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\begin{document}

\title{Effect of gut flora mediated-bile acid metabolism on intestinal immune
microenvironment}



\author[1]{Yan Zhang}%
\author[1]{Xueyan Gao}%
\author[1]{Yudi Feng}%
\author[2]{Yang Liu}%
\author[1]{Shuochen Gao}%
\author[1]{Liping Pei}%
\author[1]{Wenkang Wang}%
\author[1]{Zhenqiang Sun}%
\author[1]{Lin Liu}%
\author[1]{Chengzeng Wang}%
\affil[1]{The First Affiliated Hospital of Zhengzhou University}%
\affil[2]{Henan Cancer Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
According to reports, gut microbiota and metabolites regulate intestinal
immune microenvironment. In recent years, an increasing number of
studies reported that bile acids (BAs) of intestinal flora origin
affects T helper cells and Treg cells. Th17 cells play a
pro-inflammatory role and Treg cells usually act an immunosuppressive
role. In this review, we emphatically summarized the influence and
corresponding mechanism of different configurations of the LCA and DCA
on intestinal Th17 cells, Treg cells and intestinal immune
microenvironment. The regulation of BAs receptors G protein-coupled bile
acid receptor 1 (GPBAR1/TGR5) and farnesoid X receptor (FXR) on immune
cells and intestinal environment are elaborated. Furthermore, the
potential clinical applications above were also concluded in three
aspects. These above will help researchers better understand the effects
of gut flora on the intestinal immune microenvironment via BAs and
contribute to the development of new targeted drugs.%
\end{abstract}%



\sloppy


\textbf{Effect of gut flora mediated-bile acid metabolism onintestinal
immune microenvironment}

Yan Zhang\textsuperscript{1+*}, Xueyan Gao\textsuperscript{1,2+}, Yudi
Feng\textsuperscript{1},Yang Liu\textsuperscript{3}, Shuochen
Gao\textsuperscript{1}, Liping Pei\textsuperscript{1}, Wenkang
Wang\textsuperscript{5}, Zhenqiang Sun\textsuperscript{4*}, Lin
Liu\textsuperscript{1,2*}, Chengzeng Wang\textsuperscript{1,2*}

\textsuperscript{1}Department of Ultrasound, The First Affiliated
Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.

\textsuperscript{2}Henan Institute of Interconnected Intelligent Health
Management, The First Affiliated Hospital of Zhengzhou University,
Zhengzhou 450052, Henan, China.

\textsuperscript{3}Department of Radiotherapy, Affiliated Cancer
Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou
450008, China.

\textsuperscript{4}Department of Colorectal Surgery, The First
Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan,
China.

\textsuperscript{5}Department of Breast Surgery, The First Affiliated
Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.

\textsuperscript{+}Equal contributors.

\textsuperscript{*}Corresponding author: Chengzeng Wang, E-mail:
czw202112@zzu.edu.cn;

Yan Zhang, E-mail: fcczhangy@zzu.edu.cn;

Lin Liu, E-mail: liulin@zzu.edu.cn;

Zhenqiang Sun, E-mail: fccsunzq@zzu.edu.cn

\textbf{Running title: Bile acids regulate immunocytes}

\textbf{Highlights:}

1. Intestinal flora enzymes metabolize small molecules of bile acid.

2. Multiple configurations of bile acids regulate Th17 and Treg cells
and affect the intestinal immunity.

3. Bile acid molecules regulate the intestinal immune microenvironment
by activating or inhibiting FXR and TGR5 in immune and intestinal
epithelial cells.

4. Agonists and antagonists targeting FXR and TGR5 show great promise
for alleviating intestinal inflammation and treating tumors.

\textbf{Abstract:}

According to previous reports, the gut microbiota and metabolites
regulate the intestinal immune microenvironment. In recent years, an
increasing number of studies have reported that bile acids (BAs) of
intestinal flora origin affect T helper and Treg cells. Th17 cells play
a pro-inflammatory role and Treg cells usually play an immunosuppressive
role. In this review, we summarize the influence and corresponding
mechanism of different configurations of LCA and DCA on intestinal Th17
cells, Treg cells, and the intestinal immune microenvironment. The
regulation of BAs receptors G protein-coupled bile acid receptor 1
(GPBAR1/TGR5) and farnesoid X receptor (FXR) in immune cells and the
intestinal environment is elaborated. The potential clinical
applications described above were also concluded in three aspects. These
findings will help researchers to better understand the effects of gut
flora on the intestinal immune microenvironment via BAs and contribute
to the development of new targeted drugs.

\textbf{Keywords:} Metabolism, G protein-coupled bile acid receptor 1
(GPBAR1/TGR5), Farnesoid X receptor (FXR), Th17 cells, Treg cells.

\textbf{Introduction}

The gastrointestinal tract is an important immune organ containing
numerous immunocytes. In recent years, research on the intestinal immune
microenvironment has become increasingly extensive and in-depth, and the
imbalance of this environment is closely related to many diseases, such
as cancer \textsuperscript{1}, digestive system
diseases\textsuperscript{2}, metabolic diseases \textsuperscript{3},
nervous system diseases \textsuperscript{4}, respiratory system
diseases\textsuperscript{5}, endocrine system diseases
\textsuperscript{6}, etc.

Intestinal flora metabolism and gut immune microenvironment are closely
related. The intestinal flora transforms or modifies dietary components
into small-molecule metabolites, which influence the phenotype and
function of immunocytes \textsuperscript{7}. Recently, researchers have
explored how BAs and their derivatives regulate the development and
function of Th17 and Treg cells in the gut\textsuperscript{8} . The BA
receptors TGR5 and FXR are widely expressed in various immune and
gastrointestinal epithelial cells. Researchers have identified natural
agonists for both receptors and developed artificial agonists. Progress
has been made in studying their regulatory effects in diseases, such as
liver ischemia-reperfusion(I/R) and bowel cancer\textsuperscript{9,10}.

