Title: Elucidating role of bacteria in psoriatic disease: from skin and gut perspectives

Psoriasis is a chronic inflammatory disease characterized by skin lesions. Psoriasis development has been associated both with genetic and environmental factors. Though skin and gut microbiota has been implicated in number of pathologies including atopic dermatitis, inflammatory bowel disease, Crohn’s disease, allergy, obesity, its role has been poorly studied in psoriatic disease, which incorporates both psoriasis and psoriatic arthritis. This literature review summarizes the most recent and major findings on microbiota features in psoriatic disease as well as gives immune system role in the given condition. Despite conflicting findings, psoriasis patients were frequently found to have distinct microbial composition in both skin and guts especially in the major bacterial phyla, Firmicutes, Bacteroidetes, and Akkermansia. Furthermore, bacterial DNA has been found in psoriatic patients both locally and systemically, and altogether suggesting role of bacteria in the chronic disease and future studies in this field.


Introduction.
Psoriasis is a chronic immune-mediated inflammatory disease that occurs in 2-4% of people worldwide affecting skin and in 30% of cases joints (psoriatic arthritis) [1].It is characterized by recurrent skin plaques, epidermal keratinocytes hyperproliferation, and thickening of the skin [2,3].Psoriasis is also noted with the increased abundance of immune cells and inflammatory biomarkers both on local and systemic levels.Along with the symptoms, psoriasis increases susceptibility to cardiovascular diseases, autoimmune diseases including diabetes, which further diminishes quality of life and elevates burden of disease [4].Psoriasis occurs in both sexes predominantly before age of 40 (peak is between 16 and 22 years) in 70% of cases [5].
A growing body of literature suggest the role of microbiome, especially in guts, in chronic inflammatory pathologies including inflammatory bowel disease, atopic dermatitis, and psoriasis [6][7][8][9][10].Indeed, the human microbiota provides the organism with the nutrients and modulates the immune system.Interestingly, approximately 90% of all gut germs are similar in healthy people and compose a 'core' microbiome [11].Diet, infections, drug use, and traumas are major factors influencing human microbiome and may play a role in psoriatic exacerbations.[12][13][14] Gut microbiota can regulate the immune system not only locally, but it also possibly influences the immune mechanisms occurring outside the intestines.Additionally, dysbiosis, an imbalance of beneficial and pathogenic microbes in intestines, might take place in patients with psoriasis and psoriatic arthritis, and thus having potential of affecting systems beyond the human guts.For example, Bacterial DNA were detected in blood of psoriasis patients [15].Furthermore, bacterial metabolites were found in joints of psoriatic arthritis patients, which could occur there through blood or lymph system [16].Hence, imbalance of gut microflora can have an impact not only on skin but also on joint health.Nevertheless, there is lack of studies and reviews with an emphasis of the human bacterial microbiota peculiarities in psoriasis and psoriatic arthritis.For this reason, the review article will summarize the recent studies on skin and gut microbiota changes as well as immunologic background in psoriatic patients.
Among these cytokines, IL-22, TNF-α, and IFN-γ are regarded as the major players in psoriatic inflammation.Furthermore, they are the key molecules in the most commonly reported immune mechanism associated with psoriasis, namely IL-23/IL-17 axis [20,21].IL-17, which is produced by Th17 cells, was numerously found to be upregulated in both psoriatic lesions and bloodstream of patients with psoriasis and psoriatic arthritis [22][23][24][25][26][27][28][29].Interestingly, IL-17 seems to influence not only skin regions with lesions but also overexpression of downstream proteins in keratinocytes in the distant non-lesion skin of psoriatic patients comparing to non-psoriatic controls [30].Meanwhile, the key role of IL-23 in both psoriasis and psoriatic arthritis is supported by a study, in which IL-23 was injected to mice and triggered formation of psoriasis-like lesion in them [31].The researchers detected this impact via overexpressed levels of IL-22, TNF-α, IL-17A and IL-17F.IL-23 is also believed to participate in activation Th 17 cells, and subsequently IL-17 and IL-22 production [32].Moreover, IL-23 was found in significantly higher levels in psoriatic plaques than in the uninvolved skin [28], and thus suggesting an important role of IL-23 in psoriasis.

Role of skin and gut microbiota.
Skin and gut are the organs that comprise many functions are crucial for survival and proper homeostasis.Indeed, both of them are intensely vascularized and heavily connected with the rest of the organism via nervous, lymphatic, and blood systems.They are also densely colonized with the microbes because of their constant contact with the external environment.These features provide skin and gut their role in barrier and protection from external stimuli through immune modulation and certain microbial composition.Significant deviations in "healthy" microbiota composition are associated with number of diseases including inflammatory bowel disease, Crohn's disease and ulcerative colitis [33][34][35][36][37]. Overview of studies and their major findings in skin and gut microbiota is given in Table 1.

