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\begin{document}

\title{Curcumin alleviates IMQ-induced dermatitis and regulates gut microbiota
of mice}



\author[1]{Yibing Zeng}%
\author[2]{Zhenguo  Cai}%
\author[3]{wuqing wang}%
\author[2]{Yao Zhang}%
\affil[1]{fudan daxue fushu zhongshan yiyuan minhang fenyuan}%
\affil[2]{Shanghai Central Hospital of Minhang District}%
\affil[3]{Shuguang Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: As a polyphenolic compound originated from the food spice
turmeric, curcumin (CUR) has various pharmacological effects, such as
anti-inflammatory, anti-oxidation, anti-proliferative and
anti-angiogenic activities. Psoriasis is centered on the overproduction
of Th1- and Th2-related cytokines (e. g. IL-23, IL-17, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-22),
which is involved in the occurrence and development of its pathogenesis.
However, whether CUR is involved in the treatment of psoriasis and its
specific mechanisms are not fully understood. Methods: In this study, we
detected the therapeutic effect of CUR (100mg/kg\selectlanguage{ngerman}· d) on IMQ-induced
dermatitis in mice, analyzed by PASI scores, ELISA, HE staining,
immunofluorescence. Moreover, we further confirmed the alteration in the
relative abundance of the gut microbiota through 16sRNA to explore
whether CUR could regulate the gut microbiota of IMQ-induced mice.
Result: Through intragastric administration, CUR can alleviate
psoriasis-like lesions of mice by decreasing PASI scores, reducing the
level of IL-6, IL-17A, IL-22, IL-23, TNF-\selectlanguage{greek}α \selectlanguage{english}and TGF-\selectlanguage{greek}β\selectlanguage{english}1, promoting the
expression of IL-10. Moreover, 16 sRNA sequencing revealed that CUR
could regulate the alteration in the abundance alteration of gut
microbiota related to inflammation, such as Alistipes, Mucispirillum and
Rikenella at genus level. The correlation analysis further confirmed the
close association between important microflora and psoriasis-like
inflammation indicators. Conclusions: CUR exerts the effect of
alleviating dermatitis of psoriatic mice by regulating Th-17 related
inflammatory factors. Moreover, the changes in gut microbiota via CUR
may be another factor of relieving IMQ-induced lesions in mice.
Therefore, CUR may be a highly promising candidate for the treatment of
psoriasis.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Psoriasis is a chronic, immune-mediated skin disease that can be
accompanied by joint involvement. For its high prevalence and the
complexity of causative mechanisms, psoriasis has caused great concern
worldwide {[}1{]}. Its typical clinical manifestations are scales,
erythema, and epidermal thickening. Currently, it is well recognized
that psoriasis results from the complex interaction between
keratinocytes and immune cells {[}2{]}. Many inflammatory factors (e. g.
TNF- \selectlanguage{greek}α, \selectlanguage{english}IL-1 \selectlanguage{greek}β, \selectlanguage{english}IL-23, and IL-12) secreted by Th17 cells, Th1 cells, and
keratinocytes played crucial effects in their pathogenesis {[}3{]}. A
growing body of evidence suggests that psoriasis is closely linked to
multiple co-morbidities, such as systemic inflammation and
cardiovascular comorbidity {[}4{]}. Therefore, psoriasis has gained
significant attention worldwide. However, there are no effective
measures to achieve a cure for psoriasis.

Curcumin is a polyphenolic compound purified and isolated from Curcuma
longa. Since ancient times, turmeric had been considered an herbal
remedy for the treatment of skin and gastrointestinal disorders {[}5{]}.
Now, it is clear that its widespread use in medicine stems from its many
properties, such as antioxidant, anti-inflammatory, anti-proliferative,
anti-cancer and anti-bacterial effects {[}6{]}. It had been demonstrated
that curcumin can reduce various inflammatory factors such as TNF-\selectlanguage{greek}α,
\selectlanguage{english}IFN-\selectlanguage{greek}γ, \selectlanguage{english}IL-22 and IL-23 in mouse serum, which are closely involved in the
pathogenic mechanism of psoriasis {[}7{]}. Meanwhile, curcumin was also
considered as a protective compound that can regulate the intestinal
microflora. Currently, increasing evidence had found that gut microbes
were potentially involved in regulating the progression of a variety of
diseases closely related to inflammation, such as psoriasis, psoriatic
arthritis, inflammatory bowel diseases (IBD) {[}8, 9{]}.

To further confirm our speculation, we found that curcumin could
significantly improve the IMQ-induced mouse model, and reduce the
expression of multiple pathogenic factors in its skin lesions, such as
TNF- \selectlanguage{greek}α, \selectlanguage{english}IL-17, IL-1 \selectlanguage{greek}β, \selectlanguage{english}etc. Furthermore, we analyzed the changes of
intestinal microbiota in mice after curcumin treatment. By using 16s
rRNA technology, this study investigated whether curcumin could exert
its therapeutic effect in psoriasis, which was in relation to the
regulation of intestinal flora.