\textbf{The intestinal mucosal immune microenvironment}

The human intestinal immune barrier contains several lines of defense,
including the intestinal mucosal barrier, gut-associated lymphoid tissue
(GALT), and intestinal commensal microbiota\textsuperscript{11,12}. The
intestinal mucosal lamina propria contains a wide variety of
immunocytes, such as B cells\textsuperscript{13}, T
cells\textsuperscript{14}, dendritic cells (DC) \textsuperscript{15}and
macrophages\textsuperscript{16}. In the gut, GALT and local lymph nodes
provide sites to initiate adaptive immune responses. Effector
immunocytes disperse throughout the lamina propria and
epithelium\textsuperscript{17}. Intestinal flora exist widely in the
human gut and can directly resist exogenous pathogens or regulate the
immune system, thereby maintaining the health of the
intestine\textsuperscript{18}.

\textbf{Metabolism of BAs by intestinal flora}

The intestinal microecosystem functions as a barrier for protection,
nutrition, and metabolism. Not only do metabolites provide energy and
nutrition for gut microbiota growth and reproduction, but they also
influence the physiology of the host\textsuperscript{19,20}. Intestinal
flora metabolites include SCFAs (butyrate, propionate, and
acetate)\textsuperscript{21-23}, amino acids\textsuperscript{24},
vitamin\textsuperscript{25,26} and BAs\textsuperscript{27}. Primary BAs
(PBA) are synthesized in the liver and conjugated to taurine or glycine
before secretion into bile. A small portion of BAs is transformed into
secondary BAs (SBAs) by microbiome\textsuperscript{28}. Some of these
modified BAs are reabsorbed and exert signaling functions in the
host\textsuperscript{29}. Gut microbiota generates cholic acid(CA) and
chenodeoxycholic acid(CDCA) through deconjugation\textsuperscript{30}.
Gut microbiota encodes enzymes that exert a 7\selectlanguage{greek}α-\selectlanguage{english}dehydroxylation reaction.
After dehydroxylation, CA becomes DCA, whereas CDCA is converted to
LCA\textsuperscript{31}. CDCA can be converted to ursodeoxycholic acid
(UDCA) by HSDH\textsuperscript{32}. DCA, LCA, UDCA, and their
derivatives have different effects on Treg or Th17 cells, which will be
elaborated in the following essay.

\textbf{Microbiota influence intestinal immune}

Many intestinal flora species exist in the human gastrointestinal
tract\textsuperscript{33}, and the intestinal mucosal immune system
responds reasonably well to food antigens and commensal
bacteria\textsuperscript{34}. Local immunocytes must resist pathogenic
pathogens and maintain their immune tolerance to beneficial
microorganisms\textsuperscript{35} . Studies have shown that metabolites
mediate communication between the commensal microbiota and host immune
system by shaping the composition and function of colonic
immunocytes\textsuperscript{8,27}.

First, gut microbes promote the maturation of the host immune system.
Among these, B. thetaiotaomicron has the most important impact on the
immune system\textsuperscript{36}. It induced immune system maturation
similar to that induced by the conventional microbiota. It increased
Foxp3 expression in the mouse colon, and genes such as IL-10, TGF\selectlanguage{greek}β, \selectlanguage{english}and
PDCD1, and functions in Treg pathways were also upregulated. Second, the
gut microbes regulate the immune system. The lack of bifidobacteria is
associated with systemic inflammation and dysfunctional immunity in
early life \textsuperscript{37}. The transplantation of special
microbiota restores the balance between retinoic acid receptor-related
orphan nuclear receptor-\selectlanguage{greek}γ\selectlanguage{english}t (ROR\selectlanguage{greek}γ\selectlanguage{english}t+)~Treg cells and Th17 cells in
mice\textsuperscript{38}. ~Some studies have proposed that
microorganisms affect immunity through specific molecules such as
PSA\textsuperscript{39}. Mager et al. found that intestinal B.
pseudolongum enhances the immunotherapy response by inosine, which
requires T cells to express adenosine A2A receptors and requires
costimulation\textsuperscript{40}. The influence of commensal bacteria
on the host and the direct or indirect regulation of intestinal
immunocytes are indispensable to stabilize the intestinal immune
microenvironment.

\textbf{Gut bacteria regulates Treg and Th17 cells---mediated by BAs
metabolism}

Resident microbiota exert direct or indirect effects on Treg and Th17
cells at the cellular and molecular level \textsuperscript{41}(Fig. 1).
BAs are important bacterial metabolites that function as T cell
modulators\textsuperscript{42}. Some BAs are implicated as endogenous
etiologic agents, whereas other BAs confer resistance to pathogens, such
as Clostridium difficile \textsuperscript{43,44}. The role of BAs in
immunity has been increasingly studied, and more intrinsic mechanisms
are being discovered. BAs exert their influence mainly through
activation of TGR5, FXR, and vitamin D receptor
(VDR)\textsuperscript{45}.

\textbf{5.1 Treg cells}

Intestinal health requires Treg cells to exert an immunosuppressive
function\textsuperscript{46}. Forkhead box P3 (Foxp3+) is a
transcription factor of Treg cells\textsuperscript{27}. Induced
extrathymically by dietary or antigens from
commensals\textsuperscript{47}, Foxp3 is involved in the differentiation
and function of Treg cells \textsuperscript{27}. Conserved non-coding
sequences (CNS1-CNS3) regulate Foxp3 gene expression by interacting with
different transcription factors\textsuperscript{48}. Foxp3-expressing
Treg cells are vital in the prevention of autoimmunity and maintenance
of immune homeostasis, and dysregulation of Treg cells is also a
potential oncogenic factor\textsuperscript{49}. Gut-resident Foxp3+CD4+
Treg cells exhibit gut-specific phenotypes and
functions\textsuperscript{50}.