Skin microbiota in psoriatic disease.
Normal skin microbiota is comprised of Actinobacteria, Firmicutes, Proteobacteria, Bacteroidetes phyla [38].However, reports on diversity of skin microbiota is conflicting with majority of them reporting decreased Shannon index [39][40][41].Psoriasis involved skin as well as skin biopsy samples in psoriasis patients had the highest relative abundance of Firmicutes relative to healthy participants and the lowest proportion of Actinobacteria comparing with the uninvolved psoriatic and healthy skin [39,41].In contrast, one psoriatic subject from Drago et al., 2016 [42] revealed decreased abundance of Firmicutes, and samples taken from skin biopsies of psoriasis and control patients showed lower proportion of Actinobacteria though without statistical significance probably due to small sample size.Meanwhile, skin biopsies as well as skin swabs had greater proportions of Proteobacteria in psoriatic patients rather than in controls [41,42].However, skin biopsies were taken only from psoriatic plaques and healthy controls, and thus leaving bacterial composition in nonlesion sites underrepresented.Nevertheless, skin biopsies can give more in-depth information on microbiota in deeper levels of the skin than solely skin swabs.
Streptococcus genera, which was earlier implicated in contribution to psoriasis development from tonsils infections, was also found in greater proportions in psoriatic plaques than in uninvolved skin [39].In contrast, Drago et al., 2016 [42] showed decreased frequency of S.aureus in psoriatic patient than in atopic dermatitis and control in lesions but bacterial frequency was almost the same in non-lesion skin among three patients.Since study was performed on three patients only, and thus limiting generalizability of the results.Along with this genera, Staphylococcus and Corynebacterium were also found in greater relative abundance in psoriatic plaques in contrast to uninvolved and control skin samples in several studies [39,40,42], though Drago et al., 2016 compared psoriatic plaques with healthy skin and atopic dermatitis skin.In addition, Propionibacteria were also reported to have increased proportion in psoriatic skin comparing with control from both skin swabs and skin [40,41].In contrast, abundance of Cupriavidus, Flavisolibacter, Methylobacterium, and Schlegelella genera was significantly lower in psoriasis patients than in controls probably due to increased proportions of the previous genera leading to dysbiosis [41].Moreover, Drago et al., 2016 found that Rhodobacteraceae and Corynebacteraceae families were more abundant in psoriatic lesions than in atopic lesions and healthy controls.However, nonlesion skin in all of three types of skin (atopic dermatitis, psoriasis and healthy) did not differ in relative proportions of bacterial families.Similarly, frequency of Paracoccus was higher approximately by 50% in psoriasis patients than in atopic dermatitis and controls but did not differ in uninvolved skin between three types of patients.These findings on bacterial diversity and composition in skin of psoriasis may suggest role of bacteria in the inflammation and disease progression.

