Medicine in Microecology 4 (2020) 100016

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Medicine in Microecology
journal homepage: www.journals.elsevier.com/medicine-in-microecology

Role of skin and gut microbiota in the pathogenesis of psoriasis, an

inflammatory skin disease
Daniel K. Hsu a, Maxwell A. Fung a, Hung-Lin Chen b, *
a
Department of Dermatology, School of Medicine, University of California-Davis, Sacramento, CA, USA
b
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

A R T I C L E I N F O A B S T R A C T

Keywords: Psoriasis is a chronic inflammatory skin disease associated with epidermal keratinocyte hyperplasia and
Psoriasis epidermal immune cell over-activation. Compositions of both local skin and gut microbiome are linked to
Microbiota modulation of inflammation and disease severity in psoriasis. Owing to the situation that different bacteria may
Microbiome
elicit differential immune or inflammatory responses from epidermal immune cells and keratinocytes, and to-date
no single pathogen was highlighted to be responsible for psoriasis, disruption of homeostasis (dysbiosis) in the
original microbial ecosystems may create a disease-promoting environment, and as a whole may be a primary
causal factor. Several studies have provided evidence that the dominant IL-23/IL-17 pathogenesis pathway is
regulated by metabolites produced by gut and skin microbiota. This review summarizes the approaches
commonly used for functional characterization of the microbiome compositions associated with development of
clinical phenotypes of psoriasis. The underlying mechanisms by which microbiota modulate immune cells and
keratinocytes are also proposed.

1. Introduction infection and responds to antibiotic therapy [18,19]. However, antibi-

Psoriasis has been reported to affect 0.09%–11.4% of the general
population worldwide [1]. It is among the most common chronic skin
inflammatory diseases associated with metabolic disorders, including
metabolic syndrome [2–4]. Psoriasis is characterized by epidermal ker-
atinocyte hyperproliferation (associated with skin thickening) and
inflammation (associated with skin redness) in the epidermis and dermis.
Pruritus causes psychological stress in some patients. In addition, psori-
asis is associated with comorbidities such as obesity, hypertension,
atherogenic dyslipidemia, type 2 diabetes, and inflammatory bowel
disease [2,5–9]. Therefore, psoriasis represents a substantial cumulative
disease burden on patient quality of life, including psychological health.
The etiology of psoriasis is multifactorial and involves the interplay of
genetic and environmental factors that exacerbate innate and adaptive
immune responses [10–12]. Although the clinical manifestations of
psoriasis are in the skin, associated inflammation develops throughout
the body [13]. Psoriasis is considered a multifactorial condition, and
current therapies include antibodies to key cytokines associated with this
disease, such as Interleukin-23 (IL-23) [14,15], Interleukin-17 (IL-17)
[15,16], and tumor necrosis factor alpha (TNFα) [17]. One form of
psoriasis, guttate psoriasis, is associated with bacterial upper respiratory
otics are atypical first-line therapies for psoriasis [20].
As the largest organ of the body, the skin provides a physical barrier
to injury and microbial insults. Keratinocytes and indigenous immune
cells play indispensable roles in cell renewal and antimicrobial function,
in general [21]. Epidermal keratinocytes secrete antimicrobial peptides
[12,22,23], form tight junctions [24], and construct a physical barrier
[25] to control microbial infections through cornification [25–27].
Therefore, commensal bacteria may develop special mechanisms that
characterize their adaptation as microbiota. The microbial ecology of the
skin is mostly composed of bacteria from Firmicutes, Actinobacteria, Bac-
teroidetes, and Proteobacteria phyla. Skin from different body regions each
have their unique microbiome ecology [28] with differences associated
with variations in temperature, moisture, and pH value [29]. This pro-
vides a unique colonization environment which favors the survival of
some bacteria over others. Staphylococcus and Corynebacterium spp. are
typically the most abundant bacteria in moist sites (such as axillary vault,
antecubital fossa and inguinal crease), whereas sebaceous sites such as
glabella, alar crease and external auditory canal are enriched with Pro-
pionibacterium spp., and dry sites such as volar forearm and buttock are
enriched with some Gram-negative bacilli [25,29–32]. In lesional pso-
riasis, unlike normal skin, microbial colonization is mostly confined to

* Corresponding author. Institute of Biomedical Sciences, Academia Sinica, Taiwan.

