Results from a Validated in vitro Gastrointestinal Model (TIM) used as input Data for in silico Modeling Give Highly Predictive Information for the Human Situation
Main Article Content
Abstract
The aim of this review paper is to evaluate the predictive quality of a combination of in vitro dynamic gastrointestinal models, mucosal transit models and in silico kinetic modeling. The TNO gastro-Intestinal Model (TIM) is a computer-controlled system, mimicking essential gastrointestinal parameters of the stomach, small intestine and large intestine. The systems have dialysis or filtration units connected to the intestinal compartments. TIM settings are adapted to the condition that has to be simulated, such as fasted and fed state, age, and co-medication. In this way the transit and digestibility of food, release, dissolution, and bioaccessibility of nutrients, drugs, and metabolites can be studied. The TIM Systems have been validated in comparison to human studies for various food products and oral drugs, published in peer-reviewed journals. The results show the potential availability for absorption, called 'bioaccessibility'. Combining TIM with mucosal transit assays, it is possible to also analyze the intestinal absorption. But for predicting bioavailability and plasma concentrations in time it needs additional kinetic data, such as distribution, metabolism, and excretion. TIM bioaccessibility data and (published) kinetic data can be used as input in commercial in silico models or specifically developed in silico modeling. Validation studies show a high predictive quality for human nutrient and drug bioavailability and plasma concentrations. Maybe not (yet) in all cases the predictions will cover for 100% the human data, so there is room for improvement. However, the reviewed studies clearly show the strength of combining a validated gastrointestinal model with physiological kinetic data in in silico modeling. It certainly will replace animal experiments and will strongly increase the success rate of follow-up human studies, saving time and costs.
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How to Cite
HAVENAAR, Robert; BELLMANN, Susann.
Results from a Validated in vitro Gastrointestinal Model (TIM) used as input Data for in silico Modeling Give Highly Predictive Information for the Human Situation.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3136>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3136.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2 Minekus M, Alminger M, Alvito P et al. A standardized static in vitro digestion method suitable for food international consensus. Food Function 2014;5:1113-1124. doi:10.1039/c3fo60702.
3 Alminger M, Aura,A-M, Bohn T et al. In vitro models for studying secondary plant metabolite digestion and bioaccessibility. Compreh. Rev. Food Sci. Food Safety 2014;13:413-436.
4 Dupont D, Alric M, Blanquet-Diot S et al. Can dynamic in vitro digestion systems mimic the physiological reality? Crit. Rev. Food Sci. Nutr. 2018;Jan23:1-17. doi:10.1080/10408398.2017.1421900
5 Marze S. Bioavailability of nutrients and micronutrients: Advances in modeling and in vitro approaches. Annu. Rev. Sci. Techn. 2017;8:35-55.
6 Ting Y, Zhao Q, Xia C et al. Using in vitro and in vivo models to evaluate the oral bioavailability of neutraceuticals. J. Agric. Food Chem. 2015;63:1332-1338.
7 Kostewicz ES, Abrahamsson B, Brewster M et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur. J. Pharm. Sci. 2014;57(1):342-366.
8 Butler J, Hens B, Vertzoni M et al. In vitro models for the prediction of in vivo performance of oral dosage forms: Recent progress from partnership through the IMI OrBiTo collaboration. Eur.J . Pharmaceutics Biopharmaceutics, 2019;136:70-83.
9 Lex TR, Rodriguez JD, Zhang L et al. Development of in vitro dissolution testing methods to simulate fed conditions for immediate release solid oral dosage forms. The AAPS Journal 2022;24:40.
10 Williams CF, Walton GE, Jiang L et al. Comparative analysis of intestinal tract models. Ann. Rev. Food Sci. Technol. 2015;6:329-350.
11 Minekus M, Marteau P, Havenaar R et al. A multi compartmental dynamic computer-controlled model simulating the stomach and small intestine. Alternatives Lab. Animals (ATLA) 1995;23:197-209.