Gut microbiota in psoriatic disease.
Though role of microbiota, especially skin flora, has been reported to differ in patients with psoriasis and psoriatic arthritis, impact of gut microbiota on disease progression is still poorly studied.One of the studies speculating role of gut microbes in psoriasis used antibiotics to target gut bacteria and imiquimod to develop psoriasis-like disease, which included changes in the outer and inner layers of the skin (extensive reddening, thickening and reddening of the skin, increased proliferation of keratinocytes, and impaired epidermal differentiation [43].Overall, antibiotics-treated adult mice had decreased abundance of gut bacteria (Bacteroidetes, Actinobacteria, and Cyanobacteria) in gut and skin, less rigorous skin lesions and had decreased production of IL-22 and IL-17 producing T-cells in skin compared with control mice treated with imiquimod only.In lamina propria of guts of adult antibiotics group, Th17 cell levels were lower than in controls.Additionally, expression of chemocine receptor 6 (CCR6) molecule on T-cell surface, which takes part in migration of Th17 cells from intestines to skin was also lower compared with the nonantibiotics group.Moreover, the groups based on the antibiotics treatment time, either during neonatal or adult period, had different psoriasis-like disease development.The authors suggested that disrupted gut microbiota from early stages of life can have an impact on psoriasis development.Though mice treated with antibiotics in neonatal period had more severe symptoms and elevated levels of inflammatory cells (IL-22 and IL-17 T-cells) in skin of psoriasis-like disease than nonantibiotics group, there were no reported comparisons with adult-treated antibiotics mice from symptoms and inflammation perspectives, and thus leaving differences between antibiotics-treated groups for further investigations.Nevertheless, Bacteroidetes phylum, S24-7, Lachnospiraceae and Ruminacoccaceae families were decreased in guts of adult-treated antibiotics mice, while abundance of Tenericutes phylum, Lactobacillaceae (both gut and skin) and Alcaligenacea families were in greater proportions than in neonatally-treated antibiotics mice.These findings suggested that gut bacteria can modulate microbiota composition, inflammation mechanisms and disease progression in psoriasis.
Possible role of gut-skin axis in psoriasis was studied in imiquimod-induced psoriasis-like skin inflammation in germ-free, antibioticstreated and standard-treated mice [44].Overall, both germ-free and antibiotics-treated groups were more resistant to the disease development than conventional mice.This study revealed that these groups developed less severe skin lesions, scaling, thickening of skin, smaller extent of hyperkeratosis and acanthosis.Though they did not find imiquimod's effect on gut microbiota changes, they showed that antibiotics could result in decreased composition of Lactobacillales order (Firmicutes phylum) but increased abundance of bacteria from the same phylum, namely Clostridiales and Erysipelotrichiales orders.Additionally, Actionobacteria (Coriobacteriales and Campylobacteriales orders) were also decreased in the antibiotics group.These findings imply that gut dysbiosis can alter predisposition to psoriasis-like skin inflammation, and altered bacterial composition does not necessarily guarantee psoriasis symptoms development.Conventionally-reared mice also had larger spleens and decreased production of T cells both locally (spleen) and systemically (lymph nodes) than germ-free and antibiotics-groups Imiquimod was not found to change microbiota in gut of mice, and thus the imiquimod-induced model might not completely show the psoriasis development, similar in humans.
The most recent study on the gut microbiome composition in psoriasis patients obtained the distinguishing psoriasis microbiome [45].The authors found bacterial DNA in blood samples of psoriatic patients, especially in those with the predominance of Prevotella genus (Bacteroidetes phylum, enterotype 2) and who also had greater inflammation indicators.Regarding bacterial composition, the psoriatic patients had lower abundance of Bacteroides and greater proportions of Akkermansia species and Faecalibacterium compared to the healthy subjects.In contrast to most of the studies on skin microbiota, bacterial diversity (the Shannon index) was higher in psoriatic patients than in healthy group, but the authors explain this difference due to high PASI index in participants of this study, which could influence the gut microbiota, and sequencing methods.However, in psoriasis patients with bacterial translocation, this diversity was lower than in those without bacterial DNA in their blood, though no particular type of bacteria was peculiar for the former group.Moreover, PASI score did not differ in both groups, but bacterial translocation was previously reported to be associated with increased inflammation status in psoriasis [15].The latter patients (without bacterial translocation) were found to differ in abundance of Parabacteroides, Collinsella, Blautia, and Ruminococcus genera with the rest of the patients.Though the authors used data of healthy patients from the Human Microbiome Project Database, there is little known about whether they were appropriately matched with the psoriasis patients to avoid additional confounders apart from age and sex, which could influence the differences between groups.Nevertheless, this study provided new evidence on gut microbiome features in psoriasis and future prospective for studies in bacterial translocation and psoriasis.Scher et al., 2016 [46] also studied gut microbiota composition in psoriasis and psoriatic arthritis group.The sample size, study design (bacterial DNA regions for analysis), participants (psoriatic arthritis and psoriasis), sociodemographic characteristics as well as season of samples extraction might be the reasons for the observed differences in bacterial diversity between studies.Scher et al., 2016 [42] found Ruminococcus, Akkermansia, Pseudobutyrivibrio, and Clostridia were less present in gut of psoriatic arthritis patients, and Parabacteroides and Coprobacillus had smaller abundance in psoriasis participants than in healthy group.Notably, the gut microbiota differed among psoriasis arthritis and psoriasis only patients with the Akkermansia, Ruminococcus being less frequently found and Bacteroidetes and Coprobacillus having higher abundance in the former group.Apart from gut bacterial composition, Scher et al., 2016 [46] also looked at inflammatory status of psoriatic arthritis patients only.Notably, secretory Immunoglobulin A levels (sIgA) were increased and fecal Receptor activator of nuclear factor kappa-Β ligand (RANKL) was decreased in psoriatic arthritis group compared to psoriasis and healthy participants.Meanwhile, psoriasis patients had elevated serum psoriasin/S100 (commonly overexpressed in psoriasis) as well as fecal osteoprotegerin (OPG), which is inhibitor of RANKL [47].Moreover, the study revealed that medium-chain fatty acids (MCFAs, hexanoate and heptanoate), which previously showed antibacterial effects, were decreased in both psoriasis groups [48].Though short chain fatty acids (SCFAs) were implicated to possess anti-inflammatory effects on skin and produced by Bacteroidetes, which are commonly decreased in psoriasis, in this research, SCFAs (acetate, butyrate, propionate) levels were similar between groups.Finally, Akkermansia and Ruminococcus had positive correlation with MCFAs (hexanoate, heptanoate), Akkermansia alone was negatively corelated with fecal sIgA and short chain fatty acids (acetate, butyrate) and Coprobacillus had inverse correlation with S100.Fecal RANKL was positively corelated with Lachnosiparaceae, which were both low in psoriatic arthritis.However, sole correlation analysis can omit important confounders, which may influence observed associations.Masallat et al., 2016 [49] analyzed psoriasis and gut microbiome from different perspectives, bacterial ratio and their association with PASI index.They found out that psoriasis group had significantly higher ratio of Firmicutes/Bacteroidetes than healthy patients though bacterial count of Firmicutes, Bacteroidetes did not exert differences between groups.Nevertheless, Actinobacteria count was higher in healthy group, which is opposite to later study of Codoner et al., 2018 and in concordance with Scher et al., 2016 Firmicutes/Bacteroidetes ratio had statistically significant positive correlation with PASI index in contrast to Actinobacteria phyla.However, the participants were recruited during one year, and hence gut bacteria composition can change with the seasons and contribute to observed differences in intestinal flora.Additionally, none of the discussed studies took into account antipsoriatic therapies and diet (vegetarian, vegan, gluten-free, lactose-free), which could possibly influence immune status and microbiota composition.
The beneficial inhabitant of the human intestine, F.prausnitzii (Firmucutes phylum), produces butyrate (short chain fatty acid) that provides energy for colonocytes, takes part in protection from oxidative stress, possesses antiinflammatory features and plays role in regulation of T effector cells and regulatory T cells (Tregs) [50][51][52].Moreover, F.prausnitzii also produces mitochondria-associated membrane (MAM) protein, which has been implicated to inhibit nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB) pathway in intestines and possibly have an effect outside intestines, especially in the skin immune status [53][54].For example, Eppinga et al., 2016 [55] looked at abundance Faecalibacterium prausnitzii and E.coli (Proteobacteria phylum) in intestines of patients with psoriasis, inflammatory bowel disease and hidradenitis suppurativa.They found that psoriasis group (for all type and plaque-type psoriasis only) had significantly decreased proportion of F.prausnitizii than healthy controls.There was no correlation between PASI index and F.prausnitzii abundance, but no adjustments were made for potential confounders.Nonetheless, there were no significant differences in age, sex, smoking, BMI, race between healthy and psoriasis groups.Though the total bacterial DNA was similar between psoriasis and healthy participants, but low F.prausnitzii abundance in both groups, these findings suggest that there could be overabundance of other bacteria such as E.coli, which was increased in psoriasis group.The researchers also took data on any therapy used during the study, which was absent in most of the participants, and diet that can possibly affect gut microbiota composition.