E-mail address: hunglinc@gate.sinica.edu.tw (H.-L. Chen).

https://doi.org/10.1016/j.medmic.2020.100016
Received 18 December 2019; Received in revised form 6 May 2020; Accepted 9 May 2020
Available online 20 May 2020
2590-0978/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
D.K. Hsu et al. Medicine in Microecology 4 (2020) 100016

Table 1
Summary of previous studies on changes in the skin microbiota of psoriasis patients.
Reference Samples Methods Bacteria enriched in psoriasis Bacteria decreased in
psoriasis

Gao et al., Samples collected from 6 patients, 19
2008 cutaneous samples (13 from diseased
skin and 6 from normal skin).
Fahlen et al., Skin biopsies taken from 10
2011 patientswith Psoriasis and 12 control
subjectsfrom unmatched sites.
Alekseyenko Psoriatic lesions (lesion
et al., 2013 group).unaffected contralateral skin
frompsoriatic patients (unaffected
group), and similar skin loci in
matched healthy controls (control
group) 51 matched triplets
Drago et al., Samples from three first cousin, two
2015 lesional skin samples and two non-
lesional skin samples (for AD
andpsoriatic subjects) were taken.
Assarsson Sample collected from 30 patients with
et al., 2018 plaque type Psoriasis with indication
for nbUVB treatment
Langan et al., Swabs from lesional and nonlesional
2019 skin from 23 patients and 20 healthy
controls
Quan et al., Sample colleced from lesional
2019 andunaffected skin of 16 patients and
6 healthy controls
Fyhrquist Sample collected from healthy
et al., 2019 controls(n ¼ 115), AD (n ¼ 82) and
PSO (n ¼ 119).
Broad-range 16S rDNA PCR and Firmicutes and Streptococcus Actinobacteria and
taxonomical assignment using Ribosomal Propionibacterium
Database Project II (RDP II).
for pyrosequencing on the 454-FLX GS- Proteobacteria and Streptococci Actinobacteria,
100 platformthe. Ribosomal Staphylococci and
databaseproject (RDP) sequence data were Propionibacteria
used for analysis.
Targeting 16 S rRNA gene V1–V3 Corynebacterium, Propionibacterium, Acidobacteria Gp4 and
regionsfor pyrosequencing on the 454 Staphylococcus and Streptococcus Schlegelella
platform and RDP Classifier was used for
sequence analysis.
Targeting 16 S rRNA gene V2-4-8 and V3- Proteobacteria, Streptococcaceae, Firmicutes,
6, 7–9 regions for sequecing use Ion Rhodobacteraceae, Staphylococcaceae,
Torrent PGM platform. A Campylobacteraceaeand Moraxellaceae Propionibacteriaceae and
curatedGreengenes databased was used Propionibacterium acnes
fortaxonomical analysis.
Targeting 16 S rRNA gene V3–V4 for Psoriasis patients skin enrich Firmicutes and
MiSeq sequencing, and data was analyzed inConchiformibius, while nbUVB Staphylococcus
by CLC Software map to Greengene treatement non-responders enrich in
V13⋅516 S rRNA sequencing (V1–V2) and Staphylococcus, Finegoldia, Anaerococcus,
Peptoniphilus, Gardnerella, Prevotella and
Clostridium.
traditional culture combined with Firmicutes, Prevotella, Staphylococcu and Actinobacteria,
massspectrometry (MALDI-TOF). RDP Corynebacterium Anaerococcus and
Gold database version 9 and SILVA Propionibacterium
database(version 123) was used as
reference database.
Targeting 16 S rRNA gene V3–V4 Coryne bacterium, Brevun dimonas and Cutibacterium,
regionand library were made and Micrococcus Streptococcus and
sequenced by Miseq-system.RDP Classifier Deinococcus
was used for sequnce analysis. Targeting
16 S rRNA gene sequencing use
454, and Greengene C. simulans and C. kroppenstedtii as well Corynebacterium spp.,
database.Metagenomic shotgun asFinegoldia, Neisseriaceae species and Lactobacilli, Burkholderia
sequencing use illumina HiSeq and Coryn e bacteria spp. and P. acnes
analyzed by MetaPhlan2 and humann2.