12 Minekus M, Smeets-Peeters MJ, Bernalier A et al. A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products. Appl. Microb. Biotechn. 1999;53:108-114.
13 Aguirre M, Eck A, Koenen ME et al. Evaluation of an optimal preparation of human standardized fecal inocula for in vitro fermentation studies. J. Microbiol. Methods 2015;117: 78-84.
14 Aguirre M, Jonkers DM, Troost F et al. In vitro characterization of the impact of different substrates on metabolite production, energy extraction and composition of gut microbiota from lean and obese subjects. Plos One 2014;Nov.26:1-23. doi:10.1371/journal.pone.0113864.
15 Tabernero M, Venema K, Maathuis, AJ et al. Metabolite production during in vitro colonic fermentation of dietary fiber: Analysis and comparison of two European diets. J. Agric. Food Chem. 2011;59(16):8968-8975.
16 Van Nuenen HM, Venema K, Van der Woude JC et al. The metabolic activity of fecal microbiota from healthy individuals and patients with inflammatory bowel disease. Digestive Dis. Sci. 2004;49(3):485-491.
17 Rose DJ, Venema K, Keshavarzian A et al. Starch-entrapped microspheres show a beneficial fermentation profile and decrease in potentially harmful bacteria during in vitro fermentation in faecal microbiota obtained from patients with inflammatory bowel disease. Br. J. Nutr. 2010;103:1514-1524.
18 Kovatcheva-Datchary P, Egert M, Maathuis A et al. Linking phylogenetic identities of bacteria to starch fermentation in an in vitro model of the large intestine by RNA-based stable isotope probing. Environmental Microbiol. 2009;11(4):914–926.
19 Rajilic-Stojanovic M, Maathuis A, Heilig H et al. Evaluating the microbial diversity of an in vitro model of the human large intestine by phylogenetic microarray analysis. Microbiology 2010;156: 3270-3281.
20 Verwei M, Minekus M, Zeijdner E et al. Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms. Int. J. Pharm. 2016;498:178-186.
21 Liu J, Nagapudi K, Dolton MJ et al. Utilizing tiny-TIM to assess the effect of acid-reducing agents on the absorption of orally administered drugs. J. Pharmaceutical Sci. 2021;110:3020−3026.
22 Reis PM, Raab TW, Chuant JY et al. Influence of surfactants on lipase fat digestion in a model gastrointestinal system. Food Biophysics 2008'3:370-381.
23 Domoto N, Koenen ME, Havenaar R et al. The bioaccessibility of eicosapentaenoic acid was higher from phospholipid food products than from mono- and triacylglycerol food products in a dynamic gastrointestinal model. Food Sci. Nutr. 2013;1(6):409-415.
24 Minekus M, Jelier M, Xiao J.-Z et al. Effect of partially hydrolyzed guar gum (PHGG) on the bioaccessibility of fat and cholesterol. Biosci. Biotechnol. Biochem. 2005;69(5):932-938.
25 Van Loo-Bouwman CA, Naber TH, Minekus M et al. Food matrix effects on bioaccessibility of β-carotene can be measured in an in vitro gastrointestinal model. J. Agric. Food Chem. 2014;62(4):950-955.
26 Havenaar R, Anneveld B, Hanff LM et al. In vitro gastrointestinal model (TIM) with predictive power, even for infants and children? Internat. J. Pharm. 2013;457:327-332.
27 Fondaco D, AlHasawi F, Lan Y et l. Biophysical aspects of lipid digestion in human breast milk and Similac infant formulas. Food Biophysics 2015;10:282-291.
28 Maathuis A, Havenaar R, He T et al. Protein digestion and quality of goat and cow milk infant formula and human milk under simulated infant conditions. J. Pediatric Gastroenterol. Nutr. 2017;65 (6):661-666. doi:10.1097/MPG.0000000000001740.
