Our previous study revealed a significant anti-atherosclerotic effect of Kgengwe seed powder (KSP) in low-density lipoprotein receptor knockout (LDL-r-KO) mice. The importance of various lipid and protein metabolites, including certain amino acids and fatty acids on atherogenesis has been well established. Thus, we used plasma and fecal samples from our previous study to further study the association of such metabolites with atherosclerotic lesion development. Male LDL-r-KO mice were provided with an atherogenic diet supplemented with (treated, n = 10) or without (controls, n = 10) 10% (w/w) KSP for 20 weeks. The treated group showed significantly (P <
0.05) higher plasma levels of many amino acids plus propionic acid, indoleacetic acid, pyruvic acid, beta-hydroxybutyric acid, alpha-ketoglutaric acid, trimethylamine N-oxide, LYSOC16:0, LYSOC18:0, and LYSOC18:2, as compared with those of the control group. Similarly, several oxylipins, including 15-keto prostaglandin E2, 9,10,13-trihydroxy-octadecenoic acid, 9,10-epoxy-octadecenoic acid, and 12,13-epoxy-octadecenoic acid increased by approximately 2.0 log2 folds (P <
0.05) in the plasma of the treated group. Other oxylipins, including 15,16-epoxy- octadecadieonic acid, 13-hydroxy-octadecadienoic acid, and prostaglandin E2 showed also an increased level, but to a lesser extent. Furthermore, our findings showed a significant positive correlation between plasma concentrations of prostaglandin E2 and IL-10 in the treated mice. We also observed a significant negative association between atherosclerotic lesion size and plasma levels of citrulline, lysine, alpha-ketoglutaric acid, and 15,16 epoxy-octadecadienoic acid. Additional in vitro and in vivo studies are needed to explore the mechanisms of such associations.