Discovery and Biosynthesis of Indole-Functionalized Metabolites from the Human Blood Bacterium, Paracoccus sanguinis,...

The human microbiome plays a crucial role in health and disease, with microbial metabolites acting as key mediators of physiological processes. While extensive research has focused on gut-derived microbes, the metabolic contributions of blood-derived bacteria remain underexplored. Here, we investigate the facultative anaerobe Paracoccus sanguinis, a Gram-negative bacterium isolated from human blood, and its metabolome, revealing insights into its potential impacts on health and disease. Using advanced analytical methods, we characterized 12 metabolites (1-12), including six novel compounds (1-3, 9, 10, and 12). Biosynthetic studies demonstrated that these metabolites are derived through enzymatic and nonenzymatic pathways. Functional evaluations revealed significant antiaging activities for 1, 6, and 11 in TNF-α-stimulated normal human dermal fibroblasts (NHDFs), including suppression of reactive oxygen species (ROS), inhibition of matrix metalloproteinase-1 (MMP-1) secretion, and reduction of inflammatory cytokines interleukin (IL)-6 and IL-8. Among the tested compounds, 11 exhibited the highest antiaging efficacy, highlighting its potential as a candidate for therapeutic applications targeting skin aging. This study elucidates the biosynthetic pathways of P. sanguinis metabolites and their antiskin aging activity, underscoring their potential in modulating skin health and offering novel insights into the functional roles of blood-derived microbiota in human health.