l-theanine-targeted prefrontal cortex improves CUMS-induced depression via the gut-short-chain fatty acids-brain axis

Depression has emerged as a major global public health issue. L-theanine exerts notable anxiolytic and antidepressant effects mediated by its blood-brain barrier permeability as well as its anti-inflammatory and antioxidant properties. Nevertheless, the underlying mechanism of its key role remains elusive. In this study, chronic unpredictable mild stress (CUMS) reduced serum neurotransmitter levels in mice, impaired prefrontal cortex (PFC) and colonic barrier function, which induced depressive-like behaviors. L-theanine, especially at a dose of 800 mg/kg, down-regulated gut-brain inflammatory pathways (TLR9/NLRP3/Caspase-1) and restored barrier integrity (ZO-1 and Occludin), reversing CUMS-induced depressive-like behavior. This therapeutic effect was primarily attributed to L-theanine-mediated reshaping of gut microbiota (increased of Lactobacillus and Roseburia) and the restoration of short-chain fatty acids (SCFAs, especially acetic acid, butyric acid, and propionic acid) synthesis and their receptor functions. In summary, the Gut-SCFAs-Brain axis may serve as a potential pathway for L-theanine to improve depression.