Hypericin: A potential gut microbiota-based therapeutic for postpartum depression via modulating bile acid metabolism

Hypericin alleviates depressive-like behaviors in a rat model of postpartum depression (PPD) by restoring gut microbiota homeostasis and normalizing bile acid metabolism. • Antibiotic-induced gut microbiota ablation abolishes the therapeutic effect of hypericin, demonstrating that gut microbes are essential for its antidepressant action in PPD. • Transcriptomic and metabolomic analyses reveal that hypericin modulates the gut microbiota-bile acid-glucocorticoid signaling axis, identifying this pathway as a PPD-relevant therapeutic target. Background Postpartum depression (PPD) is a mental disorder that occurs in a special period of time, but its pathophysiological mechanism is still unclear. Although hypericin has been shown to have therapeutic effects in previous studies, the underlying mechanisms of its treatment of PPD, especially its interaction with the gut-brain axis, remain to be explored. The aim of this study was to investigate the mechanism of hypericin in the treatment of PPD. Methods The PPD rat model was established by ovariectomy and hormone withdrawal after simulating pregnancy. Postpartum depression-like behavior was assessed by sucrose preference test and open field test. We integrated 16S rRNA sequencing, targeted plasma bile acid metabolomics, brain tissue transcriptomics, histopathology and molecular biology to explain the mechanism. Results Hypericin intervention significantly improved the postpartum depression-like behavior of PPD model rats. This effect was abolished by depletion of the microbiota induced by antibiotic sweeps, thus establishing that the involvement of the gut microbiota is required for the efficacy of hypericin. Hypericin can reverse the abnormal changes of gut microbiota, bile acid metabolism and inflammatory response observed in PPD model, so as to play a role in the treatment of PPD. Conclusion Hypericin plays an antidepressant role in PPD model, mainly by restoring gut microbiota homeostasis, thereby correcting bile acid metabolism disorders. In this study, the “gut microbiota-bile acid” axis is the key pathological feature and therapeutic target of PPD, and hypericin is expected to become a therapeutic candidate based on the gut microbiota. Download: Download high-res image (303KB) Download: Download full-size image