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

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.