\textbf{Materials and methods}

\textbf{2.1 Materials}

Imiquimod cream (5\%) was gained from Sichuan Mingxin Pharmaceutical
Corporate, methotrexate was obtained from Chromabio (Chengdu, China).
Anti-PCNA mouse mAb were obtained from Proteintech. All ELISA kits used
in this experiment were purchased from Beyotime.

\textbf{2.2 Experimental sketch}

BALB/c mice (8-10 weeks, 20-22 g) used in this study were gained from
SPF (Beijing) Biotechnology Co., Ltd. All animal experiments were in
accordance with the relevant provisions and obtained the approvement
from The Animal Experiment Committee of Fudan University (Shanghai,
China). The mice were shaved a smooth area of 2 x 3 cm at the back.
Meanwhile, every mouse could acquire enough food and water during
experiment. Their living environment was also dry and comfortable. We
randomly divided the mice into four groups: 1) control (CON, N=4); 2)
imiquimod (IMQ, n=4) treated; 3) methotrexate (MTX, a clinical drug to
treat psoriasis, n=4,) treated; 4) curcumin treated group (CUR, n=4).
Except the CTR group mice, other groups mice were treated topically with
a daily dose of 62.5 mg imiquimod cream every day. The psoriasis-like
model was built after continuous 6 days. MTX treated mice and
CUR-treated mice were treated for the intragastric application with MTX
(1.0 mg/kg\selectlanguage{ngerman}\textbf{·} d) and curcumin (100 mg/kg\textbf{·} d), applied
after 1 day of imiquimod treatment. MTX and CUR were dissolved and
diluted by clean and distilled water. After killed all the mice, the
back skin and intestinal feces were collected for further processing.

\textbf{2.3 H\&E staining and immunofluorescence}

The acquired mice skin tissues were fixed in 4\% paraformaldehyde
solution, and paraffin blocks were treated and stained by
hematoxylin/eosin (HE). For immunofluorescence staining (IFC), main
steps were performed as described previously {[}10{]}. All sections were
examined with laser confocal microsopes (AOSVI, M303-HK830).

\textbf{2.4 ELISA detection of skin tissues inflammatory factors}

After adding the lysate, each collected skin tissue was broken through a
crusher to form a solution. The levels of IL-17, TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β \selectlanguage{english}in mice
skin tissues were assessed by ELISA kits (SAIPEISEN BIOLOGY). The main
steps followed the manufacturer's instructions.

\textbf{2.5 DNA extraction and polymerase chain reaction amplification}

Total DNA was extracted from mouse feces using the PowerSoil\selectlanguage{ngerman}® DNA
Isolation kit according to the manufacturer's instructions. After
extraction, the 16S full-length primer was designed according to the
conservative region 27F-1492R, for polymerase chain reaction (PCR)
amplification of the target area (10\selectlanguage{greek}μ\selectlanguage{english}L system, Solexa PCR). The
synthesized specific primers (27F-1492R) were designed as follows:
Forward primer 27F: AGRGTTTGATYNTGGCTCAG; Reverse primer 1492R:
TASGGHTACCTTGTTASGACTT.

\textbf{2.6 Sequencing and data analysis}

Quality inspection was performed on the formed sequencing library, and
processing, including barcode recognition, was performed on the
high-quality circular consensus sequencing (CCS) sequence obtained. The
generated optimization CCS was clustered at the level of 97\% similarity
(USEARCH, version 10.0), and its species classification was obtained
based on the sequence composition of the operational taxonomic unit
(OTU). The platforms 16S: Silva database and RDP Classifier were used to
analyze species annotation and taxonomy as well as the diversity of gut
microbiota.

\textbf{2.7 Statistical analysis}

All data in this study were processed with the GraphPad Prism 7.0, which
has been showed as the mean \selectlanguage{ngerman}± SD. Statistical significance of all data
was examined by one-way analysis of variance (ANOVA).

\textbf{3.Results}

\textbf{3.1 Curcumin inhibits psoriasis-like skin lesions induced by
IMQ}

To further clarify the regulatory effect of CUR on psoriasis, we
constructed psoriasis-like skin lesions induced by IMQ (Figure. 1A). As
shown in Figure.1B-D, PASI scores were largely increased in IMQ-induced
mice than in control mice. CUR could significantly decrease PASI scores
and epidermal thickness in affected lesions of IMQ-induced mice (Figure.
1B-E). Therefore, CUR could relieve the IMQ-induced mouse skin lesions
and reduce the PASI scores in the affected areas.

