evaluated the influence of S. thermophilus ST10 and tara gum on the SCORAD score. The score decreased significantly in the probiotic group after one month and the index was significantly lower in the probiotic group than in the placebo group [92]. Ivakhnenko et al. evaluated both the use of Bb-12 and Streptococcus thermophilus for 4 weeks. The results showed significant improvement of SCORAD in the probiotic group compared to blacebo [73]. Wu et al. proofed that the SCORAD index declined from baseline after two months in the LGG group [76]. Brouwer, Folster-Holst and Kirjavainen showed similar effects of this LGG bacteria in AD patients [59,63,64]. Studies which resulted in a significant decrease in the SCORAD index in AD patients by using probiotics containing single strains or combined bacterial strains, including L. salivarus LS01, were also those conducted by Drago et al. [89] and Iemoli et al., [90] L. acidofilus DDS-1-by Gerasimov et al. [80], L. plantarum-by Han et al. [82], L. fermentum-by Weston et al. [61] and L. sakei-by Woo et al. [81] Yang et al. randomly assigned their patients to the probiotic-receiving groups (L. casei, L. rhamnosus, L. plantarum, and B. lactis) or placebo groups for six weeks. The result of their trial was a significant clinical improvement in the skin condition among the probiotic groups [85]. Two of the studies also proved a positive impact on the SCORAD score by using probiotics with B. breve. Taniuchi et al. and Yoshida et al. showed a significant improvement in skin conditions during the study in the probiotic group [62,88]. Three studies assessing the impact of using bacteria mix in probiotic groups revealed a significant improvement in SCORAD scores [84,86,87].
Seven out of 27 studies in children showed no significant differences in SCORAD scores between the probiotic and placebo groups after treatment. Lin et al. proved that the SCORAD index was not significantly reduced in the B. bifidum group versus controls [74]. Grüber et al. suggested that AD improved after four weeks of supplementation (LGG vs. placebo); however, the difference was not significant [65]. Similar results were obtained by Viljanen et al.: the SCORAD score decreased by 65%, but with no statistically significant differences between treatment groups [60]. Sistek et al. evaluated the role of L. rhamnosus and B. lactic. Their findings stated that there is no significant difference between probiotic and placebo groups [78]. Rosenfeldt et al. examined probiotic Lactobacillus strains (lyophilized L. rhamnosus 19070-2 and L. reuteri DSM 122460) in combination for six weeks in 1-to 13-year-old children with AD. The total SCORAD index in this trial did not change significantly [77]. The results of the study by Gøbel et al. study on L. acidophilus and B. lactis Bi-07 (Bi-07) were that there was no benefit for the probiotics on the severity of AD. However, a post hoc analysis showed a significant reduction in severity of AD in the Bi-07 group and possible positive effects of this probiotic strain could be of further interest [68]. Gore et al. in their trial compared the effects of using B. lactis and L. paracasei. No significant differences were observed between the groups after 12-week treatment-period [71].
Five out of 36 studies did not estimate the SCORAD score, but evaluated other factors, such as puritus. Matsumo et al. in their study found that Bifidobacterium animalis subsp. lactis LKM512 may reduce pruritus by increasing expression of metabolite kynurenic acid [91]. The results obtained by Majama et al. suggest that probiotic bacteria may improve endogenous barrier mechanisms in patients with AD and those with food allergies by decreasing intestinal inflammation and may be useful in AD treatment [57]. Studies by Flinterman et al. [66], as well as by Guo et al., suggested that in vitro IgE production is decreased in the probiotic group compared to placebo [75]. Nermes et al. found that the levels of IgA and IgM-sectreting cells decreased significantly in the probiotic group compared to placebo. The baseline-adjusted ratios for treated to untreated patients after one month were 0.59 for IgA-and 0.53 for IgM-secreting cells [69].
Synbiotics. Five publications on the use of synbiotics were found; however, only one of them by Farid et al. reported a significant reduction of the SCORAD score [70]. Passeron et al. compared the effects of probiotics (L. rhamnosus Lcr35) and synbiotics in children over two years old. The study showed no statistical differences regarding SCORAD scores between the two groups [79]. Shafiei et al. showed that there is no significant difference in the mean decrease of total SCORAD between placebo (22.3) and synbiotic groups (24.2) [72]. A significantly greater SCORAD score improvement was found in the symbiotic group of infants with IgE-associated AD by van der Aa et al. [67] Wu et al. also found that a combination of L. salivarius and FOS resulted in lower SCORAD in a comparison with the control [83].