AD-atopic dermatitis; nbUVB-narrow band ultraviolet B; PSO-psoriasis.

the epidermis. In lesional psoriatic skin, pruritus-induced scratching can
cause wounding to the skin; therefore some bacteria (epidermal colo-
nizers and other bacteria) can be found in the deep dermis [33] or even
peripheral blood [34] where they readily encounter immune cells and
elicit innate and adaptive inflammation [35]. This causes dysbiosis of
skin microbiota as observed in a significantly reduced population of
Corynebacterium spp., Lactobacillus spp., Burkholderis spp., and Propioni-
bacterium acnes in lesional psoriatic skin compared with healthy skin
[36].
The gut microbiome in psoriasis is also enriched in Firmicutes and
Actinobacteria spp [37,38]. Dysbiosis may cause changes in metabolite
production and elicit anti-microbial signaling, and these may affect im-
mune cell activation through the IL-23/IL-17 signaling pathway through
IL-22 and interferon gamma (IFN-γ) production, leading to keratinocyte
hyperproliferation. Besides genetic predisposition, dietary and life-style
factors are known key regulators of gut microbiome homeostasis [39,
40]. Gut dysbiosis also promotes other inflammatory diseases such as
inflammatory bowel disease (IBD) [41], including Crohn disease [42]. In
addition, in psoriatic patients who also have IBD, the severity of symp-
toms of psoriasis correlates with that of IBD [9,43–46]. Psoriatic patients
have 3-fold higher risk of developing Crohn disease, and Crohn disease
patients have a 7-fold higher risk of developing psoriatic lesions,
compared to heathy individuals [47]. This is mainly because pathogenic
T helper type 17 (Th17) cells and Th17 cytokines are associated with
these chronic inflammatory diseases [48]. Reduction in the numbers of
specific bacteria (Faecalibacterium prausnitzii and Akkermansia mucini-
phila) have been reported in psoriasis [46,49], and these bacteria are
reported to produce short chain fatty acid (SCFA) that exert
anti-inflammatory functions [50,51]. Dysbiosis of the gut microbiome
may also exacerbate psoriasis, wherein the interactions of different
bacterial populations in the skin and gut microbiome play key roles in the
pathogenesis of psoriasis. The aim of this review is to identify a link
between the microbial ecology of the gut and skin, and their relevance to
psoriasis.
2. Methods
We searched NCBI PubMed for articles having both “psoriasis” and
“microbiome” as keywords. The search yielded 174 articles, including 81
review articles. Selected articles on skin microbiome and gut microbiome
analyses in psoriatic patients are summarized in Table 1 and Table 2,
respectively.
2.1. Genetic and environmental factors involved in psoriasis pathogenesis
Psoriasis is a complex disease in which genetic susceptibility loci and
environmental factors contribute to the disease phenotype. In the past
decade, several psoriasis susceptibility loci (PSORSs) were identified [10,
52,53]. Genes and allele within the PSORS1 locus (human leukocyte
antigen (HLA-Cw6) [54], alpha-helix coiled-coil rod homolog
(HCR*WWCC) haplotype [55] and HLA-associated S genes [56]) were
also discovered. Furthermore, HLA-B, HLA-C, HLA-C12, HLA-DQAT, and
endoplasmic reticulum aminopeptidase 1 (ERAP1), which are responsible
for antigen presentation and processing, were also identified as

