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Infogest george van aken final
- 1. In silico modellingof the physiology of the digestive system, digestion and absorption Autor: George van Aken
- 2. Underappreciated aspect indigestion modelling: Interaction of food with the body is both ways and dynamic The food’s perspective: The food is selected, masticated, digested, absorbed and processed The body’s perspective: The body receives mechanical, nutrient and pharmacological signals; affected by time of day, mood, stress, activity, … The body adapts: release of digestive fluids, residence times, absorptive capacity, post-absorptive processing, appetite
- 3. 3 Demonstrate how biofeedback regulation of digestion can be modelled in silico Modelling published physiological studies: • Digestive fluid secretion • Gastrointestinal transit • Gut hormone release by receptor cells • Absorption rates in the small intestine Modelling material science knowledge on in vitro behaviour of food matrials: • Enzyme kinetics of digestion • Buffer capacities of proteins, mucin • Gelling behaviour of proteins • In silico (or in vitro)
- 4. 4 Main physiological mechanismsfor gastrointestinal control of nutrient absorption • Digestive fluid release • saliva, gastric fluid, gastric mucin, bile pancreatic secretion and intestinal secretion • Adjusted to needs • Gastric emptying rate • Limiting the delivery of calories to the small intestine • Avoiding harmfull acity in the small intestine • Intestinal absorption rate • Limiting the absorption rate of calories by the small intestine • Seems to avoid blocking of protein absorption by carbohydrates and fat • Satiety • Limits the amount of calories ingested, by nervous and hormonal signals by the small intestine Receptor cells are present in the absorptive cell layer covering the inside of the small intestine, reacting on the detection of food material and absorbable nutrients in the small intestine
- 5. Compartmental in-silico digestionmodel Plate 1 Food composition Corpus Antrum Duodenum Jejunum 1 Jejunum 2 Jejunum 3 Ileum 1 Ileum 2 Ileum 5 Ileum 6 Colon Ileum 3 Ileum 4 nutnut nut nut nut nut nut nut nut nut pylorus Nutrient density in chyme L-cells PYY, GLP1 Bile Water flux Bile absorbed Mouth (saliva, residence time) absorptionFundus Plate 3 Food composition Plate 2 Food composition Plate 4 Food composition Plate 5 Food composition Food composition Food compound fat Absorbable species Food compound Food compound protein carbohydates Degistive fluids I-cells CCK K-cells GIP
- 6. About the model •1 single model that has been extended and refined over the years • Mechanisms and parameters are derived from physiological and in vitro studies • Some parameters have been derived by fitting to in vivo studies and then retained by adding them to the model • The modelling results shown are not fits to the data but results from the program as is with parameters derived from previous studies • Complication encountered: Variations between individuals in a study are larger than the deviations between measured and simulated averages • LIKE TO DISCUSS HOW TO DEVELOP IT FURTHER: • With whom? • What modelling platform? 6
- 7. Modelling gastric motility 7 fundus antrum corpus duodenum Solid proteins Freeproteins Fed state: 3 peristaltic cycles/min; 0 < C < 1 0< C < 1/3: X% fundus empties into corpus * based on measurements by Tack 1998 and Janssen 2011 pepsin Fractional emptying F: 0<F<1: F is a function of intestinal and blood hormone stressors: pH, osmotic value, nutrient detection, blood CCK, GIP, PYY
- 8. Modelling gastric fluidsecretion 8 fundus antrum corpus water 96% mucus 2% HCl 0.1 M pepsin 0.5% duodenum Solid proteins Buffering free proteins pH pH pH pH Basis rate 0.1 ml/min Stimulated* mole H+/min = Reduce stimulated secretion by a factor: ̶̶ *Based on fit of measurements by Konturec (1971) + = 1 (simulates the effects of gastrin and secretin)
- 9. Physiological limit tointestinal caloric absorption rate measured in pig 9 Governing equation derived and applied in the model (Weber, Ehrlein, Digestive diseases and science, 1998, 43(6), 1141-1153) Caloric rate of absorption increases with infusion rate, independent of the relative ratios carbohydrate, protein and fat
- 10. Modelling results - Liquidbeverages: gastric emptying, fullness and hunger - Leucin blood levels after protein solutions - Cheese gastric digestion and effect of fullness and hunger - Glycemic effects of carbohydrates 10
- 11. Liquid beverages: gastric emptying,fullness and hunger Gastric emptying of beverages Mixed nutrient beverages varying in calories and viscosity In vivo experiments: Guido Camps, Thesis, Wageningen University (2017) 11 Gastric volume measured by MRI- imaging
- 12. Gastric emptying ofbeverages 12 In vivo experiments: Guido Camps, Thesis, Wageningen University (2017) How do caloric content and viscosity affect gastric volume during emptying?
