Ultraviolet radiation reshapes the metabolome of skin commensal bacteria, influencing AhR signaling and barrier function

ABSTRACT Ultraviolet radiation (UVR) is an environmental stressor to the skin and its associated microbiota. Many commensal bacteria produce tryptophan-derived metabolites that modulate epidermal barrier function through aryl hydrocarbon receptor (AhR) signaling. However, the effects of UVR on these metabolic outputs and the subsequent effects on skin barrier function remain unclear. This study examined these interactions. Individual skin commensal bacteria were irradiated with 37.5 mJ/cm² or 150 mJ/cm² of solar-simulated radiation (SSR). Cell-free supernatants (CFSNs) were collected and analyzed for tryptophan metabolites (using LC–MS), untargeted metabolites (using GC–MS), and AhR agonist activity (via a reporter assay). The effects on barrier function were assessed by measuring transepithelial electrical resistance (TEER) of CFSN-treated keratinocyte cultures. Time-course expression of tryptophan-related genes after irradiation was measured by qPCR. Unirradiated bacterial metabolomes were species-specific. Following irradiation, the abundance of metabolites generated by the indole pathway generally increased after 37.5 mJ but decreased following 150 mJ. Untargeted analyses revealed several decreases in amino and organic acid production after high-dose SSR, while 37.5 mJ resulted in fewer changes. Low-dose SSR upregulated genes involved in tryptophan metabolism ( ipdC , ALDH ) and synthesis ( trpE ). AhR agonism increased in 8/11 organisms following irradiation, statistically correlating with increased levels of indole-pathway metabolites (indole-3-acetamide, tryptophol, indole-3-carboxaldehyde, and tryptamine). Keratinocytes treated with irradiated Staphylococcus hominis , Micrococcus luteus , and Staphylococcus capitis CFSNs showed enhanced TEER, concurrent with increased AhR activation; inhibition of the AhR removed this effect. UVR significantly alters the metabolomes of skin commensal bacteria, with knock-on effects for AhR signaling and barrier integrity, potentially influencing the skin’s response to UVR. IMPORTANCE The skin and its commensal bacteria are regularly exposed to ultraviolet radiation (UVR). Many skin bacteria generate tryptophan-derived metabolites that influence host physiology through activation of the aryl hydrocarbon receptor (AhR), a key regulator of barrier integrity and stress responses. However, the impact of UVR on the metabolic activity of skin commensals and the downstream consequences for epidermal barrier function remains poorly understood. Here, we show that UVR significantly alters the metabolic outputs of diverse skin commensals, shifting production of indole-pathway metabolites and modulating AhR agonist activity. These changes translated into measurable effects on keratinocyte barrier function, including enhanced transepithelial electrical resistance following UVR exposure. Our findings reveal a previously underappreciated role for bacterial photometabolism in shaping epidermal barrier regulation and host responses to UVR.