Abstract
Endotoxemia induced by the administration of low-dose lipopolysaccharide (LPS) to healthy human volunteers is a well-established experimental protocol and has served as a reproducible platform for investigating the responses to systemic inflammation. Since metabolic composition of a tissue or body fluid is uniquely altered by stimuli and provide information about the dominant regulatory mechanisms at various cellular processes, understanding the global metabolic response to systemic inflammation constitutes a major part in this investigation complementing the studies undertaken so far in both clinical and systems biology fields. This article communicates the first proof-of-principle metabonomic analysis which comprised of global biochemical profiles in human plasma samples from healthy subjects given intravenous endotoxin at 2 ng/kg. Concentrations of a total of 366 plasma biochemicals were determined in archived blood samples collected from 15 endotoxin treated subjects at 5 time points within 24 hour post-treatment and compared with control samples collected from 4 saline treated subjects. Principal component analysis within this dataset determined the 6
th
hour as a critical time point separating development and recovery phases of the LPS induced metabolic changes. Consensus clustering of the differential metabolites identified two distinct subsets of metabolites which displayed common coherent profiles with opposing directionality. The first group of metabolites, which were mostly associated with pathways related to lipid metabolism, was up-regulated within the first 6 hr and down-regulated by the 24
th
hr following LPS administration. The second group of metabolites, in contrast, was first down-regulated until the 6
th
hr, then up-regulated. Metabolites in this group were predominantly amino acids or their derivatives. In sum, non-targeted biochemical profiling and unsupervised multivariate analyses highlighted the prominent roles of lipid and protein metabolism in regulating the response to systemic inflammation while also revealing their dynamics in opposite directions.