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Review paper

Skin Microbiota as a Therapeutic Target for Psoriasis Treatment: Trends and Perspectives Running head: Skin Microbiota: Trends and Perspectives

Rigon, R.B. PhD1,*; de Freitas, A.C.P. B.Pharm.1; Bicas, J.L. PhD2; Cogo-Müller, K. PhD 1; Kurebayashi, A.K. B.Pharm.3; Magalhães, R.F. PhD 4; Leonardi, G.R. PhD 1.

1

Faculty of Pharmaceutical Sciences, University of Campinas (UNICAMP), Campinas – SP, Brazil.

2

School of Food Engineering, University of Campinas (UNICAMP), Campinas – SP, Brazil.

3

Protocolo Consultoria Personal e Health Care, São Paulo – SP, Brazil.

4

School of Medical Sciences, University of Campinas (UNICAMP), Campinas – SP, Brazil.

*Corresponding author: Name: Roberta Balansin Rigon. Address: Rua Cândido Portinari, 200 - Cidade Universitária, Campinas - SP, 13083-871 Phone: +55 (19) 3521-7067. e-mail: [email protected]

Manuscript word

Number of

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references

2,392

40

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1

2

Conflicts of Interest The authors have no conflicts of interest to declare.

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/JOCD.13752 This article is protected by copyright. All rights reserved

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Acknowledgment The authors thank Espaço da Escrita – Pró-Reitoria de Pesquisa - UNICAMP - for the language services provided.

Funding Sources This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior Brasil (CAPES) - Finance Code 001. Andréa Carolina Pinheiro de Freitas thanks Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) for master scholarship.

Author Contributions Conceptualization, R.B.R., and G.R.L.; Formal Analysis, R.B.R., A.C.P.F., J.L.B., K.C.M., R.F.M., and G.R.L.; Writing—Original Draft Preparation, R.B.R., and A.C.P.F.; Writing—Review & Editing, R.B.R., A.C.P.F., J.L.B., K.C.M., A.K.K., R.F.M., and G.R.L.; Supervision, G.R.L.; Project Administration, R.B.R.

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Article type

: Review Article

Running head: Skin Microbiota: Trends and Perspectives

Abstract

Psoriasis is a chronic, immune-mediated disease that has a major negative impact on a patient's

quality of life. Although several literature reviews indicate that skin microbiota may play an important role in the development and regulation of the immune and inflammatory response of psoriasis, few clinical studies are demonstrating the benefits of using pre-, pro- and synbiotics as a therapeutic alternative at the management of the disease. In this review, we showed the use of probiotic microorganisms that may contribute to skin homeostasis and compiled the clinical trials that demonstrate the effect of therapy with probiotics on patients with psoriasis, an important area for scientific exploration in dermatology and being the first review article to compile this information.

Keywords: Skin microbiota, psoriasis, prebiotics, probiotics, dysbiosis.

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1. General aspects of psoriasis Psoriasis is a chronic and immunomediated disease, with a major negative impact on

the quality of life. It affects both men and women and can be divided into two peaks of incidence, the first beginning between 20 and 30 years of age, and the second between 50 and 60 years of age. Because it is a disease with no need for registration, the data related to the overall prevalence of psoriasis, describing a variation between 0.09 and 11.4%, has low reliability1. According to a survey conducted by the Brazilian Society of Dermatology (2015/2016), the prevalence in Brazil ranges between 1.10 and 1.50%, with great variability between regions: from 0.92% (North) to 1.88% (Southeast). The etiology of psoriasis and its associated comorbidities is complex and results from

the interaction between skin, immune system, genetic susceptibility, and multiple environmental or internal triggers such as solar radiation, medications, infections, stress, or trauma2. In addition, the commensal microbiota of the skin plays an important role in

maintaining skin integrity by acting, along with the epidermis, as a barrier 3. Thus, recent

studies have shown that disturbances in the skin’s microbiological community in patients with psoriasis may also be an important factor to consider when describing the etiology of the disease3. Psoriasis is most often seen in the scalp, face, hands, feet, and nails, genitals, and

joints (Fig. 1). Its severity can be measured according to three indices: the Psoriasis Area and Severity Index (PASI), the percentage of body surface area (BSA) affected, and the Dermatology Life Quality Index (DLQI).

