An Atlas of Inter-Organ Metabolite Trafficking in Health and Atherogenic Conditions

Mammalian organs continuously exchange circulating metabolites for organismal health and survival. However, the landscape of this fundamental process and its perturbation by diet and disease is unknown. Using arteriovenous metabolomics, tissue transcriptomics, hormone arrays and multiple metabolic disease models in pigs, we generated a blueprint of ~1300 circulating metabolites trafficking across 10 organs during fasting/feeding, Western diet and cardiovascular disease progression induced by low-density lipoprotein receptor (LDLR) deficiency. We discovered numerous feeding-dependent and -independent inter-organ metabolite trafficking events and mechanisms by which these are disrupted by Western diet via altered metabolite concentration gradients and hormone imbalances. Surprisingly, both Western diet and LDLR deficiency trigger release of bile acids by multiple extra-hepatic organs. Such abnormality dramatically elevates circulating bile acids, which induce atherogenic inflammation. These findings and resources in highly relevant pig models reveal intricate inter-organ crosstalk across pathophysiological conditions, offering unparalleled insights into diet effects and disease mechanisms.