\textbf{3.2 CUR ameliorate the morphology changes of psoriasis-like
dermatitis in mice}

We further processed the skin tissues collected from all groups of mice
for HE staining and IFC staining. The results showed that oral curcumin
alleviated IMQ-induced dermatitis in mice, such as parakeratosis,
erythema, and infiltrating inflammatory cells (Figure. 2A). Moreover,
PCNA was a highly proliferative marker of keratinocytes at psoriatic
lesions {[}11{]}. The IFC results showed that CUR significantly
decreased the expression of PCNA in the back skin of model mice (Figure.
2B). Thus, the data revealed that CUR can markedly inhibit
over-proliferating keratinocytes in IMQ-induced lesions of mice.

\textbf{3.3 CUR regulates the inflammatory indicators associated with
psoriasis-like lesions in mice}

To further explore whether CUR regulates the inflammatory responses
induced by IMQ, we explored the expression levels of multiple
inflammatory indicators in mouse skin lesions by ELISA kit. As shown in
Figure. 2C-D, CUR can significantly the epidermal expression levels of
IL-6, IL-17A, IL-22, IL-23, TNF-\selectlanguage{greek}α, \selectlanguage{english}TGF-\selectlanguage{greek}β\selectlanguage{english}1 compared with IMQ group. In
addition, the expression levels of IL-10 in CUR group were higher than
in the IMQ group (Figure. 2C). The results demonstrated that CUR can
repress the expression of inflammation factors related to psoriasis
onset and development.

\textbf{3.4 CUR reshapes the intestinal microflora composition of mice}

Next, we further investigated the effect of CUR on the intestinal
microbiota of mice. We examined the V3 and V4 regions within the 16sRNA
of all mouse gut microbiota, and the rarefaction curves showed extremely
high coverage in every sample (Figure. 3A). From the principal
coordinate analysis (PCoA) results, we found a significant separation of
the microflora distribution between groups CON, IMQ and CUR (Figure.
3B). After analyzing the flora diversity among the CON, IMQ and CUR
groups, Simpson and Shannon index showed that the CON and CUR groups
were significantly higher than the IMQ group (Figure. 3C-D). Moreover,
the analysis of the microflora diversity results showed that it mainly
included 10 classes: \emph{Bacilli} , \emph{Clostridia}
,\emph{Bacteroidia} , \emph{Desulfovibrionia} , \emph{Deferribacteria}
,\emph{Campylobacteria} , \emph{Saccharimonadia} , \emph{Coriobacteriia}
,\emph{Gammaproteobacteria} , \emph{Alphaproteobacteria} (Figure. 4A).

For further exploring these data, we performed high dimensional analysis
by line discriminant analysis effect size (LEfSe) that determined
significant differences in the main flora between CON, IMQ and CUR
groups. The dominant flora was Lactobacillus at the genus level IMQ
group, which we speculated is due to reduced diversity of microflora.
The CUR group showed the dominant flora were\emph{Mucispirillum}
\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}\emph{unclassified\_desulfovibrionaceae} at the genus level, while
\emph{Deferribacters} , \emph{Desulfovibrionia} at the class level. The
CON group revealed that the predominant flora was\emph{Ruminococcaceae}
at the family level (Supplementary Figure. 1A-B).

Subsequently, we performed Kruskal-Wallis test to detect the microflora
differences between the three groups. Compared with CON and CUR groups,
the relative abundance of \emph{Bacilli} at the class level was marked
increased in IMQ group, while the result of \emph{Desulfovibrionia} was
contrary (Figure. 4B-C). Moreover, compared with IMQ group, the relative
abundances of clostridia, \emph{Deferribacteres} at the class level were
significantly promoted in the CUR group, while the result
of\emph{Saccharimonadia} was opposite (Figure. 4B-C). Ultimately, at the
genus level, the abundance of \emph{Alistipes} , \emph{Mucispirillum}
,\emph{Rikenella} in CON and CUR groups was markedly higher than in the
IMQ group (Figure. 5A-D).

\textbf{3.5} \textbf{Changed intestinal microflora by CUR was associated
with psoriasis-related factors}

To further understand the role of altered gut microbiota by CUR and its
connections with psoriasis, we treated psoriasis-related inflammation
indicators as a variable by spearman correlation analysis at the genus
level based on OTU abundance, presented with a heatmap. As shown in
Figure.6A, \emph{Ligilactobacillus} and \emph{Anaeroplasma} (inhibited
in CUR mice) were positively correlated with multiple psoriasis-related
factors, such as IL-6, IL-17A, IL-22, Il-23, while \emph{Rikenella,
Alistipes,} and \emph{Mucispirillum} (promoted in CUR mice) were
negatively correlated with them. These results indicated that the gut
flora changes induced by CUR are associated with the inflammatory
factors in psoriasis.