The role of microbiome composition in allergic diseases is well-known, with lower biodiversity found as a factor inducing their development. Modulating the microbiome with probiotics balances the gut microflora, protects the function of intestinal barrier and lowers the level of pro-inflammatory cytokines produced. Probiotics also influence Toll-like receptors, which play an important role in T-cell differentiation and the development of allergic reactions. As skin colonization with S. aureus plays an important role in AD, a promising new perspective of displacing it with more desirable species is also considered [93].

Psoriasis
Psoriasis is a common inflammatory disease that affects around 2-3% of the population [142]. It manifests with papulosquamous skin lesions with variable distribution and severity [143]. The pathogenesis of the disease is not yet fully elucidated. However, it is known that genetic, immunological and environmental factors may act as triggering factors, making the keratinocytes start secreting pro-inflammatory cytokines [14]. In the skin lesions, increased abundance of Streptococcus spp., Corynebacterium spp., Cutibacterium spp., Staphylococcus spp., Finegoldia spp. and Neisseria spp. can be found. The biodiversity of microbiota is generally decreased in moderate-to-severe psoriatic patients in contrary to mild psoriatic patients [5].
Based on the reported alterations in gut microbiome, attempts were made to use probiotics and prebiotics in the treatment of psoriasis. Two original studies, one case report and four mice studies were published. In the case report described by Vijayashankar and Raghunath, a supplementation with L. sporogenes for 15 days allieviated the symptoms accompanying the sudden onset of generalised pustular psoriasis in a 47-year-old female [94]. Groeger et al. demonstrated a significant decrease in serum CRP, TNF-α levels in psoriatic patients administered with B. infantis 35264 for 8 weeks [95]. In the study by Navarro-Lopez et al., supplementation with B. longum CECT 7347, B. lactis CECT 8145 and L. rhamnosus CECT 8361 for 12 weeks resulted in a significant reduction in PASI scores [96]. In three out of four mice studies, the probiotics were administered orally, while in one study it was administered topically. In all studies, the psoriasis-like skin inflammation was induced by topical appliaction of imiquimod. Chen et al. found that in administering L. pentosus GMNL-77, both for five or seven days, causes a reduction in erythaematous scaling lesions, decreases TNF-α, IL-6, IL-23, IL-17A/F and IL-22 levels in the skin, decreases spleen weight and reduces the number of IL-17-and IL-22-producing CD4+ T cells in the spleen [97]. In the study by Lu et al., seven different groups of six mice each were given different strains of probiotics. B. adolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillus paracasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines. On the contrary, B. animalis CCFM1148, L. paracasei CCFM1147 and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines [99]. Ogawa et al. showed that administering Leuconostoc mesenteroides NTM048 to imiquimod-induced mice suppressed erythema, scaling, upregulated IL-17 production, increased the levels of plasma deoxycholic acid and altered the faecal microbiota composition. Changes in the gut microbiome were indicated by the increased abundance of Akkermansia and a decreased abundance of Staphylococcus and Streptococcus [100]. The only study concerning a topical application of probiotics was conducted by Rather et al. Application of ethanol extract (SEL001) isolated from L. sakei proBio-65 resulted in an inhibition of the imiquimod-induced changes in the skin, as well as decreased IL-19, IL-17A and IL-23 levels [98]. It was shown that the gut microbiome plays an important role in the pathogenesis of psoriasis-patients suffering from this disease present with an increased amount of Bacteroidetes and decreased levels of Firmicutes, Proteobacteria and Actinobacteria, probably altering the intestinal barrier integrity, T-cell response and population-type balance, chemotaxis along with carbohydrate, cobalamin, and iron metabolism [144].

Chronic Ulcers
The use of probiotics as a novel treatment for diabetic foot ulcers (DFU) was first published in 2014. It was suggested that the application of probiotic agents would enable the healing of diabetic ulcers and would prevent diabetic foot infections by activating Tolllike receptors and producing β-defensins, which stimulate skin immune functions [145].
Mohseni et al. investigated the advantages of probiotics in patients with DFU. After the 12-week intervention of probiotic supplementation (L. acidophilus, L. casei, L. fermentum, B. bifidum), it had beneficial effects on the DFU size. It also decreased the serum total cholesterol and CRP and increased plasma nitric oxide (NO) and total plazma antioxidant capacity [102].
