Clinical study on the modulating effects of Jiaotaiwan on the microbiota-SCFAs-neurotransmitter/immune axis in patients with depression

Abstract

Objective: To investigate the antidepressant mechanism of Jiaotaiwan (JTW), a classic Traditional Chinese Medicine formula, by examining its effects on the gut microbiota short-chain fatty acid (SCFA) neurotransmitter/immune axis in patients with depression.

Methods: In this 8-week multicenter randomized controlled trial, 120 patients with depression were randomized to receive JTW, selective serotonin reuptake inhibitors (SSRIs), or JTW+SSRIs, and 30 healthy volunteers were enrolled as controls without intervention (healthy controls, n = 30). Gut microbiota profiling (16S ribosomal RNA [16S rDNA] gene sequencing), fecal SCFA quantification (gas chromatography-mass spectrometry), and plasma levels of neurotransmitters (5-hydroxytryptamine [5-HT], norepinephrine [NE], dopamine [DA]) and gut barrier/inflammatory markers (lipopolysaccharide [LPS], soluble zonula occludens-1 [sZO-1], high mobility group box 1 [HMGB1]) were assessed pre- and post-treatment. Correlations between brain gut peptides, gut flora, SCFAs, and gut barrier/inflammatory markers were analyzed using Spearman correlation analysis.

Results: Treatment with JTW, particularly in combination with SSRIs, significantly modulated gut microbiota composition by reducing Bacteroidetes abundance and increasing Firmicutes. It selectively ameliorated SCFA metabolic disturbances, notably elevating fecal levels of branched-chain fatty acids, including isobutyric and isovaleric acids. These changes were accompanied by increased plasma levels of 5-HT and DA, and reduced levels of LPS and HMGB1, suggesting improved gut barrier integrity and attenuated systemic inflammation. Correlation analysis revealed a positive association between Firmicutes abundance and sZO-1 levels, and overall coordination among microbial shifts, metabolic changes, and neurotransmitter improvements.

Conclusion: JTW may alleviate depressive symptoms through multitarget modulation of the microbiota-SCFA-neurotransmitter/immune axis, potentially involving the restoration of microbial composition, enhanced beneficial SCFA production, improved intestinal barrier function, reduced inflammation, and elevated monoamine neurotransmitters. Synergistic effects were observed when JTW was combined with SSRIs, thereby providing a mechanistic basis for using JTW in microbiota-directed approaches for treating depression.

Keywords

Depression / Jiaotaiwan / Microbiota / Neurotransmitter/immune / SCFAs

Conflict of interest statement

Chunquan Yu is an editorial board members member of this journal. The other authors declare no conflict of interest.

Funding

This work was supported by the National Natural Science Foundation of China (82074220).

Author contributions

Yang Tong, Yuanyuan He, Mengnan Huang: wrote the paper draft, participated in research design, the writing of the paper, data analysis and performance of the research; Yijia Liu, Fengmin Liu, Yuting Li, Shan Gao: participated in the performance of the research; Li Shen, Qiang Xu, Chunquan Yu: corrected the draft, supervised the experimentators, participated in funding acquisition, project administration, writing - review & editing. All authors read and approved the final manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Ethical approval of studies and informed consent

This research followed guidelines of the Declaration of Helsinki and Tokyo for humans. The study protocol was approved by the Ethics Committee of Tianjin University of Traditional Chinese Medicine (No. TJUTCMEC20210006). This study protocol has been registered in the International Traditional Medicine Clinical Trial Registry (No. ITMCTR2025000151). All participants provided written informed consent before any study procedures were performed. Specific measures to protect participant rights, including the confidentiality of their data, the voluntary nature of their participation, and their right to withdraw from the study at any time without penalty, were rigorously implemented throughout the trial.

Acknowledgments

None

Data availability

This research data includes sensitive information such as patient data so the research data is unavailable to access.

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