Hang et al. found that BAs metabolites directly modulate the Th17/Treg
balance in the intestinal lamina propria \textsuperscript{8}. The energy
resources of Treg cells mainly originate from oxidative
phosphorylation\textsuperscript{51}. The results showed that as a
derivative of LCA, isoalloLCA increases mitochondrial reactive oxygen
species (mitoROS), increases the formation of an open chromatin
structure, and promotes H3K27ac at the Foxp3 promoter region to increase
Foxp3 expression in Treg cells\textsuperscript{8}\textbf{.} This process
also requires TGF-\selectlanguage{greek}β-\selectlanguage{english}induced signaling (Fig. 1). Bacterial-derived small
molecules such as butyrate and vitamin A derivatives increase Foxp3
expression in Treg cells depending on CNS1, and isoalloLCA enhances
Foxp3 expression requires CNS3 \textsuperscript{8}. The differentiation
of Th17 cells can be initiated by IL-6 and TGF-\selectlanguage{greek}β, \selectlanguage{english}and ROR\selectlanguage{greek}γ\selectlanguage{english}t expression
requires CNS6 and CNS9\textsuperscript{48}. Studies of Foxp3 and ROR\selectlanguage{greek}γ\selectlanguage{english}t
expression and related regulatory molecules have provided us with a
deeper understanding of the activities of Treg and Th17 cells.
Transcription factor NR4A1, a key regulator of T cell dysfunction, is
stably expressed at high levels in tolerant T cells. Its overexpression
inhibits the differentiation of effector T cells, and NR4A1 deletion
enhances anti-tumor immunity\textsuperscript{52}. Li et al. showed that
NR4A1 is required for isoalloLCA-mediated differentiation of Treg
cells\textsuperscript{42}. IsoalloLCA treatment increased the binding of
NR4A1 to the Foxp3 locus and promote Foxp3 gene transcription in a
CNS3-dependent manner. These results indicate that isoalloLCA can exert
immunosuppressive effects through NR4A1 in the intestinal tract, which
may affect local intestinal immunity and lead to tumors and other
diseases.

ROR\selectlanguage{greek}γ\selectlanguage{english}t belongs to the family of nuclear receptors and is an intracellular
transcription factor \textsuperscript{53}. Many colonic CD4+FoxP3+~Tregs
express Ror\selectlanguage{greek}γ \selectlanguage{english}\textsuperscript{54}. Helios and Nrp1 are markers of
thymus-derived Tregs, and are absent in colonic ROR\selectlanguage{greek}γ\selectlanguage{english}+~Tregs. Colonic
Treg cells express higher levels of Vdr than splenic Treg cells,
especially ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cells\textsuperscript{29}. VDR is a
ligand-dependent nuclear transcription factor that regulates cell
proliferation and differentiation \textsuperscript{55}. The removal of
VDR in Treg cells induces severe enteritis via DSS\textsuperscript{29}.
Song et al. showed that some intestinal PBAs, such as CA, CDCA, and
UDCA, as well as some SBAs species, such as LCA and 3-oxo-LCA, modulate
ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cells through the BAs receptor VDR \textsuperscript{29}(Fig.
1). The regulation of ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cells by VDR in colon tissue cells is
not mediated by DC or epithelial cells that have high VDR expression but
is inherently regulated by ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cells\textsuperscript{29}. It can
be speculated that changes in VDR genes or intestinal metabolites lead
to heterogeneity in intestinal Treg cells and cause diseases, such as
inflammation or tumors. Song et al. found that a combination of
LCA/3-oxo-LCA restored colonic ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cell counts; however, a
similar effect was not found in colonic Th17 cells\textsuperscript{29}.
The modulatory function of BAs on Treg cells is limited to specific
cells and tissue types. Interestingly, at the onset of colitis, BAs
supplementation increased ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cell counts. After the onset of
colitis, BAs supplementation barely alleviated the colitis. This
phenomenon indicates that maintaining the ROR\selectlanguage{greek}γ\selectlanguage{english}+ Treg cell pool by BAs
during homeostasis affects the treatment effect in host DSS colitis.

DC is antigen presenting cells\textsuperscript{56}. They process
antigens, secrete cytokines and chemokines, and induce and maintain an
immune tolerance\textsuperscript{57}. Campbell et al. found that SBAs
isoDCA induced Foxp3 by influencing FXR and reducing immunostimulatory
functions of DCs \textsuperscript{27}, ablating FXR in DCs increased the
number of Treg cells, and the transcriptional profile in DCs resembled
that induced by isoDCA \textsuperscript{27}(Fig. 1). Furthermore,
consortia that produce isoDCA increase colonic ROR\selectlanguage{greek}γ\selectlanguage{english}t+ Treg cells, and
this effect relies on CNS1. However, isoDCA did d not affect Th17 cell
generation. This study found that the FXR of myeloid cells influences
the induction of pTreg cells; however, more information concerning
immunocytes and BA-sensing receptors that mediate the effects of BAs on
the mucosal immune environment deserves further study.

\textbf{5.2 Th17 cells}

Th17 cells are CD4+T cells that secrete cytokines, such as IL-17, IL-21,
and IL-22 \textsuperscript{58}. On the one hand, Th17 cells resist
pathogens such as fungi, maintain the immune barrier integrity of
digestive tract\textsuperscript{59}. However, excessive inflammatory
induction by Th17 cells leads to various disease \textsuperscript{60},
such as experimental autoimmune diseases and human inflammatory
conditions \textsuperscript{59}.

After culturing with the LCA + E. lenta DSM2243 (3\selectlanguage{greek}α \selectlanguage{english}HSDH+) supernatant,
the differentiation of naive CD4+ T cells into Th17 cells was inhibited.
After Citrobacter rodentium significantly induced Th1 and Th17 cells,
3-oxoLCA treatment resulted in decreased Th17 and IFN-\selectlanguage{greek}γ \selectlanguage{english}+Th17 cell
levels in the colon, while Th1 and Treg cells were
unaffected\textsuperscript{61}. LCA processing showed the opposite of
the above results. 3-oxoLCA and isoLCA reduced the differentiation of
Th17 cells by interacting with ROR\selectlanguage{greek}γ\selectlanguage{english}t and inhibiting its transcriptional
activity\textsuperscript{8,61}(Fig. 1). Notably, isoalloLCA reduced the
differentiation of Th17 cells without affecting ROR\selectlanguage{greek}γ\selectlanguage{english}t expression and did
d not impair cell viability\textsuperscript{8}. The regulatory effects
of 3-oxoLCA and isoalloLCA on Th17 and Treg cells did not affect
intestinal commensal bacteria; they directly regulated Th17 and Treg
cells in mice. However, these metabolites are not present in germ-free
mice, implying that the production of these metabolites needs
commensals\textsuperscript{8}. More studies are needed to determine the
identity of gut-residing bacteria and the corresponding enzymes that
convert LCA into 3-oxoLCA and isoLCA \textsuperscript{61}. It has been
shown that 3\selectlanguage{greek}β-\selectlanguage{english}HSDH encoded by BF3538 in B. fragilis enables the
production of isoLCA; 3\selectlanguage{greek}α-\selectlanguage{english}HSDHs encoded by Elen\_0690 and its homologues
in E. lenta strains are required for 3-oxoLCA. The researchers used
3\selectlanguage{greek}α-\selectlanguage{english}HSDH and 3\selectlanguage{greek}β-\selectlanguage{english}HSDH positive and negative bacteria as tools to study the
effects of the two LCA derivatives on TH17 cells. The study of the genes
encoding various metabolism-related enzymes in the strain will help
clarify the link between the intestinal flora and immune cells. It
provides a reference for the development of engineered bacteria, which
benefits scientific research and treatment of diseases.

