Effect of Chaihu-Shugan-San on functional dyspepsia and gut microbiota: A randomized, double-blind, placebo-controlled trial

Chaihu-Shugan-San (CSS) is a classic traditional Chinese medicine (TCM) formula from the Ming Dynasty "Jingyue's Complete Works". In China, it is prevalent for the treatment of a wide range of ailments, with a particular emphasis on functional gastrointestinal disorders (FGIDs). Clinical evidence suggests that CSS has been found to be a highly effective therapeutic approach for the treatment of Functional Dyspepsia (FD), however, there is a limited amount of high-quality clinical evidence, particularly randomized, double-blind, placebo-controlled trials to support this claim. To evaluate the therapeutic efficacy of Chaihu-Shugan-San (CSS) for treating functional dyspepsia (FD) by comparing it to placebos, as well as to investigate the impact of CSS on the gut microbiota in individuals diagnosed with FD. This was a randomized double-blind, placebo-controlled clinical trial implemented at Shuguang Hospital in Shanghai. Between May 2021 and December 2022, 94 participants satisfying the Rome IV diagnostic criteria for FD were enrolled. They were assigned randomly to either the CSS group or the placebo group, with an equal allocation ratio of 1:1. Patients in both groups received the intervention for four weeks. The primary outcome was the dyspepsia symptom scores evaluated by using single dyspepsia symptom scale (SDS) after four weeks of treatment. The secondary outcomes were the solid gastric empties rate measured by a barium strip method, Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), and Functional dyspepsia Quality of life scale (FDDQL). In addition, after unblinding, 30 patients in the CSS group were randomly selected and divided into before and after treatment of the FD groups (FD1, FD2), and 30 healthy participants were selected as healthy control group (HC), and the gut microbiota was analyzed by 16S rRNA sequencing. After four weeks of treatment, the SDS score exhibited a significant improvement in the CSS group compared to the placebo group (t = 4.882; P <0.001). The difference in barium strip gastric emptying rate in the CSS group showed a significant ascent compared to the control group (P < 0.01). The HAMA, HAMD, and FDDQL scores in the CSS group showed a statistically significant increase compared to the control group (all P < 0.01). The results of 16S rRNA sequencing revealed that FD patients had less diverse and abundant microbiota than the healthy people. Additionally, the application of CSS resulted in the modulation of certain bacterial populations, leading to both up-regulation and down-regulation of their quantities. These findings suggested that CSS is more effective compared to a placebo in treating FD, relieves anxiety and depression, increases gastric emptying rate in FD patients, and that CSS also affects the bacterial community structure in FD patients. ChiCTR, ChiCTR2100045793. Registered 25 Mach 2021. URL: https://www.chictr.org.cn/showproj.html?proj=125049.