Specific microbiota tryptophan metabolites—indole-3-aldehyde and indole-3-lactic acid are key mediators in alleviating atopic dermatitis

Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disorder of global significance. Long-term use of conventional treatments like topical corticosteroids is associated with adverse effects and a substantial economic burden. Building on prior work demonstrating that specific probiotic strains and a tailored dietary fiber combination ameliorate AD in mice by modulating gut microbiota-derived tryptophan metabolites via the gut-skin axis, but the precise bioactive indoles and their underlying mechanisms remain elusive. Here, we induced AD in mice using 2,4-dinitrofluorobenzene and administered five representative indole derivatives via intragastric gavage. Disease amelioration was assessed through ear swelling quantification, histopathological analysis, enumeration of infiltrated mast cells, and measurement of serum IgE and cytokines by ELISA. Only indole-3-acetaldehyde (IAId) and indole-3-lactic acid (ILA) markedly attenuated AD pathology, reducing ear swelling by over 30% alongside decreased skin thickness and mast cell infiltration. Immunomodulatory profiling revealed these metabolites downregulated IL-4, IL-13, and TSLP expression by 25%–40% and upregulated IFN-γ production by 50%, thereby restoring the Th1/Th2 immune balance. To dissect the mechanism, we employed an aryl hydrocarbon receptor (AhR) inhibitor in parallel experiments, which completely abrogated the protective effects of IAId and ILA, confirming strict dependency on AhR pathway activation. Collectively, our study identifies IAId and ILA as microbiota-derived tryptophan metabolites that regulate immune homeostasis via the gut-skin axis in a murine AD model. These findings provide experimental support for the potential of targeting these specific microbial metabolites, warranting further investigation into their therapeutic or nutritional applications for AD.