Gut Microbiota Is the Key to the Antidepressant Effect of Chaihu-Shu-Gan-San

Abstract

Accumulating evidence highlights the link between gut microbiota and depression. As an antidepressant herbal drug in clinic, Chaihu-Shu-Gan-San (CSGS) has also been used in China for the treatment of various gastrointestinal disorders. Therefore, we hypothesize that the gut microbiota might be involved in the effect of CSGS. Here, we investigated the antidepressant effects of CSGS against chronic variable stress (CVS)-induced depression rats with and without antibiotic treatment using 16S rRNA gene sequencing and ultra-performance liquid chromatography coupled with time of flight mass spectrometry (UPLC-Q-TOF/MS) based metabolomics approaches. As a result, the prominent effects of CSGS against the depression-like behavioral disorder of CVS-induced rats were significantly weakened when the gut microbiota was changed after oral administration of the broad-spectrum antibiotic. The mediation of CSGS on hippocampal levels of serotonin (5-HT) and glutamic acid (Glu) was also receded with the antibiotic treatment. Further investigation on the diversity of microbiome indicated that the improvement effect of CSGS on gut microbiota dysbiosis—especially the phylum level of Firmicutes—was attenuated after the CSGS combined antibiotic treatment. Moreover, 3-hydroxypicolinic acid (H4) and inosine (H8) in the hippocampus were considered as important biomarkers for depression and are also associated with gut microbiota mediated CSGS efficacy. Taken together, our current study indicated that gut microbiota is a critical factor in the antidepressant effect of CSGS, which improve depression-related metabolic disturbance partly through gut microbiota.

Chaihu-Shugan-San (Shihosogansan) alleviates restraint stress-generated anxiety and depression in mice by regulating NF-κB-mediated BDNF expression through the modulation of gut microbiota

“…Liang et al reported that CSS suppressed the Enterobacteriaceae population in the feces of rat with high fat diet-induced obesity [ 19 ]. However, Yu et al reported that chronic exposure to imipenem/cilastatin increased Proteobacteria and Bacteroidetes populations and suppressed the Firmicutes in the gut microbiota of rats [ 20 ]. They also reported that oral gavage of CSS alleviated stress/antibiotics-induced depression in rats by suppressing stress/antibiotics-induced Oscillibacter population and increasing stress/antibiotics-suppressed Bacteroidetes population.…”

“…Jang et al reported that the induction of Proteobacteria, particularly Enterobacteriaceae, by antibiotic ampicillin significantly caused anxiety/depression in mice and the suppression of Proteobacteria by Lactobacilli alleviated anxiety/depression [ 21 ]. However, Yu et al reported that CSS increased stress/antibiotics-suppressed Firmicutes and Proteobacteria populations in mice, resulting in the amelioration of depression [ 20 ]. To clarify the discrepancy, we examined the fecal transplantation of FN, FR, and FC in mice with RS-induced depression.…”

“…Furthermore, it suppresses high-fat diet-induced the inflammatory response including proinflammatory cytokine expression and gut dysbiosis including increased Enterobacteriaceae and Staphylococcaceae population in rats [ 19 ]. Recently, Yu et al reported that CSS alleviated imipenem/cilastatin/stress-induced depression and increased imipenem/cilastatin/stress-suppressed Proteobacteria and Firmicutes populations in mice [ 20 ]. Jang et al reported that the disruption of gut microbiota, particularly increased Proteobacteria population, by antibiotic ampicillin significantly caused psychiatric disorder in mice by suppressing NF-κB mediated BDNF expression [ 21 ].…”

Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control

“…Antidepressant treatment was also found to influence the gut microbiome in MDD patients, with greater microbiome diversity in those patients exhibiting remission (Bharwani et al., 2020). Interestingly, broad‐spectrum antibiotic treatment reversed the antidepressant effects of a Chinese herbal drug and also suppressed serotonin and glutamic acid levels in the rat hippocampus (Yu et al., 2020). Antibiotic treatment also reversed the beneficial effect of the drug in improving Lactobacillus numbers and caused gut dysbiosis and reduced gut microbiome diversity.…”

Impact of Inosine on Chronic Unpredictable Mild Stress-Induced Depressive and Anxiety-Like Behaviors With the Alteration of Gut Microbiota

“…Fluoxetine ( Lukic et al., 2019 ; Sun et al., 2019 ), ketamine ( Qu et al., 2017 ), escitalopram, and duloxetine ( Lukic et al., 2019 ) can improve depressive and anxiety-like behaviors and are associated with alterations in gut microbiota composition. It was recently reported that the downregulation of inosine in the hippocampus of rats caused by depression was corrected after treatment with traditional Chinese medicine, and that these variations in inosine were eliminated after antibiotic intervention ( Yu et al., 2020 ). The serum metabolite level of inosine was restored by Lactobacillus treatment in mice with gut microbial dysbiosis ( He et al., 2017 ).…”