2
D.K. Hsu et al.
contributory. In addition to these factors, the following are all involved in
the pathogenesis of psoriasis: Nuclear factor kappa B (NF-ƘB) signaling,
Janus kinases (JAKs) signaling, transforming growth factor beta (TGF-β)
signaling, T cell regulation, interleukin 23–interleukin 17 (IL-23-IL-17)
signaling, disruption of epithelial barrier function, and dysregulated
apoptosis and autophagy, [10,57,58]. Environmental risk factors
including ultraviolet exposure [59], medications, including [anti-
proliferative agents (imiquimod), antivirals and antidepressants
(lithium), antihypertensives (beta-blockers) and TNF-α] [60,61], smok-
ing [62], obesity [63] and alcohol intake [64], as well as stress [62] and
infection [65], combine with the genetic burden to initiate and exacer-
bate epidermal inflammation [11]. The innate immune response plays a
critical role in an imiquimod (IMQ)-induced psoriasis mouse model [66].
The activation of TLR-7 by IMQ triggers IL-23 secretion from conven-
tional dendritic cells (DCs). In addition, IMQ directly induces
interleukin-36 alpha (IL-36α) expression in bone-marrow derived Lang-
erhans cells, and in granulocyte-macrophage colony-stimulating factor
(GM–CSF)–induced DCs. IL-36α then acts on bone-marrow derived
Langerhans cells and keratinocytes to produce IL-23, interleukin 1 beta
(IL-1β), C–C Motif Chemokine Ligand 20 (CCL20), and C-X-C Motif
Chemokine Ligand 1, 2 (CXCL1 and CXCL2). Apart from IMQ, IL-36α can
be induced in DCs by other microorganism ligands such as the β-glucan
from Candida albicans, suggesting that dysbiosis of the skin microbiome
may cause a psoriasis-like (psoriasiform) dermatitis [66]. In humans, the
critical cellular and molecular pathways in lesional psoriatic skin are
orchestrated by the activation of dermal DCs, which secrete IL-23 to
promote IL-17 production by gamma delta (γδ) T cells and type 3 innate
lymphoid cells (ILC3), but not αβ T cells (Fig. 1). IL-17 then stimulates
keratinocytes to produce chemokines such as CXCL1, CXCL2, CCL20,
interleukin 6 (IL-6), and interleukin 8 (IL-8), causing leukocyte infiltra-
tion. The ILC3 can respond to stimulating cytokines including IL-1β,
interleukin 18 (IL-18) and IL-23 by secreting IL-22 and IL-17 [67], which
stimulate keratinocyte hyperproliferation. Topical imiquimod applica-
tion or intradermal IL-23 injection can induce skin inflammation and
psoriasiform plaques in a mouse psoriasis model. However,
antibiotic-treated or germ-free mice failed to establish chronic skin
inflammation and exhibited reduced psoriasiform plaque formation [68].
This suggests that the microbiome on lesional skin, and possibly other
niches, play important roles in the triggering of prolonged inflammation
and the establishment of psoriasis. Recently, CD109, a glycoprotein
expressed in keratinocytes, was found to suppress murine psoriasiform
dermatitis [69], occurring through regulation of the infiltration of γδT
cells, and thus impact of IL23/17 signaling; a potential involvement of
TGFβ in skin homeostasis may also exist. Keratinocytes, which are pri-
marily responsible for the formation of the skin barrier, are known to
produce several antimicrobial peptides and proteins that assist in the
maintenance of the normal microbial ecosystem. Dysbiosis of the
microbiome commonly occurs in skin diseases including atopic derma-
titis and psoriasis. Therefore, the normal skin microbiome contains both
beneficial and harmful microbes, which regulate resident immune cells
and keratinocytes, and these cells actively participate in the development
of inflammation.
2.2. Dysbiosis of the skin microbiome in psoriasis
In a previous study, the sampling procedure for cutaneous micro-
biome analysis (i.e., swab vs scrape vs biopsies) using matched controls
(i.e., healthy individual vs non-lesional sites from patients) was noted to
be more challenging compared to sampling the fecal microbiome [33].
The most abundant microbial phyla in the skin swabs were Firmicutes,
Actinobacteria, and Proteobacteria. It is worthy of note that the order
Clostriadales and Bacteroides were more enriched in biopsy samples
compared to swab samples.
In addition, due to the different analytic technologies available, for
example, species-specific polymerase chain reaction (PCR), cultured-
bacterial PCR, 16 S rRNA gene full length PCR and 16 S rRNA gene
3
Medicine in Microecology 4 (2020) 100016
fragment amplicon, and mass-spectrometry, data of different studies can
only be partially integrated [30,31,36,70–77]. Metagenomic shotgun
sequencing is an advanced and very informative sequencing technology
but also expensive; therefore, more limited cost-effective sequencing of
16 S rRNA V1-3 and/or V3–V4 regions are commonly used for micro-
biome analyses. Some studies have suggested that V1–V3 is more
appropriate for cutaneous microbiome profiling; however, V4 and V3–V4
amplicons are suitable for fecal microbiome analysis. Apart from
sequencing technologies, the use of appropriate databases for the map-
ping of phylogenetic information is also critical. To that end, we sum-
marize different studies and the associated technologies for psoriasis in
Table 1.
In psoriasis, the relative abundance of Streptococcus pyogenes increases
in swabs compared with healthy controls and non-lesional skin [76,77].
M protein of Streptococcus has sequence homology with the 50-kDa type I
keratin, suggesting that streptococcal super antigen-induced T cells
target skin-specific antigens through molecular mimicry, which leads to
chronic inflammation [78,79]. Dysbiosis is commonly observed in the
skin of psoriasis patients. Yan et al. reviewed the analysis of changes in
microbiome alpha-diversity [73]. A large cohort study reported 75 pso-
riasis cases (both lesional and non-lesional) and 124 controls in analyses
of skin swab microbiomes [31,73]. Significant decreases in richness and
Shannon-index were reported in lesional samples compared with
non-lesional and control samples. This study also included a longitudinal
analysis (17 psoriasis patients and 15 controls) that examined micro-
biome changes in systematic therapies (i.e. methotrexate and TNF-α in-
hibitors). At 12 weeks after systematic therapy, the richness and
Shannon-index declined for both lesional and non-lesional samples, but
at 36 weeks, only the richness and Shannon-index of the control samples
returned to the baseline, suggesting an interplay between the immune
system and microbiome ecology. In addition, anti-microbial substances
are secreted in the lesional site, and hence, lesional skin lacks adequate
environmental support for microbiota colonization. Fyhrquist et al.
conducted a microbiome analysis of skin swabs in 115 healthy volunteers
(HV), 82 atopic dermatitis (AD), and 119 psoriasis (PSO) subjects using
16 S rRNA V3–V4 sequencing platform and whole genome sequencing.
They found that some bacterial distributions showed significant differ-
ential changes even after adjusting for confounding factors (e.g. Cory-
nebacterium kroppenstedii was associated with age, Staphylococcus aureus
with anatomical location, and Lactobacillus sp. with gender), [36]. In
lesional psoriasis, the abundance of Corynebacterium simulans, Coryne-
bacterium kroppenstedii, Finegoldia spp., and Neisseria spp. increased;
however, that of Lactobacilli, Burkholderia spp. and Propionibacterium
acnes decreased, compared with that in healthy skin. Other studies also
reported that the abundance of Corynebacterium is associated with the
severity of local lesions [70]; the abundance of Corynebacterium and
Staphylococcus significantly correlated with the psoriasis area severity
index (PASI) scores. A co-occurrence relationship analysis reported that
among 24 microbes identified for psoriasis classification, 16 species
showed significant correlation as determined by an operational tax-
onomical unit (OTUs) correlation analysis tool, SparCC [36]. Coryne-
bacterium simulans and Corynebacterium kroppenstedii displayed positive
correlation with Streptococcus spp., Peptostreptococcus anaerobius, Anae-
rococcus spp., Neisseria spp., and Rothia dentocariosa. This suggests that
the microbiome ecosystem of psoriasis contains communities of both
pathogenic and non-pathogenic bacteria with potential mutualism. In
addition, several studies have suggested that a single taxonomy is unable
to discriminate psoriasis from healthy skin. The loss of homeostasis and
the presence of specific bacterial genera such as Cutibacterium, Strepto-
coccus, Deinococcus, Actinobacteria, Staphylococci, Propionibacteria, Anae-
rococcus, and Corynebacterium spp. also contribute to psoriasis.
Corynebacterium spp. are negatively associated with the interferon
signaling pathway, and this may lead to changes in its symbiotic
microbiome, contributing to the pathogenesis of psoriasis [34,36,70–73,
77], (Fig. 1).
 D.K. Hsu et al.
Table 2
Summary of previous studies on gut microbiota changes in psoriasis patients.
Reference Samples Methods Bacteria enriched in psoriasis Bacteria decreased in psoriasis