[Please, Insert Figure 1]

The available treatments (topical, systemic, and phototherapeutic) aim at the clinical

control of the disease and the improvement of the patient’s quality of life. In clinical practice, therapy is modulated according to the severity of the disease, and there is often a combination of therapies4. It should be noted that the need for treatment is most often

lifelong, which increases the chances of developing adverse reactions and toxicity to the drug.

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Topical treatment includes corticosteroids, vitamin D analogs, calcineurin inhibitors,

coal tars, anthralin, emollients, and keratolytic. It is used mainly in mild cases, in a

monotherapy regimen. Topical treatment may be indicated for cases classified as medium or severe but combined with systemic treatment5. To date, no therapy can completely cure psoriasis6. Thus, recent studies have been

exploring new alternatives with less adverse effects and that are more affordable than therapy with biological agents, to ensure better clinical efficacy and improve the quality of life of patients. Among these alternatives, the evaluation of the influence of skin microbiota on the

onset of psoriasis stands out. Therefore, this review aims to analyze treatments for the disease, focusing on those using pre- and probiotics.

2. Skin microbiome and its role in psoriasis An imbalance in skin microbiota can cause or contribute to the development of skin

diseases, not only in psoriasis, but also in other skin conditions, such as atopic dermatitis, or even in immune-inflammatory diseases, such as inflammatory bowel disease7 and periodontitis8. This concept of imbalance is also known as dysbiosis, wherein a change in the proportions of microorganisms that are part of the microbiota may damage the homeostasis between microbiota and host3, with a higher prevalence of more virulent species. The gastrointestinal microbiota has also been correlated with psoriasis, as the

decreased prevalence of Faecalibacterium prausnitzii in the feces of psoriasis patients has been reported9. However, Codoñer et al.10 suggest that bacterial translocation, i.e., the

passage of microorganisms or endotoxins through the mucosa into the bloodstream, is not induced by a specific group in psoriasis, but rather by the dysbiosis between different groups of microorganisms present in the intestines, resulting in a state of inflammation and, consequently, in bacterial translocation. The main function of the skin is to protect the interface between the interior of the

human body and the external environment, being inhabited by many microbial populations, including bacteria, fungi, viruses, and mites, despite its inhospitable characteristics, such as acidity, desiccation, and low nutrient content11. Initially, it was believed that asepsis and the removal of pathogenic bacteria from the

skin would prevent diseases; however, recent studies show that bacteria play an important This article is protected by copyright. All rights reserved

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role in maintaining a healthy and functional skin12. However, when unbalanced by environmental or even host changes, they start showing virulence factors (abnormal toxin secretion, protease production, immune system evasion, invasiveness, among others), becoming potentially harmful to health13. Skin microbiota is characterized by at least four predominant phyla: Actinobacteria,

Firmicutes, Proteobacteria, and Bacteroidetes14, with the most abundant genera being

Staphylococcus (Firmicutes), Corynebacterium and Propionibacterium (Actinobacteria)15. Members of the Actinobacteria phylum are more abundant in the skin, whereas Firmicutes and Bacteroidetes are more frequent in the gastrointestinal tract. However, the microbial profile has revealed that the relative distribution of the phyla and families of bacteria differs significantly among the various skin sites. These differences in the distribution of microorganisms reflect differences in skin temperature, humidity, glandular distribution, and environmental exposure, as well as dermatopathologies16. In healthy skin, the most frequently observed microbiota includes a population

consisting mainly of members of the Corynebacterium spp., Micrococcus spp., Staphylococcus spp., and Propionibacterium spp. Genera17. However, there is a discrepancy between authors. Gao et al. (2008)14 observed that there were higher levels of bacteria of the Firmicutes phylum and lower levels of bacteria of the Proteobacteria and Actinobacteria (Propionibacterium acnes) phyla in psoriatic regions compared to healthy patients or healthy regions in patients with psoriasis. Alekseyenko et al. (2013)18 also observed higher