Most research was carried out using in vitro models, e.g., the effectiveness of a probiotic based on L. rhamnosus and L. paracasei strains in a 1:1 ratio against microorganisms previously isolated from chronic ulcerative lesions. Following the administration of probiotics, the growth of bacteria, compared to the control, was lower in the case of such bacteria as P. aeruginosa, C. striatum, A. baumanii, S. aureus, P. mirabilis in 75%, in the case of Candida parapsilosis in 93.75%, while in the case of E. faecalis 18.75%, and 50% for the mixed flora of the mentioned pathogens. The ability to co-aggregate all pathogens that could prevent adhesion and invasion was also shown [108]. Kusumaningsih et al. investigated the differences in the number of fibroblast cells and blood vessels after the administration of the probiotic L. casei shirota topically and systemically during the onset of the healing of traumatic ulcers in Wistar rats. The number of fibroblasts and new blood vessels were significantly higher in the two intervention groups in a comparison with the control group [106]. A further study investigated wounded New Zealand rabbits infected with S. aureus and treated with L. fermentum, which secrets gaseous NO. The day after the procedure, treatment with the patch with a probiotic agent started and lasted for 21 or 20 days. Morphometric analysis of the ulcer healing revealed that it was significantly accelerated with this treatment method in both infected and uninfected ischemic wounds [104]. Stefia et al. compared the effects of two different strains of Faecalibacterium prausnitzii (SPA and SPAH) for immune cell activity and wound healing in mice. They found that the presence of these strains in the gut exhibited significantly higher patterns of reepithelialization compared to controls by inhibiting NF-kβ activation. It resulted in decreased wound proinflammatory cytokine expression and induced myofibroblast and collagen transitions [105]. In another model, L. reuteri was transformed with a plasmid containing the genetic material of the C-X-C Motif Chemokine Ligand 12 chemokine involved in accelerated wound healing. Additionally, the lactic acid produced by the probiotic bacterium lowered the pH and increased the bioavailability of the chemokine. This strain was applied to wounds in mice, accelerating ulcer healing, epithelialization, and wound closure [107].
The most relevant original work was published in 2010. L. plantarum was used in the treatment of chronic leg ulcers. The probiotic was applied to ulcers in 14 patients with diabetes and 20 non-diabetic patients. After 30 days of follow-up, 90% of the extent of ulceration had resolved in 43% of diabetic patients and 50% of non-diabetic patients. A decrease in CFU of S. aureus, S. epidermidis and P. aeruginosa was also noted. It was found that probiotics disrupt biofilm, regulate IL-8 levels and modulate the immune system [101]. In addition, Venosi et al. reported a case of an old woman who was successfully treated with a topical administration of probiotics for an ischemic and infected (K. pneumoniae, E. faecalis and P. mirabilis) chronic wound. The patient received a mixture of probiotics (L. plantarum, L. acidophilus and S. thermophiles) three times/week [103].

Seborrheic Dermatitis
Seborrheic dermatitis (SD) characterized by erythematous, scaling plaques on the the face, chest and scalp [146,147]. It is assumed that the underlying cause of the disease is the excessive activity of sebaceous glands and concomitant infection with Malassezia spp. [146]. Research indicates an increased number of Malassezia strains in the seborrheic area and a satisfactory therapeutic effect of antifungal formulas [147]. Currently, it seems that SD is the result of the skin's response to free fatty acids produced by M. furfur, which elicit an inflammatory response from keratinocytes [148,149]. M. furfur also possesses the ability to produce metabolites, which stimulate the aryl hydrocarbon receptor and thus may modulate the function of antigen-presenting cells [150].
There are limited data on the effects of probiotics and the modulation of the cutaneous microbiome on the course of SD. The use of superficial Vitreoscilla filiformis preparation in a double-blind study involving 60 patients with SD resulted in a reduction of itching, erythema and scaling. At the cellular and subcellular level, the lysate of these bacteria resulted in an increase in the activity of IL-10 produced by dendritic cells of the skin and an increase in the activity of regulatory T lymphocytes [109]. Another study involving the oral administration of ST11 demonstrated a significant reduction in symptoms, which at the subcellular level was also accompanied by a shift in immune activity consisting, as before, in an increase in IL-10 production [110]. These examples confirm the possible benefits of using both forms of probiotics in the group of patients with SD.