Studies have shown that UDCA decreases Th17 cells and IL-17 via the
pAMPK-SMILE pathway\textsuperscript{62}(Fig. 1). This revealed the role
of UDCA in regulating the balance between Th17 and Treg cells. BAs were
cytotoxic to cells at high concentrations (\textsuperscript{63}. CD4+ T
effector cells (Teff cells) include Th1 cells that produce
interferon-gamma (IFN\selectlanguage{greek}γ\selectlanguage{english}) and Th17 cells, and studies have shown that the
relationship between BAs and Teff cells, conjugated bile acids (CBA),
drives oxidative stress in Teff cells and kills transformed epithelial
cells. The xenobiotic transporter Mdr1, which is induced by CD103+ DCs,
enforces T cell homeostasis in the presence of
CBA\textsuperscript{64}(Fig. 1). Abnormal concentrations of BAs affect
the activity of T cells, and the interaction between DC and T cells can
resist adverse effects, while changes in related genes are not conducive
to the maintenance of normal homeostasis.

\textbf{Gut flora need special enzymes and BAs conformations to regulate
immunocytes}

Diet directly controls the liver synthesis of BAs, whereas the gut flora
and host mainly control the modification process of BAs in the gut. The
appearance of SBAs in stool is the major difference between
conventionalized and germ-free mice \textsuperscript{36}. The overall
concentration of BAs in mice mono-colonized with gut microflora (E. coli
and B. thetaiotaomicron) was higher, and SBAs were not detected. This
indicates that the metabolism of PBAs requires special bacteria, and
different gut microflora have their respective metabolic activities.
Ridlon et al. also concluded that bile salt hydrolysis and hydroxy group
dehydrogenation reactions are induced by extensive intestinal
anaerobes\textsuperscript{65}. However, BAs 7-dehydroxylation is
restricted to a small part of intestinal anaerobes\textsuperscript{66}.

Clostridium scindens has been widely used to convert PBAs into both LCA
and DCA in previous studies. However, an established multi-strain also
produces SBAs without this strain because Extibacter sp. GGCC\_0201
provides a 7-dehydratase that converts CA and CDCA into DCA and LCA
respectively \textsuperscript{67}. This suggests that specific enzymes
are indispensable for bacterial metabolic activity. Human gut bacteria
that convert LCA into 3-oxoLCA and related genes that encode
3\selectlanguage{greek}α-/\selectlanguage{english}3\selectlanguage{greek}β-\selectlanguage{english}HSDHs are negatively associated with Crohn's Disease (CD) in
humans\textsuperscript{61}. The generation of isoDCA requires some key
enzymes; researchers constructed several bacterial strains with key
enzymes and produced a large amount of isoDCA, which also excluded
bacterial strain backgrounds\textsuperscript{27}. Building strains that
metabolize specific molecules is a strong indication of the centrality
of enzymes and proves the operability of developing therapeutic
approaches.

IsoalloLCA enhanced FOXP3 expression, while other LCA isomers did not
show the same effect, indicating that both the 3\selectlanguage{greek}β-\selectlanguage{english}hydroxyl group and
trans (5\selectlanguage{greek}α-\selectlanguage{english}hydrogen) A--B ring configuration of isoalloLCA are required
to regulate Treg cells \textsuperscript{8}. Paik et al. observed that
isoLCA inhibited naive CD4+ T cells to differentiate into Th17 cells as
efficiently as 3-oxoLCA, whereas isoDCA, which is abundant in 3\selectlanguage{greek}β-\selectlanguage{english}OH, did
not inhibit differentiation\textsuperscript{61}. Campbell et al.
reported that the spatial orientation of specific hydroxyl (-OH) groups
is vital for isoDCA and \selectlanguage{greek}ω-\selectlanguage{english}MCA to exert effects\textsuperscript{27}.
Therefore, microbial epimerization and specific spatial conformations
bring about the unique properties of BAs to regulate immunity.

\textbf{Roles of TGR5 and FXR in immune cells and intestinal epithelial
cells}

TGR5/GPBAR1 is a receptor located on the cell membranes of cells in the
gallbladder, ileum, colon, and liver. FXR is a nuclear receptor involved
in the regulation of BAs and lipid homeostasis. There are many studies
on the influence of receptor activation on the immunocytes of the body.

7.1 Macrophage

7.1.1 TGR5

As important anti-tumor immune cells, macrophages have the ability to
chemotaxis, phagocytosis, antigen presentation, and secretion of
cytokines. The effect of TGR5 on macrophages has been extensively
studied in organ (I/R) injury, IBD, and liver disease; however, it has
been less studied in tumors.

BAR501 is an agonist of GPBAR1, and LPS-induced elevation of M1 markers
(CD38, Fpr2, and Gpr18) was reversed after treatment with BAR501(Fig.
2). Moreover, BAR501 up-regulates the markers of M2 (Egr2 and
c-myc)\textsuperscript{68}. TGR5-deficient BMDMs showed higher levels of
the M1 markers iNOS and IL-6 and lower levels of the M2 markers PPAR\selectlanguage{greek}γ
\selectlanguage{english}and Arg-1\textsuperscript{69}. UDCA enhancement of TGR5 activation is
beneficial for its anti-inflammatory effects and promotes M2
polarization. In vitro experiments showed that TGR5 inhibits macrophage
migration by inhibiting Cat E\textsuperscript{69}. Another study showed
that TGR5 inhibits macrophage migration by inducing the differential
expression of C/EBp-\selectlanguage{greek}β \selectlanguage{english}via the mTOR complex\textsuperscript{70}. The
above studies demonstrated the effect of TGR5 activation on the
macrophage phenotype and migration.

