Gut-brain axis metabolic pathway regulates antidepressant efficacy of albiflorin

Abstract

The gut microbiota is increasingly recognized to influence brain function through the gut-brain axis. Albiflorin, an antidepressant natural drug in China with a good safety profile, is difficult to absorb and cannot be detected in the brain after oral administration. Accordingly, the antidepressant mechanism of albiflorin <i>in vivo</i> has not been elucidated clearly. <b>Methods:</b> We identified benzoic acid as the characteristic metabolite of albiflorin <i>in vivo and in vitro</i>, then discovered the roles of gut microbiota in the conversion of albiflorin by carboxylesterase<i>.</i> Pharmacodynamic and pharmacokinetic studies were performed for the antidepressant activities of albiflorin in animals, and the efficacy of benzoic acid in inhibiting D-amino acid oxidase (DAAO) in brain was further investigated. <b>Results:</b> We validated that gut microbiota transformed albiflorin to benzoic acid, a key metabolite in the intestine that could cross the blood-brain barrier and, as an inhibitor of DAAO in the brain, improved brain function and exerted antidepressant activity <i>in vivo</i>. Intestinal carboxylesterase was the crucial enzyme that generated benzoic acid from albiflorin. Additionally, the regulatory effect of albiflorin on the gut microbiota composition was beneficial to alleviate depression. <b>Conclusion:</b> Our findings suggest a novel gut-brain dialogue through intestinal benzoic acid for the treatment of depression and reveal that the gut microbiota may play a causal role in the pathogenesis and treatment of the central nervous system disease.