1178-P: Portal Vein Metabolites as Intermediate Regulators of the Gut Microbiome in Insulin Resistance

Previous studies have shown that there is a strong interaction between the diet and the gut microbiome. This is often linked to circulating metabolites, however, in most studies these metabolites are measured in peripheral circulation, after hepatic clearance of intestinal venous drainage. In the present study, we have determined the effects of high fat diet (HFD) and the microbiome on changes in portal and peripheral metabolites and their link to physiology by performing global metabolomics using LC-MS/MS on portal versus systemic (cardiac) blood in C57BL/6 mice on chow diet, HFD or HFD supplemented with either vancomycin or metronidazole in the drinking water to change gut flora. Among the 644 known metabolites that were identified, 77 were more abundant in cardiac blood whereas 160 were enriched in the portal blood (FC=1.5). In portal blood there was enrichment of secondary bile acids, short-chain fatty acids (butyrate), cinnamoylglycine, indoxylsulfate and hydrocinnamate that are strongly decreased by antibiotics, indicating a direct gut microbial origin. More surprisingly, we also identified several metabolites involved in the TCA cycle, including aconitate, mesaconate and the 2-hydroxyglutarate enriched in portal blood that were not affected by diet but significantly altered by both antibiotics, indicating origin in the gut microbiome. By contrast, some metabolites were enriched in cardiac blood, such as 6, 8 dihydroxypurine, 20-hydroxydocosahexaenoic acid and C46:0 triacylglyercide, were also significantly changed by antibiotics, suggesting they are peripherally produced but depend on precursors coming from gut bacteria. Thus, the interaction between gut microbiota and circulating metabolites is complex and may affect their production from the small intestine but also from extra intestinal tissues. In addition, the gut microbiome is the source of important circulating metabolites which can enter and modify cellular metabolism at the level of the TCA cycle. Disclosure F. Moreau: None. B. B. Brandao: None. J. Avila: None. H. Pan: None. J. Dreyfuss: None. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. C. B. Clish: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences, Inc., Consultant; Self; Flagship Pioneering, Sana/Cobalt.