In non-small cell lung cancer(NSCLC), TGR5 promotes the formation of
tumor-associated macrophages (TAMs) by activating the cAMP-STAT3/STAT6
signaling pathway. This inhibits CD8+ T cells and decreases the
production of granzyme B, IFN-\selectlanguage{greek}γ, \selectlanguage{english}and TNF-\selectlanguage{greek}α, \selectlanguage{english}thus inhibiting anti-tumor
immunity \textsuperscript{71}. The phagocytosis of tumor cells by TGR5
deficient macrophages is enhanced; therefore, we can reasonably
speculate that TGR5 reduces the phagocytosis of macrophages. We can
think that in intestinal tumors, the changes in microbiota metabolites,
especially the BA molecules regulating TGR5, may affect the formation of
TAMs, thus unfavorable to anti-tumor effects. In human patients with
NSCLC tissue, TGR5 expression correlates with infiltration of TAMs, and
their high expression is associated with poorer prognosis and shorter
overall survival.\textsuperscript{71} Taurolithocholic acid (TLCA)
inhibits the expression of LPS-induced IL-6, IL-12, TNF-\selectlanguage{greek}α, \selectlanguage{english}and
TNF-\selectlanguage{greek}β\selectlanguage{english}\textsuperscript{72}. The inhibitory effect of TGR5 on IFN-\selectlanguage{greek}β
\selectlanguage{english}expression by cAMPPKA is also reflected by the downregulation of the
IFN-stimulated genes MxA and PKR in human
macrophages\textsuperscript{72}. IFN and T cells have intricate
relationships and studies have shown that IFN-\selectlanguage{greek}β \selectlanguage{english}increases the induction
of Treg cells\textsuperscript{73}. This suggested that the activation of
TGR5 regulates the expression of interferon in macrophages. This
information helps us study the coordination between macrophages and T
cells to exert antitumor effects in the intestinal tumor immune
microenvironment. In microglia, BAs, such as tauroursodeoxycholic acid
(TUDCA) or taurolithocholic acid (TLCA), reduce PKM2 expression and
regulate the glycolytic pathway\textsuperscript{74}. This deepens our
understanding of the energy regulation of BAs.

TCDCA acts on the TGR5 receptor and modulates inflammation through the
cAMP-PKA-CREB signaling pathway. TCDCA reduces inflammatory cytokines,
such as IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, IL-8, IL-12, and TNF-\selectlanguage{greek}α \selectlanguage{english}by affecting NF-\selectlanguage{greek}κ\selectlanguage{english}B
activity\textsuperscript{75}. IBD patients have higher levels of TGR5
expression in intestinal mucosal lamina mononucleus cells (LPMCs), and
TGR5 agonists and BAs (DCA and LCA) inhibit TNF-\selectlanguage{greek}α \selectlanguage{english}production in
macrophages through the TGR5- cAMP pathway. In this pathway, c-Fos
phosphorylation is induced to regulate NF-\selectlanguage{greek}κ\selectlanguage{english}B p65\textsuperscript{76}.
TGR5 inhibited the upregulation of the TLR4-NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway and activation
of Caspase-8 in vivo\textsuperscript{77}. In in vitro
hypoxia/reoxygenation macrophage models, activation of TGR5
downregulates the expression of TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-6, and upregulates the
expression of IL-10\textsuperscript{77}. Another study showed that the
activation of TGR5 alleviates inflammation through the Keap1- Nrf2
pathway. Specifically, it increased the expression of Nrf2 and Ho-1 in
the nucleus, but decreased the expression of Keap1\textsuperscript{9}.
Previous studies have shown that TGR5 inhibits NLRP3 inflammasome
activation and caspase-1 cleavage\textsuperscript{78}. A recent study
found that BA supplementation activated the NLRP3 inflammasome in
macrophages and promoted inflammation under noninflammatory conditions.
However, BA inhibits NLRP3 inflammasomes and reduces inflammation in
LPS-induced inflammatory macrophages\textsuperscript{79}.

7.1.2 FXR

FXR regulates macrophage activation and oxidative stress and contributes
to the anti-inflammatory phenotype and function of
macrophages\textsuperscript{80}. The relationship between the gut
microbiome, BAs, FXR, and NLRP3 inflammasome remains uncertain. Gut
microbiome metabolites act as natural FXR regulatory molecules and BAs
are important components. In turn, FXR alters the BAs and gut microbiome
composition\textsuperscript{81}. BAs activate the NLRP3 inflammasome by
promoting calcium influx, but FXR inhibits the NLRP3
inflammasome\textsuperscript{82}.

Osteoclasts originate in the mononuclear macrophage system, which ich is
a special type of terminally differentiated cell. FXR agonists inhibit
the c-Jun N-terminal kinase (JNK) 1/2/nuclear factor of activated
T-cells 1 (NFATc1) pathway JNK1/2/NFATc1 and alleviate subchondral
osteoclast fusion\textsuperscript{83}. Kupffer cells, which are liver
macrophages, showed decreased TNF-\selectlanguage{greek}α \selectlanguage{english}and increased IL-10 expression with
the activation of FXR by GW4064\textsuperscript{84}. GW4064 increased
FXR binding to the Abcb11 promoter and decreased the expression of genes
related to recruitment and activation of macrophages in the liver. This
is not conducive to the accumulation, activation, and infiltration of
liver macrophages\textsuperscript{85,86}. Loss of nuclear receptors FXR
and SHP leads to YAP activation in mice with unbalanced bile acid
homeostasis and spontaneous liver tumor\textsuperscript{87}.

