Genome-scale metabolic modeling and in silico analysis of opportunistic skin pathogen Cutibacterium acnes

Abstract

Cutibacterium acnes, one of the most abundant skin microbes found in the sebaceous gland, is known to contribute to the development of acne vulgaris when its strains become imbalanced. The current limitations of acne treatment using antibiotics have caused an urgent need to develop a systematic strategy for selectively targeting C. acnes, which can be achieved by characterizing their cellular behaviors under various skin environments. To this end, we developed a genome-scale metabolic model (GEM) of virulent C. acnes, iCA843, based on the genome information of a relevant strain from ribotype 5 to comprehensively understand the pathogenic traits of C. acnes in the skin environment. We validated the model qualitatively by demonstrating its accuracy prediction of propionate and acetate production patterns, which were consistent with experimental observations. Additionally, we identified unique biosynthetic pathways for short-chain fatty acids in C. acnes compared to other GEMs of acne-inducing skin pathogens. By conducting constraint-based flux analysis under endogenous carbon sources in human skin, we discovered that the Wood-Werkman cycle is highly activated under acnes-associated skin condition for the regeneration of NAD, resulting in enhanced propionate production. Finally, we proposed potential anti-C. acnes targets by using the model-guided systematic framework based on gene essentiality analysis and protein sequence similarity search with abundant skin microbiome taxa.

The Intersection between Bacterial Metabolism and Innate Immunity

“…C. acnes also stimulates lipid production in host cells to prolong inflammatory responses via propionate secretion (Fig. 1) [35, 40]. This idea was recently put forward in a study demonstrating that keratinocytes increase lipid synthesis in the presence of spent media from cultures of C. acnes [40].…”

“…Overall, the evidence clearly illustrates how the unique capacity of C. acnes to assimilate lipids from the skin and produce propionate can dramatically perturb innate immunity and suggest that bacterial pathways associated with the synthesis of SCFAs could be targeted for antimicrobial therapy in the context of acne (Fig. 1) [35].…”

“…C. acnes is known to secrete triacylglycerol lipases, which hydrolyze triglycerides, releasing free fatty acids and glycerol. The subsequent accumulation and catabolism of free fatty acids reduce oxygen levels in the sebaceous glands, which ultimately induces fermentation in C. acnes [35]. Genome-scale metabolic pathway analyses suggest that C. acnes produces propionate via a unique pathway known as the Wood-Werkman cycle, which facilitates NAD+ regeneration [35].…”

“…The subsequent accumulation and catabolism of free fatty acids reduce oxygen levels in the sebaceous glands, which ultimately induces fermentation in C. acnes [35]. Genome-scale metabolic pathway analyses suggest that C. acnes produces propionate via a unique pathway known as the Wood-Werkman cycle, which facilitates NAD+ regeneration [35]. The Wood-Werkman cycle is highly efficient at fermenting glycerol, resulting in the secretion of high concentrations of propionate (Fig.…”

“…The Wood-Werkman cycle is highly efficient at fermenting glycerol, resulting in the secretion of high concentrations of propionate (Fig. 1) [35].…”