Abstract
Paeoniflorin, the main component of Xiaoyao Wan, presents low oral bioavailability and unclear antidepressant mechanism. To elucidate the potential reasons for the low bioavailability of paeoniflorin and explore its antidepressant mechanism from the perspective of the gut microbiota, here, a chronic unpredictable depression model and forced swimming test were firstly performed to examine the antidepressant effects of paeoniflorin. Then the pharmacokinetic study of paeoniflorin in rats was performed based on the gut microbiota; meanwhile, the gut microbiota incubated with paeoniflorin in vitro was used to identify the possible metabolites of paeoniflorin. Molecular virtual docking experiments together with the specific inhibitor tests were applied to investigate the mechanism of paeoniflorin metabolism by the gut microbiota. Finally, the intestinal microbiota composition was analyzed by 16S rRNA gene sequencing technology. The pharmacodynamics tests showed that paeoniflorin had significant antidepressant activity, but its oral bioavailability was 2.32%. Interestingly, we found paeoniflorin was converted into benzoic acid by the gut microbiota, and was mainly excreted through the urine with the gut metabolite benzoic acid as the prominent excreted form. Moreover, paeoniflorin could also regulate the composition of the gut microbiota by increasing the abundance of probiotics. Therefore, the metabolism effect of gut microbiota may be one of the main reasons for the low oral bioavailability of paeoniflorin. Additionally, paeoniflorin can be metabolized into benzoic acid via gut microbiota enzymes, which might exert antidepressant effects through the blood–brain barrier into the brain.
Highlights
IntroductionDepression, which is preceded only by cardiovascular disease, is expected to become the second largest threat to human health by 2020 (Nestler et al, 2002; Dennis and Allen, 2008)
Depression is a common disease that seriously impairs social function
Ultra-performance liquid chromatography method was used to determine the content of paeoniflorin in Xiaoyao Wan
Summary
Depression, which is preceded only by cardiovascular disease, is expected to become the second largest threat to human health by 2020 (Nestler et al, 2002; Dennis and Allen, 2008). A growing number of studies have shown that the gut microbiota is widely involved in metabolic syndrome, autoimmune diseases, emotional cognitive dysfunction and other diseases, and have important effects on and significance for human health and diseases. The gut microbiota plays an important role in human central nervous system diseases (Wang and Kasper, 2014), affecting the normal development of the nervous system as well as participated in the pathogenesis of many mental illnesses; the gut microbiota could regulate anxiety, mood, cognition, and pain (Mohajeri et al, 2018)
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