- 13. Leucin blood levelsafter protein solutions • Leucin promotes muscle protein growth, relevant for top sporters and the eldely • Faster and higher peaks of blood Leucin are thought to be advantageous 13
- 14. Modelling protein digestionand absorption Included in the model: • pH dependence of pepsin activity • Adjust the dynamic release of pepsin in such a way that an activity in gastric juice of 2000 U/ml is obtained for the fed state at the pH optimum Based on: Minekus et al, A standardized static in vitro digestion method suitable for food – an international consensus, Food and Function (2014) 5, 113-1124) • Curves of pH versus gastric acid addition for mucin and alimentary proteins (-casein, BSA and -lg) • Luminal CCK Releasing Protein, competing with alimentary digestable protein and peptides for digestion by pancreatic proteases. It’s detection leads to CCK secretion by I-cells, exciting pancreatic fluid an bile release and slowing gastric emptying and reducing gastric tone • Formation of a protein gel under gastric conditions for -casein 14 • -casein: Pertzoff and Carpenter, 1932. • BSA: Curvale, 2009. • -lg: Tanford and Nozaki, J. Biological Chem., 1959. • Gastric mucin: Li, et al., 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences, 2011.
- 15. Example: Appearance ofLeucine in the blood plasma 15 Experimental work from publications by Dangin 2001, 2002 and 2003 Appearance of exogenous Leucine Tracer Leucine appearance in blood. • Tracer Leucine added separately • Tracer Leucin incorporated in the protein P L L L L P L L whey casein Whey, casein Gelling protein (casein) Non gelling protein (whey) Preferred: Fast peaked release and no leucine off taste
- 16. Extrapolation, predicted effectof coadministration of glucose or fat 16 Same as Figure 2, but now with a co-administration of 20 g glucose. Same as Figure 2, but now with a co-administration of 20 g fat. 20 g whey protein supplement
- 17. Cheese gastric digestionand effect of fullness and hunger - Cheese clumps remain in the stomach for longer 17
- 18. Effect of solidsin the stomach 18 Control meal: Yoghurt with emulsified fat Active meal: Yoghurt with grated cheese Similar nutrient composition and energy content In vivo experiments in collaboration with IFR: Mackie, A.R., Rafiee, H., Malcolm, P., Salt, L., van Aken, G.A., Specific structuring of food emulsions leads to increased satiation and hunger suppression. Am. J. Physiol. Gastrointestinal and Liver physiology (2013), 304, G1038-G1043. Included in the model: cheese particles erode away at their surfaces by pepsic digestion. This is slower than digestion of the protein in solution
- 19. Experimental data versussimulation -8,00 -6,00 -4,00 -2,00 0,00 2,00 4,00 6,00 8,00 -50,00 0,00 50,00 100,00 150,00 200,00 250,00 Time after meal (minutes) Change in Hunger Active Control -4,00 -2,00 0,00 2,00 4,00 6,00 8,00 10,00 -50,00 0,00 50,00 100,00 150,00 200,00 250,00 Time after meal (minutes) Change in Fullness Active Control Hunger calculated from simulated nutrients in SI Fullness calculated from simulated gastric tone simulated simulated simulated (a.u.) simulated
- 20. Glycemic effects ofcarbohydrates Sucrose, Glucose, Arabinose, Starches, Inulin, Pectins, …. 20
- 21. SI absorption glucosemeasured in vivo • The Role of Sodium in Intestinal Glucose Absorption in Man, Ward A. Olsen and Franz J. Ingelfinger, J Clin Invest. 1968 May; 47(5): 1133-1142 • Absorption of glucose, sodium, and water by the human jejunum studied by intestinal perfusion with a proximal occluding balloon and at variable flow rates, R. Modigliani, J. J. Bernier, Gut, 1971, 12, 184-193 Appears to follow Menten kinetics, Kmax and Ki measured for oligosacharides, sugars, petides, amino acids
- 22. Only fast monomerabsorption of glucose, galactose and fructose Transporter proteins across the apical cell membrane of absorptive enterocytes • Glucose and galactose co-absorbed with Na+ and water by SGLT-1 (high capacity) Sodium-dependent GLucose coTransporter 1 co-transports 2 Na+ and 260 H2O per glucose. About 3 liter of water every 100 grams of glucose absorbed! • Fructose and Glucose by GLUT5 (lower capacity) GLUcose Transporter type 5 22
