Commensal Cutibacterium acnes-derived indolelactic acid safeguards skin barrier function through the aryl hydrocarbon receptor

Skin microbial dysbiosis is a key characteristic of atopic dermatitis (AD). Although Cutibacterium acnes (C. acnes) is the most abundant bacterium in the skin microbiota, its precise functions in AD remain unclear. Here, whole-genome sequencing of C. acnes isolates reveals strain-level genomic and functional heterogeneity between AD patients and healthy individuals. Metabolomic profiling identifies reduced indolelactic acid (ILA), a tryptophan metabolite, in AD skin and in cultures of AD-associated C. acnes strains. In murine models of epidermal-barrier-damaged and AD-like dermatitis, topical ILA application activates the aryl hydrocarbon receptor (AhR) pathway in keratinocytes, upregulating tight junction proteins and suppressing interleukin (IL)-33 to restore barrier integrity and mitigate dermatitis. A proof-of-concept clinical trial confirms ILA's efficacy in reducing transepidermal water loss and alleviating AD symptoms. Our study establishes C. acnes-derived ILA as a crucial regulator of skin barrier repair via AhR signaling, offering therapeutic potential for AD. Clinical trial registration: ChiCTR2400090988.