Scheret al. Fecal samples from PsA (n ¼ 16), Patients with Targeting 16 S rRNA gene V1–V2 regionfor Bocteroidetes Akkermansia, Ruminococcus, Akkermansia,
2015 Psoriasis of the skin(n ¼ 15), and healthy, matched sequencing by 454 pyrosequencing method Coprococcus
control subjects (n ¼ 17). species and Coprobacillus
Tan et al., 2018 Healthy controls (n ¼ 14) and patients with vulgaris Targeting 16 S rRNA gene V4 region for sequencing Bocteroidaceae, Enterococcaceae, Akkermansia muciniphila, Verrucomicrobia,
Psoriasis (n ¼ 14) wererecruited. and analyze using RibosomalDatabase Project (RDP) Enterococcus, Bacteroides andClostridium Jenericutes, Mollicutes,
Naive Bayesian Classifier v.2.2. citroniae Verrucomicrobiae,Verrucomicrobiaes and
RF39
Codoner et al., 52 patients and over 300 healthyindividuals extracted The V3–V4 of the bacterial 16s rRNA genewas Streptococcus, Bifidobocterium, Bacteroides
2018 from the humanmicrobiome project(http://hmp amplified and sequenced with aMiSeq lllumina Akkermansia, Akkermonsia spp and
dacc.org/). Platform and analyzedusing NCBI 16s rRNA Faecalibacterium
database.
Chen et al., Psoriasis (n ¼ 32) and age-, gender- and body mass Targeting 16S rRNA gene V3-V4 region for Firmicutes, Ruminococcus and Megasphaera Bacteroides
2018 index (BMI)-matched non-psoriasis subjects (n ¼ 64). sequencing by lllumina MiSeq 2000 platform and
analyze using Greengenes 13.5 database.
Shapiro et al., psoriasis subjects (n ¼ 64)Fecal samples from 24 platform and analyze using Greengenes13_5 Firmicutes, Blautia, Faecalibacterium,Ruminococcus, Lachnospira, Collinsella, Sutterella and
4

