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.
Keywords: Metabolism, G protein-coupled bile acid receptor 1
(GPBAR1/TGR5), Farnesoid X receptor (FXR), Th17 cells, Treg cells.
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 1, digestive system diseases2, metabolic diseases 3, nervous
system diseases 4, respiratory system diseases5, endocrine system diseases 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 7. Recently, researchers have
explored how BAs and their derivatives regulate the development and
function of Th17 and Treg cells in the gut8 . 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 cancer9,10.
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 microbiota11,12. The
intestinal mucosal lamina propria contains a wide variety of
immunocytes, such as B cells13, T
cells14, dendritic cells (DC) 15and
macrophages16. In the gut, GALT and local lymph nodes
provide sites to initiate adaptive immune responses. Effector
immunocytes disperse throughout the lamina propria and
epithelium17. 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
intestine18.
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 host19,20. Intestinal
flora metabolites include SCFAs (butyrate, propionate, and acetate)21-23, amino acids24, vitamin25,26 and BAs27. 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 microbiome28. Some of these
modified BAs are reabsorbed and exert signaling functions in the
host29. Gut microbiota generates cholic acid(CA) and
chenodeoxycholic acid(CDCA) through deconjugation30. Gut microbiota encodes enzymes that exert a
7α-dehydroxylation reaction. After dehydroxylation, CA becomes DCA,
whereas CDCA is converted to LCA31. CDCA can be
converted to ursodeoxycholic acid (UDCA) by HSDH32.
DCA, LCA, UDCA, and their derivatives have different effects on Treg or
Th17 cells, which will be elaborated in the following essay.
Microbiota influence intestinal immune
Many intestinal flora species exist in the human gastrointestinal
tract33, and the intestinal mucosal immune system
responds reasonably well to food antigens and commensal
bacteria34. Local immunocytes must resist pathogenic
pathogens and maintain their immune tolerance to beneficial
microorganisms35 . Studies have shown that metabolites
mediate communication between the commensal microbiota and host immune
system by shaping the composition and function of colonic
immunocytes8,27.
First, gut microbes promote the maturation of the host immune system.
Among these, B. thetaiotaomicron has the most important impact on the
immune system36. 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, TGFβ, 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 37. The transplantation of special
microbiota restores the balance between retinoic acid receptor-related
orphan nuclear receptor-γt (RORγt+) Treg cells and Th17 cells in
mice38. Some studies have proposed that
microorganisms affect immunity through specific molecules such as
PSA39. 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
costimulation40. 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.
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 41(Fig. 1).
BAs are important bacterial metabolites that function as T cell
modulators42. Some BAs are implicated as endogenous
etiologic agents, whereas other BAs confer resistance to pathogens, such
as Clostridium difficile 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)45.