\textbf{Discussion}

Psoriasis is well recognized as a chronic inflammatory disease prone to
recurrent attacks. Its typical symptoms are well-demarcated erythema and
skin scales accompanied with systemic symptoms {[}12{]}. Curcumin, as a
polyphenolic compound stemmed from turmeric, owns multiple
pharmacological effects, comprising anti-inflammatory,
anti-proliferative, antioxidant, and anti-angiogenic activities
{[}13{]}.

It is well known that the typical histological changes of psoriasis show
excessive proliferation of keratinocytes and infiltration of
inflammatory cells, increased PCNA in skin lesions, and elevation of
various inflammatory factors, such as IL-6, IL-17A, IL-22, IL-23, IL-1\selectlanguage{greek}β\selectlanguage{english}
{[}14, 15{]}. We found that CUR could significantly alleviate
IMQ-induced psoriasis-like dermatitis, decreasing lesion thickness of
mice, inflammatory cell infiltration, dyskeratosis, and spinous layer
hypertrophy. In additions, CUR could inhibit the levels of PCNA in the
epidermis of IMQ-induced mice, and the epidermal expression of IL-6,
IL-17A, IL-22, IL-23, TNF-\selectlanguage{greek}α, \selectlanguage{english}TGF-\selectlanguage{greek}β\selectlanguage{english}1. Thus, the results revealed a
possible effective mechanism of CUR against psoriasis-like dermatitis
induced by IMQ.

Recently, reports had shown that the occurrence and development of
psoriasis were closely associated with intestinal microbiota, and some
pro-inflammatory gut microbes promoted Th1/Th17 activation in psoriasis,
which then could cause the expression of various inflammatory factors in
the epidermis, such as IL-17 and TNF-\selectlanguage{greek}α\selectlanguage{english} {[}16{]}. Therefore, the
intestinal microbiota can be regarded as a potential therapeutic target
for alleviating psoriasis. Meanwhile, it had been shown that CUR can
participate in the regulation of intestinal microbiota {[}17{]}. Taken
together, we reasoned that CUR reshaped the diversity of the mouse gut
microbiota.

To further investigate the supposition, we detected the effect of CUR on
intestinal flora by using 16S rRNA sequencing. Remarkably, we found that
the abundances of genus \emph{Alistipes} , \emph{Rikenella}
and\emph{Mucispirillum} were promoted in CUR group. The researchers
found that \emph{Alistipes} and \emph{Odorbacter} were positively
correlated with intestinal acetate and propionate production, which
inhibits the inflammatory activity of inflammatory bowel diseases (IBD)
{[}18{]}.\emph{Rikenella} had been shown to be associated with the
formation of short-chain fatty acids (SCFAs). It had been reported that
the intestinal microflora and its metabolites can catabolize
polysaccharides to produce SCFAs. SCFAs can maintain the intestinal
barrier function, which is important for intestinal homeostasis. SCFAs
not only maintained the cellular barrier but also prevented the transfer
of LPS from the intestinal barrier {[}19{]}. Moreover, the abundance
of\emph{Mucispirillum} positively correlated with the concentration of
the inflammatory suppressor IL-10 in breast cancer model mice {[}20{]}.
Interestingly, \emph{Lactobacillus} at the genus level was increased,
which was probably due to the decreased diversity of gut microbiota of
mice in the IMQ group.

Taken together, although there was no direct evidence to demonstrate
that the gut flora changes induced by CUR linked with psoriasis, these
bacteria were associated with inflammation. Furthermore, Moreover, the
correlation analysis further showed a significant association between
the three picked gut microflora at genus level regulated by CUR and
inflammatory factors. We thought that there was a close connection
between them. Therefore, inflammation served as an important role to
connect CUR, psoriasis, and intestinal microbiota together. To be brief,
CUR could relief psoriasis-like lesions of mice by repressing Th-17
related inflammatory factors, and regulate intestinal microbiota
associated with inflammation, showing CUR may be a promising drug for
alleviating psoriasis.

\textbf{Conflict of Interest}

The authors have no any conflicts of interest to declare.

\textbf{Author Contributions}

ZC, WW, and YZ designed and guaranteed the whole experiment studies; ZC,
WW carried out all the experiments, ZC and YZ analyzed the statistical
data, ZC, WW and YZ drafted the manuscript; ZC, YZ edited and revised
the whole manuscript; all authors read and approved the final
manuscript.

\textbf{Sources of Funding}

The work in this study was supported by the grant of Natural Science
Foundation of Shanghai (YKHHFX01190408) and High-level Backbone
Physicians Training Program of Minhang District (2020MZYS18).

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