Burns
The analysis of studies conducted both in animal models and in clinical trials, mostly showed at aleast partial positive effect of the use of probiotics on the healing of infected wounds by inhibiting microbiome growth, microfilm formation and interbacterial communication [151].
Among the various used bacterial strains, the most evidence exists for L. plantarum. Peral et al. established the effectiveness of L. plantarum probiotic treatment with a topical application in human patients. L. plantarum would compete with bacterial pathogens and would be able to promote tissue repair [111]. El-Ghazzey et al. studied the effect of L. fermentum and L. delbruekii treatment in pediatric post-burn patients. They conclude that probiotic administration is safe to use and improves wound healing [115]. In a case report, oral application of L. casei resulted in the appearance of multi-drug sensitive P. aeruginosa instead of an extremely drug-resistant strain [113]. Perdanakusuma et al. demonstrated that B. infantis 35624 single-strain probiotics were more effective compared to Lactobacillus reuteri protectis in altering intestinal immunity [116].
Valdez et al. has been shown in adult inbred BALB/c mice that L. plantarum and/or its by-products could be a potential therapeutic agent for P. aeruginosa burn infections [120]. Brachkova et al. found that the application of calcium alginate films containing L. plantarum reduced P. aeruginosa in a rat model of burns [121]. Argenta et al. proved in mice that probiotic therapy (L. plantarum) suppressed the induction of TNF-α, IL-6 and IL-10 in liver and inhibited the accumulation of the pathogen in remote organs [122]. Satish et al. L. plantarum as a therapeutic agent alleivates burn wound infection and scaring after burn injury in rabbits [123]. Sürmeli et al. demonstrated that L. plantarum has a protective role in non-infected burn wounds against meticillin-resistant Staphylococcus aureus (MRSA). Additionally, the therapeutic effect of L. plantarum was not shown in MRSA infection [124].
Herek et al. investigated that the Saccharomyces boulardii could effectively decrease the incidence of antibiotic-induced bacterial translocation in burned rats [118].
Khan et al. demonstrated the importance of the method of probiotic application in a thermal burn mouse model. The use of the bioskeleton compared to traditional forms of probiotic application resulted in acceleration of epithelialization, collagen production and formation of hair follicles, as well as an inhibiton on the growth of pathogenic bacteria, reducing infection and accelerating wound healing [125]. As a result of burns due to systemic stress, the intestinal barrier is significantly impaired, resulting in inflammation and oxidative stress, leading to the destruction of the intestinal barrier and abnormal intestinal function. The studies on the animal model of burns show that the application of glutamine and probiotics reduced the apoptosis of the intestinal epithelial cells [119].
Fleming et al. performed a retrospective study in connection with preventing potential antibiotic-associated C. difficile colitis by giving probiotics to burned patients in a critical condition. Otherwise, they found no significant difference in C. difficile infection between the control group and the intervention group [117]. Olguin et al. proposed that the regular intake of prebiotics might help to increase the gastrointestinal permeability in burn patients. Following the application of oligofructose (OF), they found no difference between the control and OF groups [126].
Due to the damaged intestinal barrier and the impaired immune system function caused by burns, there is a potential risk that probiotic bacteria may translocate and ultimately result in infection. Mayes et al. demonstrated the efficacy and safety of probiotics in the pediatric population hospitalized due to skin burns [114]. However, there are known cases of severe infections and probiotic-induced sepsis in critically ill people [112].

Acne
Acne is a chronic skin disease, affecting the pilosebaceous units, with multifactorial pathogenesis including hormonal influence, the immunological state of the host, diet, deregulation of insulin-like growth factor, excessive sebum production and FoxO1 deficiency [152,153]. Considering the pathogenesis of acne, Cutibacterium acnes has been implicated as an important pathogenic factor. Fitz-Gibbon et al. compared the Cutibacterium strains in patients suffering from acne and healthy individuals, finding remarkable differences [154]. More and more evidence suggests that dysbiosis on the phylotype/strain level leading to a diversity loss is also a major factor in the pathogenesis of acne [155]. The role of the gut microbiome in acne is also raised, as a study conducted in 2018 showed that patients with acne present with lower gut microbiota diversity (abundance of Firmicutes, Clostridium, Clostridiales, Lachnospiraceae, Ruminococcaceae increased Bacteroides levels) [156].
