The FXR mediated anti-depression effect of CDCA underpinned its therapeutic potentiation for MDD

Emerging evidence from animal and human studies has suggested that small microbial metabolites generated in the gut influence host mood and behavior. Our previous study reported that patients with major depressive disorder (MDD) reduced the abundance of genera Blautia and Eubacterium, the microbials critically regulating cholesterol and bile acid metabolism in the gut. In this study, we further demonstrated that the levels of plasma bile acid chenodeoxycholic acid (CDCA) were significantly lower in Chinese MDD patients (142) than in healthy subjects (148). Such low levels of plasma CDCA in MDD patients were rescued in remitters but not in nonremitters following antidepressant treatment. In a parallel animal study, Chronic Social Defeat Stress (CSDS) depressed mice reduced the plasma CDCA and expression level in prefrontal cortex (PFC) of bile acid receptor (FXR) protein, which is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. We found that CDCA treatment restored the level of FXR in the CSDS mice, suggesting the involvement of bile acid receptors in MDD. We observed that CDCA decreased the activity of the NLRP3 inflammasome and caspase-1 and subsequently increased the levels of phosphorylation and expression of PFC glutamate receptors (GluA1) in the PFC. In addition, CDCA showed antidepressant effects in the tests of sucrose preference, tail suspension, and forced swimming in CSDS mouse model of depression. Finally, in agreement with this idea, blocking these receptors by a FXR antagonist GS abolished CDCA-induced antidepressant effect. Moreover, CDCA treatment rescued the increase of IL-1β, IL-6, TNF α and IL-17, which also were blocked by GS. These results suggest that CDCA is a biomarker and target potentially important for the diagnosis and treatment of MDD.