Probiotics in psoriatic disease.
Provision of beneficial microbes and their effect on patients with psoriasis has also been studied.For example, Bifidobacteria infantis (B.infantis), which was previously reported to induce regulatory T cells in peripheral blood of healthy participants, was also shown to substantially decrease TNF-α, Creactive protein levels and in a small extent IL-6 in 75% of psoriasis patients after 6-8 week of daily probiotic intake [15,56].Notably, all these pro-inflammatory biomarkers were increased in psoriasis patients compared with the healthy controls.
Chen et al., 2017 [57] induced psoriasislike disease with imiquimod treatment in mice and fed them with Lactobacillus pentosus (L.pentosus) GMNL-77 to look at symptoms development and immune status differences.Strains of L.pentosus has been implicated with suppression of inflammatory mechanisms in C.albicans infection in stomach, modulating production of immunoglobulins A and M, IL-6, IL-10, IFN-γ in intestines, reduction of microbial lipopolysaccharide in guts and blood, decrease of Firmicutes/Bacteroidetes ratio in intestines, and possession of antibiotic properties [58][59][60][61][62][63].The findings of Chen et al., 2017 [57] revealed that mice given L.pentosus GMNL-77 had significantly less psoriasis-like skin lesions and decreased hyperproliferation of keratinocytes compared with the imiquimod only treated group.The probiotic-treated mice had reduced expression levels of inflammatory biomarkers such as TNF-α, IL-6, IL-23, IL-17A, IL-22 in skin.Meanwhile, T cells' (Th17 and Th22) number in spleen and the organ's size itself was as well.Though this study looked at skin and spleen omitting gut microbiota composition and intestinal immune status, its findings suggest that probiotics can take role in alleviating symptoms and inflammation in psoriasis and provide new directions for usage of beneficial bacteria in treatment of the psoriatic disease.

Conclusion.
Recent evidence suggests that the gut microbiome can contribute to the development of psoriasis and psoriatic arthritis.On the other hand, the skin microbiome may be important in the development of psoriasis, but it is not clear whether it plays a role in the development of its systemic forms.Hence, since psoriasis is associated with altered skin and gut microbiome, it is tempting to suggest that skin and gut complement each other in the pathogenesis of psoriasis, and possibly of psoriatic arthritis.Further studies are needed to evaluate properly the interrelation between skin and gut microbiota and psoriatic disease.