- 23. Modelling brush bordertransporters and digestive enzymes GLUCOSE absorption rate form in vivo intubation measurements, SUCROSE, ISOMALTULOSE and STARCH as extension on glucose absorption model by including modelled amylase and brush border digestion; includes calculation of the concentrations at the brush border
- 24. Glucose homeostasis Periferal blood glucose Toliċ atal. J. Theor. Biol. (2000) Liver Muscles, adipose Brain, nerves Liver, gut insulin − Delay time ~ 36 min + ++ + Glycemic peak becomes high if the rate of glucose absorption is high: fast increase of carbohydrates that are quickly absorbed as glucose by the gut. based on mathematical fits of many in vivo and in vitro physiological studies + difference Empirical
- 25. Glycemic effects of25 g glucose or sucrose in 250 ml water B.M. Lee and T.M.S. Wolever, European Journal of Clinical Nutrition (1998) 52, 924-928 Blood glucose peaks: • Higher for glucose than for sucrose • For both at about 30 min Blood insulin peaks: • Higher for glucose than for sucrose • For both at about 30 min glucose Sucrose reference bread fructose
- 26. Sucrose and isomaltulose 75g of either sucrose or isomaltulose + 400 g water in healthy pre-diabetics Van Can et al. 2009, Br. J. Nutrition, 102, 1408–1413 Isomaltulose Sucrose Vmax for brush border digestion ~70% smaller than for sucrose
- 27. L-Arabinose uncompetitively inhibitssucrase R. Nolles and A. Benschop, L-Arabinose: A Novel Food Ingredient For A Healthier Living, Biotech, Biomaterials and Biomedical: TechConnect Briefs 2016, 5-8 L-arabinose The small discrepancy may suggest that the absorption of arabinose is modelled slightly too fast
- 28. Ideas on howto bring this further? - Academic collaborations? - In silico modelling platforms? - Direct inclusion into in vitro modelling? - Commercial applications?
- 29. Proteolysis simulation symplified schemefor the digestion of protein “1” as used in the model 1Pep 1 1PepPan pepsin pancreatin 1AA > 1 kDa > 1 kDa < 1 kDa 1Pan > 1 kDa < 1 kDa < 1 kDa DH DH DH Leu EAA NEA pancreatin 1Peptides < 1 kD BB peptidases
- 30. Modelling brush bordertransporters and digestive enzymes Brush border enzyme kinetics is usually not rate limiting for the pure carbohydrates However: • many real foods contain inbitors • various intolerances related to inadequacies (lactose, sucrose intolerance)
- 31. Steady state enzymeinhibitor equations •Michaelis-Menten equation for competitive, uncompetitive and non- competitive enzyme inhibition • Kinetic inhibitory constants have been measured in vitro for various substances • Applicable for digestion modelling if the concentrations at the absorptive surface is known. For example sucrase is inhibited competitively by maltose, isomaltulose and acompetitively by arabinose and xylose.
- 32. Diffusive and convective transport,absorption and production/removal by brush border enzymes Small intestinal lumen Stirred by perstalsis Unstirred mucus layer Absorptive enterocites Portal blood cb cl Diffusion + liquid drag from water absorption and secretion Absorption Transport to blood Receptor cells Mucus coating thickness Factorial surface increase F Circulation Brush border enzymes 1 cm2 cb calculated analytically:
- 33. Calculation cycle Calculate concentrations at thebrush border Calculate digestion by brush border enzymes into absorbable species Calculate absorption rate Correct absorption rates to maximum caloric absorption rate 33 Calculate brush border neural and hormone signals Calculate digestive fluids release Calculate gastric tension, motility and emptying Calculate adjusted gut transit rate Calculate digestion Calculate entry to portal blood Calculate insulin release and degradation Calculate blood glucose Input from in vitro digestion studies About 1 cycle/second
- 34. Gastric emptying ofbeverages 34 Together to the next level In vivo experiments: Guido Camps, Thesis, Wageningen University (2017) Possibly nutrients detected further down the SI enhance CCK secretion, further reducing gastric tone Low calory drinks give less hunger reductionLow calory drinks give relatively more fullness Various references for physiology of fullness and hunger, e.g.; Little, Gastroenterology 2007, 133, 1124-1131 Welch et al, Gut (1988), 29, 306-311