To characterize the intestinal, hepatic, muscle, and renal release and uptake of xenometabolites (non-host derived metabolites) and endogenously modified xenometabolites by measuring their across-organ net release and uptake in a post-absorptive conscious pig model.
Twelve 2–3 months old female pigs (25.6 ± 2.2 kg) had surgically-implanted catheters across portal drained viscera (PDV), splanchnic area (SPL), liver, kidney, and hindquarter muscle. Ten days after catheter implantation, overnight fasted arterial and venous plasma was collected in a conscious state and stored at -80°C. Thawed samples were analyzed by liquid chromatography-mass spectrometry. Xenometabolites were identified by retention time and MS2 spectra from in-house authentic standards and expressed as peak areas. Plasma flow measurements determined with para-aminohippuric acid dilution technology. Net organ balance rate (peak area/kg body weight/min) was calculated. Significant (P > 0.05) release or uptake was determined if tissue net balance differed from zero, using the Wilcoxon Signed Rank Test.
Forty-eight xenometabolites were structurally identified in this model. Of these, 31 had at least one tissue with a significant net release or uptake. Metabolites suggestive of intestinal origin (i.e., significant PDV net release) included 2-hydroxybenzoic acid, 4-hydroxyphenyllactic acid, acetic acid, atrolactic acid, dodecanedioic acid, hydroxycinnamic acid, p-cresol sulfate, p-cresol glucuronide, stercobilin, and several bile acids and indole derivatives. Of these, atrolactic acid, hydrocinnamic acid, indole-3-acetic acid, stercobilin, and all of the bile acids were taken up by the liver; p-cresol glucuronide was taken up by the kidneys. No xenometabolite released from the gut was taken up by muscle, but 4-hydroxyphenyllactic acid, dodecanedioic acid, and indole-3-carboxaldehyde were also released by muscle tissue.
Our study confirm gastrointestinal origins for a number of known xenometabolites. Liver and kidney are key organs for xenometabolite uptake. Other putative xenometabolites appear to have either non-gut origins or released by other tissues.
Funding provided by the US Department of Agriculture-Agricultural Research Service.