7.2 DC

The expression of TGR5 is down-regulated during the differentiation of
monocytes into DC. BA-cultured DC produce lower levels of IL-12 and
TNF-\selectlanguage{greek}α \selectlanguage{english}under the stimulation of symbiotic bacterial antigens, which is
mediated by the TGR5-cAMP pathway\textsuperscript{88}. DCA regulated the
function of DC through the TGR5-cAMP-PKA pathway and inhibited the
activation of NF-kB (Fig. 3). DCA decreased the secretion of IL-1\selectlanguage{greek}β,
\selectlanguage{english}IL-6, IL-12, and TNF-\selectlanguage{greek}α \selectlanguage{english}from LPS-induced bone marrow-derived DCs. It is
noteworthy that the expression of the DC co-stimulatory molecules CD40,
CD80, CD86, and MHC II was also inhibited. It is not conducive to T cell
differentiation and Th1 and Th17 cell development, and the secretion of
IL-17 and IFN-\selectlanguage{greek}γ \selectlanguage{english}is reduced \textsuperscript{89}. The discovery that bile
acids regulate T cell differentiation and function through DC suggests
the potential research value of bile acid signaling molecules in the
local immune microenvironment, which is conducive to promoting related
research on inflammatory and tumor diseases, especially intestinal
cancer.

7.3 NKT

Natural killer T (NKT) cells are a special T cell subgroup with both TCR
and NK cell receptors on the cell surface. According to the constancy of
the TCR, NKT cells are divided into types I and II. Type I NKT cells
mainly play an antitumor role, while type II NKT cells can promote the
development of tumors \textsuperscript{90}. Type I NKT cells include
pro-inflammatory NKT1 subsets that produce IFN-\selectlanguage{greek}γ, \selectlanguage{english}and regulatory NKT10
subsets that secrete IL-10. In a mouse model of hepatitis, ablation of
GPBAR1 exacerbated liver damage and resulted in a phenotype of type I
NKT cells biased towards NKT1. While activation of GPBAR1 rescues liver
damage, NKT cells are polarized into NKT10. In addition, GPBAR1
excitation significantly expanded the IL-10-secreting type II NKT cell
subsets\textsuperscript{91}. LCA inhibits hematopoietic stem cell
activation via the Smad pathway (reduces TGF-\selectlanguage{greek}β\selectlanguage{english}) or MAPK-ERK pathway. LCA
increases recruitment of NK cells and reduces activation of NKT cells.
However, the effect of LCA weakened when antibiotics reduced the
diversity and abundance of gut microbes\textsuperscript{92}.

7.4 MDSC

Intravenous infusion of TDCA decreased serum proinflammatory cytokines,
increased the number of granulocyte myeloid suppressor cells (MDSCLTS)
in the spleen of septic mice, and inhibited T cell
proliferation\textsuperscript{93}. Activation of FXR enhances the
immunosuppressive activity of MDSCs on T-cell proliferation by binding
to and upregulating the PIR-B promoter. FXR activation drives the
accumulation of MDSCs in the liver through upregulation of S100A8 mRNA
expression\textsuperscript{94}.

7.5 B cell

Immunoglobulin A (IgA) is present in mucosal tissue and resists the
invasion of pathogens, and its absence leads to intestinal
inflammation\textsuperscript{95}. In PBA-fed rats, IgA levels in the
ileum mucosa were increased\textsuperscript{96}. UDCA belongs to SBAs,
and in in vitro experiments, UDCA inhibits the production of IgM, IgG,
and IgA in peripheral blood monocytes. UDCA also acts on B cells by
suppressing Ig production in human B cells\textsuperscript{97}. The
effects of various BAs on local B cells and mucosal immunity in vivo
warrant further investigation.

7.6 Intestinal epithelial cells

In an oxazolone-induced colitis model, the GPBAR1 agonist BAR501
alleviated the symptoms of enteritis, inhibited inflammatory markers
such as IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6, and IFN-\selectlanguage{greek}γ, \selectlanguage{english}and increased the expression of TGF-\selectlanguage{greek}β,
\selectlanguage{english}IL-10, and Foxp3\textsuperscript{68}. Gut microbiota-BAs-TGR5 Axis is
beneficial for restoring the integrity of the damaged colonic
epithelium\textsuperscript{98}. During organoid growth, TGR5 activation
increases the activation of Yes-associated protein 1 (YAP1) and its
upstream regulator SRC from intestinal stem cells (ISCs). TGR5 activates
ISCs and promotes epithelial cell regeneration, causing them to renew
and proliferate in response to injury\textsuperscript{99}. Another study
indicated that DCA retards wound healing in colon epithelial cells by
activating the AKT pathway via GPCR5\textsuperscript{100}.

Fibroblast growth factor 15/19 (FGF15/19) is a hormone released by ileal
gut cells in response to stimulation by FXR (usually via absorbed BAs)
that provides negative feedback for BAs synthesis in
hepatocytes\textsuperscript{101}. In intestinal epithelial cells, FXR
activates the transcription of intestinal bile acid-binding protein
(I-BABP) and FGF15, both of which regulate key aspects of the liver and
intestinal homeostasis. SHP is a regulatory gene of FXR and the
synthetic ligand of FXR can reduce organ damage and immune cell
activation in vivo. Activation of FXR increased the expression of
I-BABP, FXR, and SHP in the colon and decreased the expression of IL-1\selectlanguage{greek}β,
\selectlanguage{english}IL-6, TNF-\selectlanguage{greek}α, \selectlanguage{english}iNOS, cyclooxygenase (COX)-1, and COX-2 in THP1 cells,
reducing the severity of the disease\textsuperscript{102}.

In mouse models of intestinal tumors and chronic colitis, loss of FXR
promotes Wnt signaling in the intestinal mucosa through neutrophil and
macrophage infiltration and TNF-\selectlanguage{greek}α \selectlanguage{english}production, leading to early death and
increased tumor progression. When activated, FXR induces apoptosis and
clearance of genetically altered cells\textsuperscript{103}. This
suggests that strategies to reactivate FXR expression in colon tumors
may be useful for the treatment of colon cancer. BA-activated FXR not
only increases GLUT2 expression and controls glucose uptake through the
FXR-S1PR2-ERk1/2 signaling cascade but also reduces cell energy
production by inhibiting oxidative phosphorylation\textsuperscript{104}.
In the case of bowel cancer, how FXR regulates tumor growth by affecting
energy is worthy of further investigation. DCA activates the STAT3
signaling pathway, interferes with the gastric microbiome and BA
metabolism, and induces gastrointestinal
metaplasia\textsuperscript{105}. DCA reduces the expression of FXR,
activates the Wnt signaling pathway, increases the levels of \selectlanguage{greek}β-\selectlanguage{english}catenin
and c-Myc, and promotes the proliferation and migration of colon cancer
cells. The FXR agonist GW4064 reduces the proliferation of colon cancer
cells by inhibiting the Wnt signaling pathway\textsuperscript{106}.
These studies suggest a relationship between DCA, FXR, and the Wnt
signaling pathway. The authors highlighted the value of FXR agonists in
intestinal cancers.

