Anxiolytic and Antidepressant Effects of 1-Phenyl-1-propanol-Mediated Bile Acids in a Chronic Unpredictable Mild Stress Mouse Model Chen et al.

In this study, we hypothesized that 1-Phenyl-1-propanol (PP)—a well-known cholagogue that enhances bile secretion—may exert antidepressant and anxiolytic effects by modulating the interplay between bile acid signaling, circadian rhythm regulation, and the gut–brain–microbiota axis. To test this, we used a chronic unpredictable mild stress (CUMS) mouse model, randomly assigning animals to receive PP, cholestyramine (CHO; a bile acid sequestrant used as a mechanistic control), or vehicle. Behavioral assessments were combined with molecular, histological, and microbiome analyses. Our data showed that PP significantly improved mood-related behaviors and protected against CUMS-induced hippocampal damage—evidenced by reduced microglial activation (lower Iba-1 expression), preserved neuronal architecture, decreased neuroinflammation (reduced IL-6), and increased serotonin (5-HT) levels in both the hippocampus and plasma. Moreover, PP enhanced gut microbial diversity and reinforced intestinal barrier integrity. Most notably, PP uniquely upregulated or normalized the expression of core circadian clock genes Cry2 and NPAS2 in the hippocampus, suggesting that bile acid directly influences central circadian machinery under stress. This multi-system mechanism positions PP as a promising, low-cost, and low-side-effect candidate for treating mood disorders rooted in gut–brain dysregulation.