A limited number of studies concerning probiotics and prebiotics use in acne is available. Yet, it is known that the beneficial components of the microflora may ameliorate skin lesions via the suppression of the Treg cell population. In addition, the suppression of B and Th cells due to the modulation of inflammatory cytokine production along with increasing IgA and butyrate secretion may also have an important effect [144]. A clinical trial investigating oral supplementation of L. rhamnosus SP1 (LSP1) had been reported to bring health benefits to the patients such as LSP1 normalized skin expression of genes involved in insulin signalling and an improvement in the appearance of adult acne [127]. However, a mix of B. lactis W51, B. lactis W52, L. acidophilus W55, L. casei W56, L. salivarius W57, and L. lactis W58 was reported to be a trigger for elevated IL-10 serum levels [129]. The results concerning oral prebiotics supplementation remain more consistent, as both lactoferrin as well as GOS and FOS were associated with positive effects [35,128]. Topical application of probiotic-enriched formulas also seem to have a promise: all of the analyzed studies involving the use of E. faecalis SL-5 [130], Nitrosomonas eutropha [131] or L. acidophilus showed improvement in the skin condition. L. acidophilus was also reported to decrease the population of C. acnes [132]. These findings were also confirmed in in vitro studies: Al-Ghazzewi et al. showed that probiotic bacteria and konjac glucomannan hydrolysates inhibit C. acnes growth [133]. Similar effects were reported by Kang et al., who investigated the properties of L. reuteri on the proliferation of C. acnes and S. epidermidis [134]. Bifidobacterium spp. [135]. as well as two S. salivarius strains and one L. plantarum strain, were also reported to show antimicrobal activity in in vitro studies against C. acnes and other pathogens [136].

Limitations
The present review focuses on a subject that is relatively new and is still not investigated in full detail. One of the major limitations is the small number of publications reporting clinical studies, especially multi-center, double-blinded, placebo-controlled clinical trials. The number of patients in the presented studies were usually low and many studies involved animal models, which cannot be extrapolated to humans. Since the exact pattern composition of a "healthy microbiome" is impossible to establish, there are no objective measures to investigate a universal model. The bacteria used in different studies presented various genera and properties; moreover, they were derived from different sources, often with no exact information on the method of production, storage and other properties. Moreover, the skin diseases presented in the paper were chosen based on their duration and the number of studies available; however, single studies show that the microbiome modulation, e.g., via a fecal microbiota transplant, may be also effective in the treatment of other dermatological conditions, for example in alopecia areata [157].

Conclusions
It can be stated that the microbiome plays an important role in dermatological diseases, at the same time as being an attractive target of therapeutic interaction. This may contribute to the promotion of beneficial (from the point of view of inflammation) activation of the immune system, a reduction of the inflammatory state and, above all, could constitute a physical barrier to the colonization of the skin by pathogenic bacteria. The perspective of treating skin diseases with microbiome modulation via oral and topical probiotics, prebiotics or synbiotics are becoming a part of reality.
There is a growing number of studies into the beneficial effects of probiotics in patients with atopic diseases. It is estimated that the oral application of probiotics or prebiotics during delivery or in the first months of life could delay or alleviate the appearance of AD in infants. From another point of view, probiotics could have the potential to reduce the SCORAD index as a treatment method. On the basis of the available evidence, a recommendation on probiotic intake in order to avoid AD cannot be currently made. Administering probiotics may influence the composition of the gut microbiome, which is more and more often considered to be a factor in the development of psoriasis. The suspected efficacy of probiotics in alleviating the course of psoriasis may be connected to lowering the levels of plasma pro-inflammatory cytokines. Since the data and the amount of research on this topic are limited, it still requires new, randomized, placebo-controlled trials, which would gain an insight into the pathogenesis and novel strategies of psoriasis treatment. There are very limited data available at the moment in the context of chronic ulcers. The positive effects of probiotics were shown mainly in studies focusing on ulcers resulting from diabetes complications. Probiotics may prevent or reduce the infection of burned wounds. Most research has focused on the L. plantarum and has showed at least a partial positive effect of the use of probiotics on the healing of infected wounds by inhibiting pathogen growth, microfilm formation and interbacterial communication. Concerning SD and acne, the very limited available data on probiotic administration have showed inconsistent results.
The studies have shown that probiotics and prebiotics both administered orally or applied topically may have a positive influence on the course of skin diseases. Despite the continuous increase in promising data on the effectiveness of the use of probiotics and prebiotics, further clinical trials are needed to assess the efficacy and long-term safety profile of probiotics and prebiotics in the treatment of patients with dermatological diseases.