\textbf{BAs, immune and disease}

BAs promote the absorption of lipid nutrients in the intestine and act
as signaling molecules. BAs also influence immune homeostasis and energy
utilization. Disorder of intestinal flora and an imbalanced BAs pool
lead to various diseases (Fig. 5).

Intestinal microbiota regulate enteric
virus\textsuperscript{\textbf{107,108}} , norovirus infections are major
causes of gastroenteritis \textsuperscript{\textbf{109}} . ~FXR is
expressed differently in the gut, and the proximal bacterial
biotransformed BAs initiate a type III interferon response and resist
viral infection. Therefore, commensal bacteria inhibit viral infection
of the proximal gut, while promoting viral infection of the distal
gut\textsuperscript{\textbf{110}} . The cause of enteritis is
complex\textbf{.} Studies have shown that dietary astragalus
polysaccharide influences the gut microbiota, metabolites, and Th17/Treg
balance in necrotic enteritis (NE)
chickens\textsuperscript{\textbf{111}} . Primary sclerosing cholangitis
(PSC)-IBD is also a result of a dysregulated Th17/Treg
balance\textsuperscript{112}. IBD is often accompanied by dysregulated
bacterial flora, BAs, and pro-inflammatory factors\textsuperscript{113}.
Genes encoding various metabolism-related enzymes in the gut flora
regulate anti-inflammatory BAs small molecules and their derivatives,
and are negatively correlated with intestinal
IBD\textsuperscript{27,61}.

The intestinal flora and BAs are also closely associated with endocrine
and metabolic diseases. ~ Glycodeoxycholic acid induces ILC3 to secrete
IL-22, which improves the phenotype of Polycystic ovary
syndrome\textsuperscript{114}. Pigs hyocholic acid (HCA) acts on
enteroendocrine cells, activates TGR5, and inhibits FXR to promote the
production and secretion of glucagon-like peptide-1 (GLP-1),
consequently improving glucose homeostasis and avoiding diabetes
\textsuperscript{115}. In mice, feces from patients with coronary artery
disease (CAD) promote intestinal inflammation by disturbing the lamina
propria Th17/Treg cell balance and worsening gut barrier permeability
\textsuperscript{116}. These studies offer a new perspective on the
treatment of metabolic and endocrine system diseases.

Hydrophobic BAs damage intestinal cells and are risk factors for
colorectal cancer (CRC)\textsuperscript{117}. High-fat diet and APC
mutation of WNT signaling change BAs profiles and promote Lgr5+ cancer
stem cell cells (CSC) proliferation and DNA damage\textsuperscript{10}.
However, activation of intestinal FXR limits its growth and suppresses
CRC progression. The role of FXR implicates it as a potential
therapeutic target for CRC. Moreover, DCA and LCA derivatives that
promote Treg cell differentiation and inhibit Th17 cell differentiation
may also cause CRC. Studies on TGR5, FXR, and their activation in
macrophages, DC, NKT cells, MDSC, B cells, and intestinal epithelial
cells also provide references for the exploration of the etiology of CRC
and for better cancer treatment.

\textbf{Clinical applications}

\textbf{9.1 Agonists of TGR5 and FXR}

Progress has been made in the study of the efficacy of natural or
synthetic TGR5 and FXR agonists in the treatment of liver and intestinal
diseases. In an oxazolone-induced colitis model, the GPBAR1 agonist
BAR501 alleviated the symptoms of enteritis and inhibited inflammatory
markers\textsuperscript{68}. GW4064 activates FXR and improves
LPS-induced ileocolitis by inhibiting mitochondrial dysfunction in
mice\textsuperscript{118}. FXR activation also inhibits endoplasmic
reticulum stress and inflammation \textsuperscript{119}. In
tumor-bearing models, the FXR agonist synergistically inhibited the
growth of hepatocellular carcinoma with the anti-PD-1
antibody\textsuperscript{120}. Obeticholic acid (OCA) is a clinically
approved selective FXR agonist and Nanoemulsion-loaded OCA (OCA-NE)
results in increased secretion of CXCL16, IFN-\selectlanguage{greek}γ. \selectlanguage{english}The number of NKT cells
in the tumor increases, resulting in a better liver tumor inhibition
effect. The development of BA receptors, such as TGR5 and FXR agonists,
and the targeted delivery of these drugs have greatly facilitated
precision cancer therapy\textsuperscript{121}. OCA is used to treat
non-alcoholic steatohepatitis (NASH) by inhibiting activation of the
NLRP3 inflammasome\textsuperscript{122}. OCA accelerates the maturation
of mouse intestinal epithelial cells in a constitutive androstane
receptor (CAR)-dependent manner\textsuperscript{123}. Further research
on OCA is necessary to expand its application range. Salvia-Nelumbinis
naturalis (SNN), a traditional Chinese medicine, is effective in the
treatment of NASH. It activates the FXR-FGF15 signaling pathway in the
colon by increasing BA-associated microbiome\textsuperscript{124}.
Research on the regulatory mechanism of traditional Chinese medicine on
hepato-intestinal disease has important implications for better
application of traditional Chinese medicine and the development of new
targeted drugs.

