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.