levels of Firmicutes in psoriatic lesions, and significant reductions in the abundance of bacteria belonging to the Proteobacteria (Cupriavidus spp., Schlegelella spp. e Methylobacterium spp.) and Bacteroidetes (Flavisolibacter spp.) phyla in patients with psoriasis compared to healthy patients. Fahlen et al. (2012)19, on the other hand, found a

greater abundance of Actinobacteria in normal skin and of Proteobacteria in psoriasis samples. More recently, a study using two identification methods (bacterial 16S rRNA gene

sequencing and a traditional microbial culture associated with mass spectrometry) found that 1. Firmicutes was the most common phylum and Actinobacteria the least common phylum in samples with psoriatic lesions, and that; 2. Prevotella spp. and Staphylococcus spp. were associated with psoriatic lesions, whereas Propionibacterium spp. were associated with unaffected areas20. This article is protected by copyright. All rights reserved

Anaerococcus

spp. and

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The combination of the four genera (Corynebacterium spp., Propionibacterium spp.,

Staphylococcus spp. e Streptococcus spp.) is more abundant in psoriatic lesions than in unaffected skin or in the skin of healthy patients18. Anaerococcus spp. and Propionibacterium spp. are associated with uninjured skin20, and the presence and levels of Staphylococcus spp. are associated with psoriasis17, the latter, together with Propionibacterium spp., being the least abundant in skin microbiota. The Streptococcus spp. genus alone has been reported as the most abundant in psoriatic lesions19. Thus, there is still considerable variation among the studies’ findings regarding the

proportions of bacteria associated or not with psoriasis. These differences could be due to the different skin sites studied, the regions of the bacterial 16S ribosomal gene sequenced (V1-V3/ V3-V5)20, or the variations between patients and treatments. Even though there is no consensus on the predominance of phylum and genera in the disease, there is a tendency related to dysbiosis involving the Firmicutes, Actinobacteria, and Proteobacteria

phyla, and the Staphylococcus spp., Streptococcus spp. and Propionibacterium spp. Genera21 in psoriatic lesions, confirming that imbalance in skin microbiota may be associated with its onset, development or been a result of it (Fig. 2)21. Also, Fry et al.22 propose that psoriasis is caused by decreased immune tolerance to

the natural commensal microbiota of the skin, with activation of the innate immune system (notably interleukin-23 and nuclear factor κB), rather than being an autoimmune disease. The authors describe that there is an increase in the incidence of periodontitis and Crohn’s disease in patients with psoriasis, the immune-inflammatory response of which may be exacerbated by stimuli from the local microbiota.

[Please, Insert Figure 2]

3. Pre- and probiotics and possible benefits for the treatment of psoriasis Probiotics have been defined by the World Health Organization’s food and nutrition

division as “live microorganisms, which when administered in adequate amounts, confer a health benefit on the host”23. Prebiotics, on the other hand, has been defined as “a selectively fermented ingredient that allows specific changes, both in the composition and/or activity in the gastrointestinal microflora, that confer benefits upon host well-being and health”24, a concept that was originally developed for the intestines, but that can be

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applied to modulate the composition of any community of microorganisms, including skin microbiota25. Synbiotics allude to the synergism that may exist in prebiotic-containing products that selectively favors the probiotic component26. In food, the use of probiotics for regulating the systemic immune response is already

well defined. Such therapy is aimed at the homeostasis of the healthy microbiota with the intestinal mucosa using different mechanisms27. Some strains promote a physical barrier by blocking pathogens from entering epithelial cells or favoring mucus production. Others increase the expression of cell junction proteins while maintaining intestinal permeability; some secrete antimicrobial factors, and others can stimulate the innate immune system, signaling dendritic cells to produce anti-inflammatory cytokines27. The human skin microbiota plays a significant role in human health and well-being9.

