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NCSB/TIFN Short-chain fatty acid project TNO, UMCG, WUR

NCSB/TIFN Short-chain fatty acid project TNO, UMCG, WUR. Barbara Bakker Albert A. de Graaf Vitor Martins dos Santos. Transorgan SCFA metabolism. In vitro and animal models to probe SCFA metabolism. Liver metabolism. Colonic metabolism. Whole body metabolism. e.g. 50 mM butyrate.

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NCSB/TIFN Short-chain fatty acid project TNO, UMCG, WUR

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  1. NCSB/TIFN Short-chain fatty acid projectTNO, UMCG, WUR Barbara Bakker Albert A. de Graaf Vitor Martins dos Santos

  2. Transorgan SCFA metabolism • In vitro and animal models to probe SCFA metabolism Liver metabolism Colonic metabolism Whole body metabolism e.g. 50 mM butyrate bacterial production portal vein hepatic vein SCFA SCFA SCFA SCFA e.g. 10 uM butyrate liver colon cells arterial pool colon lumen ? SCFA substrate SCFA project - WP2

  3. Structure of the project SCFA project – WP1

  4. WP1 - Gut microbiomics of SCFA metabolism & metagenome-scale metabolic modelsVitor dos Santos Purpose The construction of genome-scale metabolic models of the gut microbiota, focusing on SCFA metabolism and the metabolic reconstruction and subsequent classification of metabolism of all sequenced species found in the gut, allowing for a reconstruction of the gut food web SCFA project – WP1

  5. WP1 – Metagenome pathway analysis of gut microbial consortia, for SCFA production SCFA project – WP1

  6. WP2 - Purpose Develop computational models that allow to predict the rates of intestinal SCFA production and the rates of the main SCFA-derived metabolic processes in the host, using knowledge on the composition of the intestinal microbiota and the given substrate • Focus on processes associated with the proximal colon as this is the principal site of SCFA production • Use available data (acquired in TIFN C-012 “Microbe-mediated gut metabolism” project) SCFA project - WP2

  7. WP2 Data type overview – TIM-2 in vitro model e.g. 50 mM butyrate HITchip data [U-13C] starch, inulin, lactose bacterial production RNA-SIP profiles SCFA colon lumen SCFA profiles Various other unlabeled carbohydrate substrates substrate SCFA kinetics SCFA isotopomers SCFA project - WP2

  8. WP2 Data type overview - mouse [1-13C]butyrate Liver metabolism Colonic metabolism Whole body metabolism portal vein hepatic vein SCFA SCFA SCFA SCFA e.g. 10 uM butyrate liver colon cells arterial pool colon lumen ? SCFA substrate SCFA isotopomers Amino acid isotopomers + kinetics SCFA project - WP2

  9. Potential isotopic markers of colonocytes TCA cycle activity 2 [1-13C] butyrate 1-13C aspartate & 1 4-13C aspartate 4 1 5-13C glutamate 5 3 1 1-13C glutamate & SCFA project - WP2 13CO2

  10. WP2 Data type overview – pig [1-13C]butyrate Liver metabolism Different infusion rates Colonic metabolism Whole body metabolism portal vein hepatic vein SCFA SCFA SCFA SCFA e.g. 10 uM butyrate liver colon cells arterial pool colon lumen ? SCFA Levels of [1-13C]butyrate SCFA project - WP2

  11. WP2- The regulation of SCFA production • Experimental • unlabeled substrates in TIM-2  SCFA profile analysis and HITchip analysis • 13C labeled substrates in TIM-2  bacterial pathway kinetics and SIP analysis • 13C labeled caecal bolus of butyrate butyrate metabolism • 13C labeled caecal infusion of butyrate  transorgan absorption/metabolism of butyrate in pig • Computational • Multivariate “substrate characteristics  SCFA profile” prediction model • Correlation map of microbiota composition and SCFA profile • Bottom-up ODE models of fatty acid production • Extend visibility of bacterial & colonocyte fluxes from 13C experiments • Regulation Analysis of interorgan butyrate metabolism

  12. WP 3 + 4 (Groningen)The role of SCFA in mouse metabolism Short-chain fatty acids SCFA metabolism? Regulation? CO2 +ATP/ Elongation, storage Carbohydrate and (long-chain) fatty-acid fluxes

  13. The role of SCFA in mouse metabolism • Experimental • 13C labelled rectal infusion of acetate / propionate/ butyrate  fate of SCFA • 13C labelled tracers (glucose, glycerol, acetate) infusion in blood  regulatory effect of SCFA on central energy metabolism • Computational • Extend visibility of fluxes from 13C experiments • Stoichiometric map of mouse fatty acid metabolism, incl. SCFA • Bottom-up ODE models of fatty acid oxidation and the regulatory role of SCFA • Regulation Analysis • Modular Control Analysis

  14. Glucose Glucose Peripheral disposal accessible blood [1-13C]-acetate Glucose Glycogen Glucose Glucose-6-P glycerol Pyruvate CHOL Intestine alanine Acetyl-CoA lactate FFA

  15. Calculations

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