Oral Administration of Lactiplantibacillus plantarum KBL396 Regulates Serum 5-Hydroxytryptamine and Gut Microbiota: Evidence from a Preclinical Mouse Model and a Randomized Controlled Human Trial

Emerging evidence links gut microbiota to major depressive disorder via the gut-brain axis. Here, we provide comprehensive evidence from a preclinical mouse model and a randomized controlled human trial for the psychobiotic potential of Lactiplantibacillus plantarum (L. plantarum) KBL396, a strain isolated from a healthy Korean adult. We demonstrate that L. plantarum KBL396 potently induces Tph1 gene expression in vitro (p < 0.001), which encodes the rate-limiting enzyme tryptophan hydroxylase 1 for 5-hydroxytryptamin (5-HT) synthesis. L. plantarum KBL396 administration ameliorated depressive-like behaviors (p < 0.05), increased serum 5-HT, and modulated immune cell populations in mice with chronic social defeat stress. Critically, these preclinical findings translated to humans: the 8 weeks of randomized, double-blind, placebo-controlled trial (the KBL396 group: n = 62; the placebo group: n = 30) showed that L. plantarum KBL396 significantly elevated the serum 5-HT and dopamine level (p < 0.05). L. plantarum KBL396 administration remodeled gut microbiota with the increases of Lactiplantibacillus and Akkermansia. Collectively, our findings preliminarily demonstrate that L. plantarum KBL396 is a psychobiotic candidate that mechanically links gut-derived neurotransmitter production to beneficial mental health-related outcomes across preclinical model and clinical settings.