Moreover, the administration of bacterial cells may act on the microbiota’s modulation,

promoting beneficial effects28. In general, the use of these bacteria by patients may occur via ingestion or topical application25,28; however, there is no scientific consensus on which microorganisms may be employed for this purpose. The literature suggests the use of varieties of species with different mechanisms in

probiotic therapy. Propionibacterium freudenreichii represents the most common phylum (Actinobacteria) in the skin of healthy individuals. Called probiotic bacteria due to their similarity to the Bifidobacterium spp. genus, they produce cobalamin in abundance,

promoting benefits to the host, an interesting fact given the low levels of this vitamin in patients with psoriasis29. Another representative of this phylum, Bifidobacterium infantis is related to the reduction in the inflammatory process of the disease by mimicking commensal-immune interactions30 (Table 1). Some studies involving the topical application of probiotics confirm that they are a

strategy for rebalancing skin microbiota. One example is the work published by Ouwehand et al.29, who demonstrated that topical treatment with propionibacteria resulted in

antimicrobial activity against various skin pathogens, including Malassezia furfur, Candida

albicans, and Staphylococcus aureus, attributed to the secretion of organic acids and/or competition for binding sites in keratin. In another study, Guéniche et al.31 reported that the topical application of a cream containing Bifidobacterium longum promoted an increase in the resistance of sensitive skin against chemical (topically applied products) and physical (heat, cold and wind) aggression. This article is protected by copyright. All rights reserved

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In psoriasis, inflammatory skin reactions cause severe ceramide depletion and

increase transepidermal water loss, contributing to skin dehydration and clinical severity of the disease32. Dimarzio et al.33 demonstrated that the addition of Streptococcus thermophilus in a cosmetic product applied to healthy humans increased the levels of ceramides in the stratum corneum, which may contribute to the improvement in the skin’s lipid barrier and effectiveness of resistance against skin xerosis. Moreover, there is an abnormal differentiation of keratinocytes in psoriatic skin, with

consequent alteration of the expression of cell junction components, more specifically Zonula occludens-1 (ZO-1) and occludin. Clinical improvement, consisting of the lesion’s healing, may be associated with the restoration of the distribution of occludin, ZO-1, and also involucrin34. Recent studies show that probiotics can increase the integrity of cell junctions in

healthy human keratinocytes by increasing the skin barrier without inducing a pathological immune response. Putaala et al.35 demonstrated that positive regulation of occludin and ZO-

1 was observed after treatment with Lactobacillus acidophilus NCFM® in keratinocytes and that ZO-1 was also positively regulated by Bifidobacterium lactis. Several studies have also emphasized the therapeutic role of probiotics in various

inflammatory conditions. Rather et al.36 reported that the topical application of ethanolic extract from Lactobacillus sakei proBio65 (SEL001) improved the erythema and severity

scale scores, as well as histoclinical symptoms in an animal model with imiquimod-induced psoriasis. Besides, there was a decrease in the infiltration of inflammatory cells in the dermis, with reduced levels of expression of proinflammatory cytokines associated with psoriasis, including IL-17A, IL-19, and IL-23 (Table 1). Table 1 describes a compilation of studies demonstrating the action of the topical or

oral use of probiotics in the clinical improvement of psoriasis. It is possible to observe that the most used probiotics are Lactobacillus spp., with a reduction of proinflammatory cytokine levels, and improvement of the lesions.

[Please, Insert Table 1]

4. Future Perspectives

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Although several literature reviews indicate that skin microbiota may play an

important role in the development and regulation of the immune and inflammatory response of psoriasis, few studies are demonstrating the benefits of using probiotics as a therapeutic alternative for the management of the disease, and none on the use of prebiotics and synbiotics, these being important areas for scientific exploration in dermatology. For this reason, studies indicating which probiotics may contribute to skin

homeostasis are necessary. This justifies the need for a better understanding of the microbiota of healthy and psoriatic skin, as well as the effect of the replacement of microorganisms on the patient’s therapeutic improvement. Probiotics are found to have the ability to optimize, maintain, and restore skin

microbiota in different ways. However, the application of live probiotics on the skin creates several challenges, including ensuring the viability of probiotic bacteria. Also, due to microenvironment differences, it is difficult to recolonize the skin after adding them40, which may be a possible explanation for their low use in dermatological products for the treatment of psoriasis. Given the vulnerability that probiotic cells may show under adverse conditions in

cosmetic and dermatological formulations, including pH, amount of oxygen, water activity and temperature, the incorporation of these cells into atypical media require the use of technologies such as encapsulation, an important tool that promotes microbial protection in the most diverse applications, and that is already widely employed in food technology, with the use of pre- and probiotics in food products. There are broad challenges to be overcome when it comes to skin microbiota.

