Qing-Re-Qu-Shi formula improves clinical outcomes and is accompanied by gut microbiota and microbial metabolite remodeling in adults with moderate atopic dermatitis: a randomized placebo-controlled multi-omics trial

Background The gut–skin axis is increasingly implicated in atopic dermatitis (AD), but randomized adult studies linking clinical response to paired gut microbiome and circulating metabolite profiling remain limited. We evaluated Qing-Re-Qu-Shi formula in adults with moderate AD and examined associated microbiome and serum metabolite changes. Methods In this randomized, double-blind, placebo-controlled 12-week trial, 152 adults with moderate AD were assigned 1:1 to Qing-Re-Qu-Shi formula or placebo. Outcomes included Eczema Area and Severity Index (EASI), SCORAD, Patient-Oriented Eczema Measure (POEM), pruritus numerical rating scale (NRS), Dermatology Life Quality Index (DLQI), and responder rates. The primary clinical analysis followed the intention-to-treat principle. Paired fecal 16S rRNA sequencing and targeted serum metabolomics were performed in the biospecimen subset. Differential feature analyses adjusted for baseline level, age, and sex; β diversity was assessed using repeated-measures-aware PERMANOVA. Results All randomized participants were included in clinical analyses; 124 contributed paired fecal and serum specimens, and 102 also had week-12 clinical data for cross-domain analyses. Compared with placebo, Qing-Re-Qu-Shi produced greater week-12 improvements in EASI (adjusted mean difference, −3.78; 95% CI, −4.54 to −3.01), SCORAD (−9.73; 95% CI, −11.54 to −7.93), POEM (−3.39; 95% CI, −4.06 to −2.73), pruritus NRS (−0.94; 95% CI, −1.15 to −0.72), and DLQI (−2.86; 95% CI, −3.47 to −2.26) (all p < 0.001). EASI-50 and EASI-75 responses were more frequent with Qing-Re-Qu-Shi. Shannon diversity changed little, whereas β diversity showed a small but significant group-by-time effect ( p = 0.001, R 2 = 0.016). Full-feature CLR analyses identified higher Blautia, Bifidobacterium, Lactobacillus, and Agathobacter and lower Escherichia/Shigella, Enterococcus, Prevotella, and Collinsella after false-discovery-rate correction. Serum metabolomics showed higher short-chain fatty acid and indole-related signals and lower kynurenine-related signals. Cross-domain correlations aligned these changes with greater symptom improvement. Conclusion Qing-Re-Qu-Shi formula improved clinical severity and patient-reported outcomes in adults with moderate AD. These benefits were accompanied by selective gut microbial remodeling and circulating microbiota-related metabolite changes, supporting an associative link between clinical improvement and gut ecosystem remodeling rather than proving causality.