Abstract
The microbiome is a rich source of metabolites for the development of novel drugs. Butyric acid, for example, is a short-chain fatty acid fermentation metabolite of the skin probiotic bacterium Staphylococcus epidermidis (S. epidermidis). Glycerol fermentation of S. epidermidis resulted in the production of butyric acid and effectively hindered the growth of a Staphylococcus aureus (S. aureus) strain isolated from skin lesions of patients with atopic dermatitis (AD) in vitro and in vivo. This approach, however, is unlikely to be therapeutically useful since butyric acid is malodorous and requires a high concentration in the mM range for growth suppression of AD S. aureus. A derivative of butyric acid, BA–NH–NH–BA, was synthesized by conjugation of two butyric acids to both ends of an –NH–O–NH– linker. BA–NH–NH–BA significantly lowered the concentration of butyric acid required to inhibit the growth of AD S. aureus. Like butyric acid, BA–NH–NH–BA functioned as a histone deacetylase (HDAC) inhibitor by inducing the acetylation of Histone H3 lysine 9 (AcH3K9) in human keratinocytes. Furthermore, BA–NH–NH–BA ameliorated AD S. aureus-induced production of pro-inflammatory interleukin (IL)-6 and remarkably reduced the colonization of AD S. aureus in mouse skin. These results describe a novel derivative of a skin microbiome fermentation metabolite that exhibits anti-inflammatory and S. aureus bactericidal activity.
Highlights
Skin dysbiosis has been defined as a state of microbial imbalance in the skin microbiome [1,2].Increasing evidence indicates that probiotic bacteria in the skin microbiome can mediate fermentation [3]to rein in the overgrowth of opportunistic pathogens [4,5]
The bacteria on the tape strips were cultured on mannitol salt agar (MSA) plates for 3 d
The yellow colonies were selected for 16S ribosomal RNA sequencing and identified as atopic dermatitis (AD)
Summary
Skin dysbiosis has been defined as a state of microbial imbalance in the skin microbiome [1,2].Increasing evidence indicates that probiotic bacteria in the skin microbiome can mediate fermentation [3]to rein in the overgrowth of opportunistic pathogens [4,5]. 15% to 20% of the childhood population [7] It is a chronic, pruritic inflammatory skin disease of unknown origin that usually starts in early infancy and affects a substantial number of adults [8,9]. In addition to the suppression of S. aureus growth, SCFAs, especially butyric acid, function as histone deacetylase (HDAC) inhibitors, thereby leading to increased acetylation of histones. Previous studies revealed that butyric acid can effectively inhibit HDAC in skin keratinocytes resulting in anti-inflammatory activity [12]. This is therapeutically relevant, since inflammatory processes are important drivers of AD. T helper type 2 (Th2) cytokines dominate in the early stage of AD, whereas a combination of
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