|dc.description.abstract||Microbiome plays a significant role in human health and disease pathogenesis. Our current data based on the probiotic role of the skin microbiome in dermatological manifestations like pruritus or inflammation with a special emphasis on uremic pruritus and chronic ultraviolet (UV)-B induced skin inflammation. Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERK in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed higher mRNA expression of Bruton’s tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably decreased the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.
The role of skin commensal microbiota in the CaP-induced uremic pruritus and inflammation remains uncharacterized. In this study, we have shown that skin commensal, Cutibacterium acnes (C. acnes) can solubilize CaP by the production of short-chain fatty acids (SCFAs), such as butyric acid, through glucose fermentation. Like butyric acid, the N-[2-(2-Butyrylamino-ethoxy)-ethyl]-butyramide (BA-NH-NH-BA), a butyric acid derivative, remarkably induced acetylation of histone H3 lysine 9 (AcH3K9) in keratinocytes. Topical application of fermenting C. acnes and its metabolite, butyric acid or BA-NH-NH-BA onto mouse skin effectively ameliorated CaP-induced skin itching, interleukin IL-6 up-regulation in keratinocytes, p-BTK and p-ERK in DRG. The upregulation of p-BTK and p-ERK by CaP was markedly reduced in IL-6 knockout (KO) mice. Genus Cutibacterium was detected in relatively low abundance in itchy skin of patients with CKD. Our results identify a role for the skin fermenting C. acnes in ameliorating CaP-induced activation of IL-6/p-BTK/p-ERK signaling and resulting skin inflammation. Moreover, we provide evidence for the potential therapeutic efficacy of BA-NH-NH-BA as a postbiotic for the treatment of uremic pruritus.
We have also detected the anti-inflammatory effect of skin commensal, Staphylococcus epidermidis (S. epidermidis) against chronic ultraviolet B (UVB) radiation by the production of SCFAs, such as butyric acid, through glycerol fermentation. We detected that S. epidermidis in the skin microbiome produced butyric acid in vitro at concentrations in the millimolar (mM) range. The exposure of the dorsal skin of mice to UVB light provoked a significant increase in IL-6 production. Topical application of S. epidermidis with glycerol or butyric acid alone remarkably ameliorated the UVB-induced IL-6 production. In vivo knockdown of short-chain fatty acid receptor 2 (FFAR2) in mouse skin considerably blocked the probiotic effect of S. epidermidis on suppression of UVB-induced IL-6 production. These results demonstrate that butyric acid in the metabolites of fermenting skin probiotic bacteria mediates FFAR2 to modulate the production of pro-inflammatory cytokines induced by UVB. Overall, we have unraveled the molecular signaling in uremic pruritus and UVB induced skin inflammation and validated the anti-inflammatory role of butyric acid, a major metabolite from the fermentation of carbon source by C. acnes and S. epidermidis skin probiotic bacteria could provide a therapeutic approach for the prevention and treatment of uremic pruritus and UVB induced chronic inflammation in skin.