Skin Cutibacterium acnes Mediates Fermentation to Suppress the Calcium Phosphate-Induced Itching: A Butyric Acid Derivative with Potential for Uremic Pruritus

Pruritus and inflammation associated with accumulation of calcium phosphate (CaP) under the skin are common problems among dialysis patients with chronic kidney disease (CKD). The role of skin commensal microbiota in the CaP-induced uremic pruritus remains uncharacterized. Skin 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, butyric acid or BA-NH-NH-BA onto mouse skin effectively ameliorated CaP-induced skin itching, interleukin (IL)-6 up-regulation in keratinocytes, and extracellular signal-regulated kinase (ERK) 1/2 activation in dorsal root ganglia (DRG). Activation of ERK 1/2 by CaP was markedly reduced in IL-6 knockout 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-ERK signaling and resulting skin inflammation. Furthermore, we provide evidence for the potential therapeutic efficacy of BA-NH-NH-BA as a postbiotic for the treatment of uremic pruritus.