Multi-omics analysis of Gwakhyangjeonggi-san for gastrointestinal complications in atopic dermatitis: A randomized, double-blinded, placebo-controlled, parallel-group clinical trial

In traditional Chinese medicine (TCM) and traditional Korean medicine (TKM), Gwakhyangjeonggi-san (GJS) is an herbal decoction used to treat gastrointestinal disorders and allergic diseases. However, no randomized controlled trials have reported the efficacy and safety of GJS against atopic dermatitis (AD) or its comorbidities.This clinical trial investigated the clinical efficacy and safety of GJS for treating patients with AD who have gastrointestinal symptoms, using a multi-omics approach that included 16S rRNA sequencing and metabolomics.This study was a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Fifty-two patients with AD (age: 19-60) were randomly assigned to receive either the GJS (N = 27) or placebo (N = 25) granules thrice daily for 8 weeks. The primary outcome was measured as the change in the SCORing of Atopic Dermatitis index from baseline to 8 weeks. The secondary outcomes included the eczema area and severity index, dermatology life quality index, EuroQoL 5 dimensions 5 levels (EQ-5D-5L), immunological factors, gastrointestinal status, and safety evaluation. In addition, 16S rRNA sequencing on gut-microbiomes and non-targeted metabolomics approach using mass spectrometry on sera samples were applied to investigate the GJS therapeutic mechanism.After 8 weeks, AD symptoms were reduced in both the GJS and placebo groups without any serious adverse events, but the reduction was not significantly different between the two groups. However, the EQ-5D-5L scores and gastrointestinal symptom scores, such as bitter-tasting fluid presenting in the mouth, upper abdomen bloating, and nausea, only improved in the GJS group. To further elucidate the effect of GJS on patients with AD who have gastrointestinal symptoms, 16S rRNA sequencing and metabolomics were executed. The GJS group had lower gut microbiome diversity including observed OUT, Ace, Chao1 and Shannon index than the placebo group at enrollment time, while the difference in gut microbiome diversity between GJS and placebo group was eliminated by 8 weeks of treatment. Consistently, the metabolomics results showed that the gut microbiome-derived uremic toxins, including indoxyl sulfate and phenylacetylglutamine, significantly increased in the placebo group, while these in GJS group were maintained without any significant change.These results showed that the GJS had no significant effect on AD compared to the placebo but exerted a beneficial effect on improving the quality of life and gastrointestinal symptoms in patients with AD, and it acted by modulating gut microbiome diversity and gut microbiome-derived uremic toxins. Our findings support the use of GJS for AD comorbidities and also provide evidence that multi-omics approaches can be useful for understanding herbal decoctions in TCM and TKM comprehensively.