Deoxycholic Acid Impairs Immune Tolerance during DC and CD4 T Cell Interaction through FXR-Dependent Signaling

Abstract

Deoxycholic acid (DCA) was implicated in gut dysbiosis and inflammation, but its immunoregulatory mechanisms in allergic sensitization remain unclear. This study investigated how DCA disrupts intestinal immune tolerance, thereby promoting an immune response of lymphocytes to allergens. In vivo, the functions of intestinal lymphocytes were characterized through transcriptomic profiling and spectral flow cytometry after DCA gavage. Intestinal lymphocytes were isolated and exposed to DCA in vitro to further describe the dose-response immunoregulation of DCA. Additionally, bile acid receptor antagonists were applied to explore the potential target of DCA administration in vitro. Gavage of DCA resulted in elevated IgE expression within intestinal B cells (mean difference = 27.21%, 95% CI: 11.22 to 43.19, P < 0.05) and a significant reduction (almost 50%) of Foxp3, Helios, and PD-1/PD-L1. Transcriptomic analysis further revealed that DCA downregulated markers associated with immune tolerance. 50 μM DCA suppressed PD-L1 expression on DCs (mean difference = -11.74%, 95% CI: -21.44 to -2.041, P < 0.005) and PD-1 on CD4 T cells (mean difference = -5.56%, 95% CI: -4.47 to -6.66, P < 0.005), while concurrently promoting Th2 polarization and IgE production in B cells in vitro. FXR antagonism reversed these DCA-induced effects, indicating their dependence on FXR signaling. Collectively, this study unveils a novel mechanism whereby the secondary bile acid DCA impairs intestinal immune tolerance by inhibiting the PD-L1/PD-1 immune checkpoint axis via FXR signaling, thereby promoting allergic sensitization.