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.