2019 Psoriaticpatients and 22 Control participants databaseThe V4 region of the bacterial 16 S Prevotella,Coprococcus, Bifidobacterium, Dorea and Actinomyces
rRNAgene was amplifiedand sequenced using the Christensenella
lllumina MiSeq platform and analyzed using
Greengenedatabase.
Hidalgo- The faecal microbiota of 19 patientswith Psoriasis and Ion 16STMMetagenomics Kit targeting the V2–V3 Firmicutes, Actinobacteria, Bifidobacteriaceae, Bacteroidaceae, Barnesiellaceae,
Cantabrana 20 healthy individuals from the same hypervariable regions, and sequence wasmapped to Coriobacteriaceae, Lachnospiraceae,Clostridiales Prevotellaceae, Tannerellaceae,
et al., 2019 geographiclocation. SILVA database vl32 99. Family XIII, Eggerthellaceae,Peptostreptococcaceae, Burkholderiaceae, Rikenellaceae,
Ruminococcaceae andE rysipelotrichaceae Lactobacillaceae, Streptococcaceae,
Desulfovibrionaceae, Veillonellaceae,
Marinifilaceae, Victivallaceae and
Pasteurellaceae
Huang et al., 35 Psoriasis patients in this study.Among them, 16 The V4 and V5 regions of the bacterial 16 S ribosomal Bacteroidetes, Bacillus, Bacteroides,Sutterella, Firmicutes, Thermus, Streptococcus, Rothia,
2019 were diagnosed with Psoriasis vulgaris (VUL), eight RNA gene were amplifiedand sequenced by lllumina Lactococcus, Lachnospiraceae_ UCG004,Lachnospira, Granulicatella, Gordonibacter,
withPsoriasis pustulosa (PUS), seven withPsoriasis MiSeqplatform. Mitochondria_norank,Cyanobacteria_noran and Allobaculumand Carnobacterium
arthropathica (ART), and fourwith erythroderma Parabacteroides B1:F40D35B2:FB1:F40
psoriaticum (DER).

