UVB, cis-urocanic acid and skin microbiome
There is growing evidence that the skin microbiome plays an important role in health and disease. Recently, we have shown that skin resident microbes regulate the immunomodulatory properties of ultraviolet (UV) radiation. To gain further insight into the underlying mechanisms, we exposed C57BL/6 mice to UVB or cis- urocanic acid (cis- UCA), a major UV photoproduct. We then examined the landscape of microbial communities inhabiting the skin, and their ability to metabolize cis- UCA and reduce its immunosuppressive properties in a standard model of contact hypersensitivity (CHS) to 2,4-dinitrofluorobenzene. UVB and its mediator cis- UCA induced transient and significant perturbations in skin bacterial communities with increased abundance of several bacterial phyla such as Firmicutes and Bacteroidetes. Bioinformatic analysis showed that several of the increased bacteria, such as Staphylococcus epidermidis, expressed the HutU gene, which encodes urocanase that degrades urocanic acid. In vitro culture experiments demonstrated that HutU+ but not HutU- strains used cis-UCA for growth, which certainly explains why the amount of cis- UCA available in the skin after UVB exposure was dramatically increased in mice with reduced bacterial load (when disinfected with chlorhexidine).  Comparison of the CHS response in mice with normal and disinfected skin or in gnotobiotic-like models colonized with HutU+/- strains provided functional evidence that the presence of HutU+ bacteria limits the immunosuppressive effect of cis- UCA. Moreover, topical application of the urocanase inhibitor, glycylglycine, restricted the metabolism of cis- UCA by HutU+ bacteria and restored immunosuppression.  Overall, our results provide mechanistic evidence that certain bacterial species of the skin, which consume the UVB mediator cis- UCA, influence its concentration, and thereby regulate UV-induced immunosuppression.