Anxiolytic and antidepressant effects of 1-phenyl-1-propanol-mediated bile acids in a chronic unpredictable mild stress mouse model.

1-Phenyl-1-propanol (PP), a potent cholagogue, has been proven to stimulate bile secretion effectively. Emerging research links bile acid to the pathogenesis of depression and anxiety disorders. Despite its well-established therapeutic role in ameliorating bile flow abnormalities, the impact of PP on neuropsychiatric disease remains unclear. Using a chronic unpredictable mild stress (CUMS)-induced mouse model, groups received PP, a choleretic agent, or cholestyramine (CHO), a bile acid sequestrant, orally. Behavioral tests evaluated antidepressant and anxiolytic effects. PP treatment alleviated hippocampal damage, reduced Iba-1 expression, and restored hippocampal integrity, and these effects were associated with enhanced bile secretion. It also lowered IL-6 while elevating hippocampal and plasma 5-HT. Furthermore, PP enriched gut microbiota diversity and strengthened the intestinal barrier, with these effects potentially involving bile-mediated mechanisms. Importantly, PP modulated hippocampal and colonic clock genes (Cry2/NPAS2) in CUMS mice, and this modulation was associated with choleresis. Collectively, these findings suggest that PP exerts antidepressant and anxiolytic effects likely mediated through bile-acid-associated regulation of the gut-brain-microbiota axis, positioning it as a cost-effective, low-risk therapeutic candidate worthy of further investigation for mood disorders (MDs).