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.