Therefore, studies demonstrating both the importance of the balance of the skin microbiota’s composition and its interaction with topical products should be stimulated and developed, to promote skin health and the development of new technologies that ensure the stability, viability, safety, and efficacy of new formulations containing pre- and/or

probiotics.

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40

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at:

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Table

Table 1. In vivo studies involving the use of microbiota in the clinical improvement of psoriasis.

Treatment

Bifidobacteria

Type of

Administration

Dose

Human

Oral

1g sachet with viable B.

Reduction

infantis 35264 1010 CFU for

concentration of C-reactive

8 weeks

protein and proinflammatory

sporogenes

in

the

plasma

30

cytokines (TNF-α and IL-6) Rats

Topical

proBio-65

Lactobacillus

Reference

Study

infantis 35624

Lactobacillus sakei

Benefit

Psoriasis induction:

SEL001

62.5 mg of cream with 5%

thickness and improved the

Imiquimod (IMQ)/cm

2

per

reduced

skin

erythema and severity scores

day on the back, and 20 mg

of

per day on the right ear, for

psoriasis in rats. These results

6 days.

were

Treatment: IMQ + SEL001* cream (50 mg/cm2 on the back and 10 mg on the right ear).

36

imiquimod-induced

supported

by

the

improvement of histoclinical symptoms. Reduction in the expression of IL-17A, IL-19, and IL-23.

*SEL001: ethanolic extract isolated from Lactobacillus sakei proBio-65, a potent probiotic strain

Human

Oral

Sachet, 3 times per day with

There was a reduction in the

10 mg of biotin, once per

fever and lesions after 15

day.

days of treatment, and no

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new

lesions

appeared.

Improvement of the patient’s general condition.

37

Accepted Article

Lactobacillus

Rats

Oral

pentosus GMNL-77

Probiotic

blend

Different doses were tested,

Reduction of erythematous

as follows: GMNL-77 (5x10

7

lesions and decreased levels

CFU/0.2 mL/day or 5x10

8

of proinflammatory cytokines

CFU/0.2 mL/day) or distilled

(TNF-α, IL-6, and the IL-23/IL-

water (control), for 7 days.

17A axis). Also, the treatment with L. pentosus GMNL-77 reduced spleen weight in the imiquimod-treated group and the number of IL-17 and IL22+

producing CD4 T cells in the spleen. Human

Oral

Probiotic blend with a total 9

colony-forming

blend

reduced

psoriasis

severity

of

Bifidobacterium

units (CFU) per capsule,

administered together with a

longum CECT 7347,

formulated on maltodextrin,

topical corticosteroid.

B. lactis CECT 8145

for 12 weeks.

Lactobacillus

rhamnosus 8361

1×10

Probiotic

(1:1:1)

and

CECT

38

higher

Betamethasone

calcipotriol

when

The probiotic group showed a

+

dipropionate

39

response

rate

in

PASI75 (66.7%) vs. control 0.25%

+

(Daivobet®),

group

(45.2%),

after

12

weeks.

once a day (Pacients with PASI ≥ 6) or mometasone

The probiotic group also demonstrated

furoate 0.1% (Elocom®).

a

higher

proportion of clear or almost Control patients used only topical

corticoids

and

clear patients in the PGA index. Positive

calcipotriol

changes

microbiota

gut

in

the

in

the

probiotic group contributes to the positive effect on the evolution of psoriasis. After 6 months of stopped intervention, the probiotics blend promoted more time free of relapse. +

TNF-α: Tumor Necrosis Factor-alpha; IL: Interleukin; CD4 T: Cluster of differentiation four (CD4) Tlymphocytes; PGA: Physician Global Assessment.

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Accepted Article

Figure Legends

Figure 1. Illustration of regions frequently affected by psoriasis. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com. The images used are from a private collection.

Figure 2. Illustration of bacterial dysbiosis associated with the onset of psoriasis. This figure was created using Servier Medical Art templates, which are licensed under a Creative Commons Attribution 3.0 Unported License; https://smart.servier.com.

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Accepted Article

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Accepted Article Review paper Skin Microbiota as a Therapeutic Target for Psoriasis Treatment: Trends and Perspectives Running head: Skin Microbiota...
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