Discovery and Biosynthesis of Indole-Functionalized Metabolites from the Human Blood Bacterium, <i>Paracoccus sanguinis</i>, and Their Anti-Skin Aging Activity

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 <i>Paracoccus sanguinis</i>, 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 (<b>1</b>-<b>12</b>), including six novel compounds (<b>1</b>-<b>3</b>, <b>9</b>, <b>10</b>, and <b>12</b>). Biosynthetic studies demonstrated that these metabolites are derived through enzymatic and nonenzymatic pathways. Functional evaluations revealed significant antiaging activities for <b>1</b>, <b>6</b>, and <b>11</b> 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, <b>11</b> exhibited the highest antiaging efficacy, highlighting its potential as a candidate for therapeutic applications targeting skin aging. This study elucidates the biosynthetic pathways of <i>P. sanguinis</i> 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.