Medicine in Microecology 4 (2020) 100016

PsA-psoriatic arthritis.
D.K. Hsu et al. Medicine in Microecology 4 (2020) 100016

Fig. 1. Pathogenesis of psoriasis and interactions of the immune system, keratinocytes, and skin microbiome. In humans, dysbiosis of the microbiome ecosystem may
trigger the activation of conventional dendritic cells (cDC) in the dermis to secrete IL-23 ①. IL-23 consequently promotes γδ T cells and Th17 cells to produce IL-17 ②.
In addition, type 3 innate lymphoid cells (ILC3) can respond to stimulating cytokines including IL-1β, IL-18 and IL-23, and secrete IL-17, IL-22 and IFN-γ to act on
keratinocytes ③. IL-17 stimulates keratinocytes to produce chemokines such as CXCL1, CXCL2, CXL20, IL-6, and IL-8, resulting in leukocyte infiltration ④. Infiltrated
leukocytes can further produce IL-1β and IL-18 to stimulate ILC3 cells to produce more IL-22, IL-22 thus promoting keratinocyte hyperproliferation ⑤. During skin
inflammation, hyperproliferating keratinocytes can produce more antimicrobial peptides (AMPs) such as S100 calcium-binding protein (S100A), cathelicidin anti-
microbial peptides LL-37 and beta defensin (β-defensin). The effect of these antimicrobial peptides on the microbiome at the lesional site remains to be investigated.
However, the dysbiosis of the skin microbiome in lesional skin has been characterized by several studies that identified the enrichment of Streptococcus pyogenes,
Corynebacterium, Propionibacterium, Staphylococcus, Streptococcus, Corynebacterium simulans, Corynebacterium kroppenstedtii, Finegoldia, and Neisseria spp. These
bacteria may create a proinflammatory environment that promotes the development of psoriasis through keratinocytes and resident immune cells.

