Topical Application of Indole‐3‐Acetic Acid, Present in S. epidermidis Supernatant, Alleviates Atopic Dermatitis in Mice at Least via the Aryl Hydro

ABSTRACT

Dysbiosis of the skin microbiome, characterised by Staphylococcus aureus overgrowth and imbalance of commensals such as Staphylococcus epidermidis ( S. epidermidis ), is closely associated with atopic dermatitis (AD). However, the therapeutic relevance of defined S. epidermidis ‐associated indole metabolite, especially indole‐3‐acetic acid (IAA), in AD‐like inflammation remains incompletely characterised. Here, we investigated the role of IAA, a tryptophan‐derived metabolite enriched in the culture supernatant of the tested S. epidermidis strain, in AD‐like inflammation. Public transcriptomic analyses suggested impaired AHR‐associated and tryptophan‐metabolism signatures in AD skin, particularly in lesional skin, while human metagenomic data indicated AD‐associated staphylococcal alterations. Targeted metabolomics identified IAA as an enriched indole metabolite in S. epidermidis culture supernatant. In an MC903‐induced AD‐like mouse model, cutaneous IAA levels and S. epidermidis abundance were reduced. Topical IAA attenuated AD‐like phenotypes, improved barrier‐related proteins and reduced inflammatory indices. These protective effects were diminished by the AHR antagonist CH223191. Molecular docking predicted a possible interaction between IAA and AHR, and in vitro assays showed that IAA modulated keratinocyte AHR‐associated inflammatory and barrier‐related responses. Together, our findings support IAA as a microbiome‐associated postbiotic candidate for AD management, at least partly through AHR‐associated signalling.