\textbf{9.2 Microbia-based therapy}

For diseases whose pathogenesis involves dysregulation of the intestinal
flora and disruption of the intestinal mucosal barrier, promising novel
therapies are being developed. FMT is a good therapeutic strategy for
treating Clostridioides difficile infection \textsuperscript{125}.
However, its efficacy is limited by the host inflammatory immune
status\textsuperscript{126}. Side effects such as fever and a temporary
increase in C-reactive protein levels after FMT deserves
attention\textsuperscript{67}. Defined bacterial consortia were selected
based on their desired biological functions. Atarashi et al. isolated
Treg cell-inducing bacterial strains \textsuperscript{67}. This strain
alleviates colitis and allergic diarrhea in mice. Using defined
bacterial consortia brings hope for tailoring therapeutic products for
human immune disorders. The appointed combinations of microbes have more
predictable responses, more targeted efficacy, and fewer adverse
responses, such as infection by pathogens.

\textbf{9.3 BAs-based therapy}

Researchers have synthesized LCA 3-sulfate (LCA-3-S) that binds to ROR\selectlanguage{greek}γ\selectlanguage{english}t
and selectively suppresses Th17 cell
differentiation\textsuperscript{127}. UDCA has been used clinically for
many years and has a good curative effect on PSC\textsuperscript{128}.It
also degrade TGF-\selectlanguage{greek}β \selectlanguage{english}and inhibits the differentiation and activation of
Treg cells\textsuperscript{129}, and UDCA enhances the anti-tumor
efficacy of anti-pd-1. Researchers have established a set of steps that
contain the necessary enzymes and engineer them into Clostridium
sporogenes, successfully producing DCA and LCA\textsuperscript{130}.
This also provides us with hope to take advantage of gut flora. Natural
extraction or artificial synthesis of BAs and reasonable combinations of
several kinds to achieve smooth regulation of Th17 and Treg cells is a
promising method for the treatment of IBD and other diseases. However,
drug therapy also needs to consider the condition of the patient's gut
so that it can be tailored to each individual.

\textbf{Conclusion}

Gut microbes are indispensable in the gut, and their metabolic roles
have been widely studied using metabolomics and bacterial profiling. BAs
are metabolized into various configurations by bacteria in the gut and
serve as signaling molecules to regulate immunocytes such as Th17 cells
and Treg cells in the intestine, thereby regulating intestinal immune
balance. The intricate network of relationships among the gut flora,
BAs, immunocytes, and cytokines is closely related to multiple diseases
throughout the body. Therefore, related research will be conducive to
the development of drugs for treating multiple diseases. Research on the
mechanism of the activation effect of TGR5 and FXR in macrophages, DC,
NKT cells, MDSC, B cells, and intestinal epithelial cells contributes to
the development of molecular-targeted drugs. At present, these studies
have mainly focused on liver diseases and ischemia-reperfusion injury.
These results support the possibility of using intestinal microbial
community analysis techniques, metabolomics analysis, and single-cell
sequencing techniques to further explore the immunocyte subgroup
regulated by the intestinal flora in the tumor immune microenvironment.

\textbf{Abbreviations}

Treg cells: regulatory T cells; BAs: bile acids; LCA: Lithocholic acid;
IsoLCA: isolithocholic acid; 3-oxoLCA:3-oxolithocholic acid; DCA:
deoxycholic acid; IsoDCA:3\selectlanguage{greek}β-\selectlanguage{english}hydroxydeoxycholic acid; PSA: polysaccharide
A; GALT: gut-associated lymphoid tissue; DC: Dendritic cell; SCFAs:
short-chain fatty acids; pTreg cells: peripherally induced Treg cells;
IBD: inflammatory bowel disease; Foxp3+: forkhead box P3; MitoROS:
mitochondrial reactive oxygen species; IL-17: interleukin 17;
GPBAR1/TGR5: G protein-coupled BA receptor 1; FXR: farnesoid X receptor;
VDR: vitamin D receptor; Teff cells: T effector cells; CBA: conjugated
bile acids; ROR\selectlanguage{greek}γ\selectlanguage{english}t: RAR-related orphan receptor-\selectlanguage{greek}γ; \selectlanguage{english}IFN\selectlanguage{greek}γ:
\selectlanguage{english}interferon-gamma; CNS: conserved non-coding sequence; UDCA:
Ursodeoxycholic acid; NE: Necrotic enteritis; PCOS: Polycystic ovary
syndrome; ILC3: intestinal group 3 innate lymphoid cell; HCA: hyocholic
acid; GLP-1: glucagon-like peptide-1; CAD: coronary artery disease; CRC:
colorectal cancer; Lgr5+: Lgr5-expressing; PSC: Primary sclerosing
cholangitis; FMT: Fecal microbiota transplantation

\textbf{Additional Information}

\textbf{Acknowledgements}

Not applicable.

\textbf{Authors' contributions}

Y.Z., L.L., and C.W. provided direction and guidance throughout the
preparation of this manuscript. X.G., Y.L., and Z.S. drafted the
manuscript and prepared the figures. S.G., L.P., and Y.F. collected
related references and participated in the discussion. W. W. revised the
manuscript. All authors contributed to the manuscript. All authors have
read and approved the final manuscript.

\textbf{Ethics approval and consent to participate}

Not applicable.

\textbf{Consent for publication}

All authors have approved to publish this manuscript.

\textbf{Data availability}

Not applicable.

\textbf{Competing interests}

The authors declare no conflict of interest.

\textbf{Funding}

This study was supported by The National Natural Science Foundation of
China (81972663, 82173055), Natural Science Foundation of Henan
Province(202300410446, 212300410074), Key Scientific Research Project of
Henan Higher Education Institutions (20A310024), Youth Talent Innovation
Team Support Program of Zhengzhou University (32320290), Provincial and
Ministry co-constructed key projects of Henan Medical Science and
Technology (SBGJ202102134), Key scientific and technological research
projects of Henan Provincial Department of Science and Technology
(212102310117), Health Science and Technology Innovation Project of
Henan Province (YXKC2022016), Henan Provincial Health Commission and
Ministry of Health Co-construction Project, and Henan Provincial Health
and Health Commission Joint Construction Project (LHGJ20200158).

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Fig. 1} The derivatives of DCA and LCA regulate Treg cells and
Th17 cells.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Fig. 2} Activated TGR5 and FXR regulate macrophage and
macrophage regulate T cell differentiation and fuction.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Fig. 3} Activated TGR5 and FXR regulate DC, NKT cells, MDSC, B
cells and intestinal tract/epithelium cells.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

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