L-theanine alleviates reserpine-induced depression in rats via modulation of the gut-brain axis.

L-theanine, a natural amino acid in tea, exhibits potential neuroprotective effects. However, its impact on depression via the microbiota-gut-brain axis remains unclear. Here, L-theanine alleviated reserpine-induced depression-like behaviors in rats, improving anhedonia, despair, and cognitive deficits, while reducing serum IL-1β, IL-6, and TNF-α, restoring hippocampal BDNF, and mitigating neuronal damage. Multi-tissue non-targeted metabolomics (serum, brain, colon, feces) revealed that L-theanine reversed phospholipid and bile acid disturbances and restored key neuroprotective metabolites. Targeted metabolomics validated the non-targeted findings by confirming that L-theanine alleviated bile acid dysregulation and restored SCFA profiles. Additionally, L-theanine modulated gut microbiota composition, increasing beneficial genera such as Alloprevotella and Prevotellaceae_UCG-001, while reducing potentially harmful taxa. Correlation analyses indicated that these microbiota changes were linked to bile acid and SCFA profiles, suggesting gut-brain axis involvement. Overall, L-theanine exerts antidepressant effects by modulating neuroinflammation, neuroplasticity, and metabolism, highlighting its potential as a functional food for depression.