5.1 Treg cells
Intestinal health requires Treg cells to exert an immunosuppressive
function46. Forkhead box P3 (Foxp3+) is a
transcription factor of Treg cells27. Induced
extrathymically by dietary or antigens from commensals47, Foxp3 is involved in the differentiation and
function of Treg cells 27. Conserved non-coding
sequences (CNS1-CNS3) regulate Foxp3 gene expression by interacting with
different transcription factors48. 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 factor49. Gut-resident Foxp3+CD4+
Treg cells exhibit gut-specific phenotypes and functions50.
Hang et al. found that BAs metabolites directly modulate the Th17/Treg
balance in the intestinal lamina propria 8. The energy
resources of Treg cells mainly originate from oxidative phosphorylation51. 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 cells8. This process also requires
TGF-β-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 8. The differentiation of Th17 cells can
be initiated by IL-6 and TGF-β, and RORγt expression requires CNS6 and
CNS948. Studies of Foxp3 and RORγt 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 immunity52. Li et al. showed that NR4A1 is
required for isoalloLCA-mediated differentiation of Treg cells42. 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.
RORγt belongs to the family of nuclear receptors and is an intracellular
transcription factor 53. Many colonic CD4+FoxP3+ Tregs
express Rorγ 54. Helios and Nrp1 are markers of
thymus-derived Tregs, and are absent in colonic RORγ+ Tregs. Colonic
Treg cells express higher levels of Vdr than splenic Treg cells,
especially RORγ+ Treg cells29. VDR is a
ligand-dependent nuclear transcription factor that regulates cell
proliferation and differentiation 55. The removal of
VDR in Treg cells induces severe enteritis via DSS29.
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
RORγ+ Treg cells through the BAs receptor VDR 29(Fig.
1). The regulation of RORγ+ 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 RORγ+ Treg cells29. 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 RORγ+ Treg cell counts; however, a
similar effect was not found in colonic Th17 cells29.
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 RORγ+ Treg cell counts. After the onset of
colitis, BAs supplementation barely alleviated the colitis. This
phenomenon indicates that maintaining the RORγ+ Treg cell pool by BAs
during homeostasis affects the treatment effect in host DSS colitis.
DC is antigen presenting cells56. They process
antigens, secrete cytokines and chemokines, and induce and maintain an
immune tolerance57. Campbell et al. found that SBAs
isoDCA induced Foxp3 by influencing FXR and reducing immunostimulatory
functions of DCs 27, ablating FXR in DCs increased the
number of Treg cells, and the transcriptional profile in DCs resembled
that induced by isoDCA 27(Fig. 1). Furthermore,
consortia that produce isoDCA increase colonic RORγt+ 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.