29 Denis S, Sayd T, Georges A et al. Digestion of cooked meat proteins is slightly affected by age as assessed using the dynamic gastrointestinal TIM model and mass spectrometry. Food Function 2016;7(6):2682-2691.
30 Bellmann S, Lelieveld J, Gorissen T et al. Development of an advanced in vitro model and its evaluation versus human gastric physiology. Food Res. Internat. 2016;88:191-198.
31 Hopgood M, Reynolds G, Barker R. Using Computational Fluid Dynamics to Compare Shear Rate and Turbulence in the TIM-Automated Gastric Compartment With USP Apparatus II. J. Pharmaceutical Sci. 2018;107(7):1911-1919.
32 Smeets-Peeters MJ, Minekus M, Havenaar R et al. Description of a dynamic in vitro model of the dog gastrointestinal tract and an evaluation of various transit times for protein and calcium. Alternatives Lab. Animals (ATLA) 1999;27:935-949.
33 Avantaggiato G, Havenaar R, Visconti A. Assessment of the muli-mycotoxin binding efficacy of a carbon/aluminosilicate based product in an in vitro gastrointestinal model. J. Agricul. Food Chem. 2007;55:4810-4819.
34 Martinez RCR, Cardarelli HR, Borst W et al. Effect of galactooligosaccharides and Bifidobacterium animalis Bb-12 on growth of Lactobacillus amylovorus DSM 16698, microbial community structure, and metabolic production in an in vitro colonic model set up with human or pig microbiota. FEMS Microbiol. Ecol. 2013;84:110-123.
35 Williams GA, Koenen ME, Havenaar R et al. Survival of Mycobacterium bovis BCG oral vaccine during transit through a dynamic in vitro model simulating the upper gastrointestinal tract of badgers. Plos One 2019;14(4):e0214859. doi.org/10.1371/journal.pone.0214859.
36 Brito-de la Fuente E, Secouard S, Siegert N et al. Determination of dissolution profile and bioaccessibility of ketosteril using an advanced gastrointestinal In vitro model. Dissolution Technol. May2019. doi.org/10.14227/DT260219P30.
37 Havenaar R, Barker R, Butler J et al. Repeatability and reproducibility of simulated fasted and fed state gastrointestinal conditions and paracetamol bioaccessibility in the dynamic in vitro models TIM-1 and tiny-TIMsg. 2022.(submitted for publication).
38 Havenaar R, Maathuis A, De Jong A et al. Herring roe protein had a high digestible indispensable amino acid score (DIAAS) using a dynamic in vitro gastrointestinal model. Nutr. Res. 2016;36:798-807.
39 Helbig A, Silletti E, van Aken GA et al. Lipid digestion of protein stabilized emulsions investigated in a dynamic in vitro gastro-intestinal model system. Food Dig. 2013;4:58–68. doi:10.1007/s13228-012-0029-6.
40 Lafond M, Bouza B, Eyrichine S et al. In vitro gastrointestinal digestion study of two wheat cultivars and evaluation of xylanase supplementation. J. An. Sci. Biotechnol. 2015;6(1)Art.#5.
41 Haraldsson A-K, Rimsten L, Alminger M et al. Digestion of barley malt porridges in a gastrointestinal model: Iron dialysability, iron uptake by Caco-2 cells and degradation of ß-glucan. J. Cereal Sci. 2005;42:243-254.
42 Salovaara S, Larsson-Alminger M, Eklund-Jonsson C et al. Prolonged transit time through the stomach and small intestine improves iron dialyzability and uptake in vitro. J. Agric. Food Chem. 2003;51:5131-5136.
43 Verwei M, Arkbåge K, Havenaar R et al. Folic acid and 5-Methyl-tetrahydrofolate in fortified milk are bioaccessible as determined in a dynamic in vitro gastrointestinal model. J. Nutr. 2003;133:2377-2383.
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