2.3. Dysbiosis of gut microbiome in psoriasis
Gut microbiome dysbiosis is associated with psoriasis, as well as other
diseases (e.g., metabolic syndrome, abdominal obesity, hypertension,
type 2 diabetes, insulin resistance, and non-alcoholic fatty liver disease),
and typically involves an impaired gut epithelial barrier [39–42]. Apart
from that, a dysfunction of gut microbiome function including activation
of regulatory T cells, bacterial chemotaxis, and carbohydrate transport
have been predicted to be associated with an increase in the Firmicu-
tes-to-Bacteroidetes ratio (F/B ratio) and loss of some bacterial genera
(Ruminococcus and Megasphaera) [38]. In a human microbiome project
involving 52 psoriasis patients and 300 healthy controls, Codoner et al.
reported that microbiome diversity was higher in psoriasis patients than
in the healthy controls [80]. The study of Scher et al. demonstrated that
in a small cohort of samples (16 psoriatic arthritis (PsA), 15 psoriasis
(PSO), and 17 controls), the microbiome of the PSO group was less
diverse than that of the controls [81]. The discrepancy in diversity be-
tween these two studies may have resulted from differences in sample
collection, DNA extraction, sequence library preparation, and/or data
analyses. In general, at the plylum level, Firmicutes and Actinobacteria as
well as the Firmicutes-to-Bacteroidetes ratio (F/B ratio) increases in
psoriasis; however, some studies also found an enrichment of Bacter-
oidetes and a decrease of Actinobacteria in the gut of psoriasis subjects
(Table 2). At the species level, psoriasis has an increased abundance of
Ruminococcus gnavus, Dorea formicigenerans, and Collinsella aerofaciens
[82]. Surprisingly, Akkermansia spp. and Faecalibacterium increased in a
cohort of psoriasis patients [80]. Other studies demonstrated the deple-
tion of Akkermansia muciniphila and Faecalibacterium prausnitzii in psori-
asis patients [49,83], which has also been reported in IBD and Crohn
disease patients [42,49,84]. This discrepancy between studies again
indicated the importance of using standard methods for sample collec-
tion, DNA extraction, sequence library preparation, and/or data analysis.
Increased abundance of A. muciniphila causes reduced body weight and
gut barrier dysfunction [85]. Faecalibacterium prausnitzii is a butyrate
producer that fuels enterocytes and has an anti-inflammatory function
[86,87]. All these reports suggest that gut microbiome homeostasis is
important for the maintenance of epithelial barrier integrity. The
dysfunction of the gut barrier is associated with increased blood intes-
tinal fatty acid binding protein (I-FABP) and bacterial DNA levels [34,
88]. This evidence suggests that the regulation of gut microbes could
have a potential ameliorating effect on skin inflammation by regulating
the systemic immune system [34,89–91].

5
D.K. Hsu et al.
2.4. Regulation of the gut-skin axis attenuates psoriasis
There are studies indicating that a gut-skin axis exists. For example,
probiotics such as Bifidobacterium infantis 35,624 and Lactobacillus pen-
tosus GMNL-77 have shown beneficial effects in psoriasis patients, and in
mice with imiquimod-induced psoriasis [90,91]. The levels of serum
proinflammatory cytokines (i.e. TNF-α and IL-6) and plasma C-reactive
protein (CRP) levels were reduced by probiotics. Higher circulating levels
of these cytokines are also associated with psoriasis [92,93], and other
co-morbid diseases [94]. This implies that the immune modulatory
function of probiotics is not limited to the gut mucosa. These observa-
tions provide an opportunity to investigate the interaction of the human
gut microbiome and the skin and systemic immune systems, in order to
unravel the significance of the gut-skin axis in the pathogenesis of
psoriasis.
3. Conclusion
The gut and skin share many common features and functions. Each
site has a unique ecosystem of normal flora interacting with epithelial
and immune cells. The IL-23/IL-17 signaling pathway plays a critical role
in the inflammation of both the gut and the skin. With newer and more
advanced technologies such as culturomics, metagenomics, whole
genome analysis, metabolite analysis, and germ-free animal models, re-
searchers will be able to identify critical microbiomes and unravel their
mechanisms in human psoriasis. In addition, keratinocytes primarily
responsible for skin barrier integrity express several important genes
(e.g., CD109, antimicrobial peptides, TLRs, C-type lectins, and galectins) [69,
95–99], that may potentially regulate the interaction of the microbiome
with immune cells. This network of microbiome interactions is an
exciting and wide-open topic to researchers in diverse fields.
Author contribution
Hung-Lin Chen: Conceptualization, Writing- Original draft manu-
script, Figure and Table preparation. Daniel K. Hsu: Writing- Reviewing
and Editing manuscript. Maxwell A. Fung: Writing- Reviewing and
Editing manuscript.
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgements
We thank Dr. Fu-Tong Liu for proofreading the article and providing
insights to the pathogenesis of psoriasis.
This work was supported by the Next-generation Pathway of Taiwan
Cancer Precision Medicine Program (Grant No. ASKPQ-107-TCPMP),
Academia Sinica, Taiwan.
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