Can dynamic in vitro digestion systems mimic the physiological reality?

ABSTRACT During the last decade, there has been a growing interest in understanding the fate of food during digestion in the gastrointestinal tract in order to strengthen the possible effects of food on human health. Ideally, food digestion should be studied in vivo on humans but this is not always ethically and financially possible. Therefore simple static in vitro digestion models mimicking the gastrointestinal tract have been proposed as alternatives to in vivo experiments but these models are quite basic and hardly recreate the complexity of the digestive tract. In contrast, dynamic models that allow pH regulation, flow of the food and injection in real time of digestive enzymes in the different compartments of the gastrointestinal tract are more promising to accurately mimic the digestive process. Most of the systems developed so far have been compared for their performances to in vivo data obtained on animals and/or humans. The objective of this article is to review the validation towards in vivo data of some of the dynamic digestion systems currently available in order to determine what aspects of food digestion they are able to mimic. Eight dynamic digestion systems are presented as well as their validation towards in vivo data. Advantages and limits of each simulator is discussed. This is the result of a cooperative international effort made by some of the scientists involved in Infogest, an international network on food digestion

[1]  R. Havenaar,et al.  A computer-controlled system to simulate conditions of the large intestine with peristaltic mixing, water absorption and absorption of fermentation products , 1999, Applied Microbiology and Biotechnology.

[2]  C. Cueva,et al.  The Computer-Controlled Multicompartmental Dynamic Model of the Gastrointestinal System SIMGI , 2015 .

[3]  L. Marciani,et al.  Effect of intragastric acid stability of fat emulsions on gastric emptying, plasma lipid profile and postprandial satiety , 2008, British Journal of Nutrition.

[4]  W. Verstraete,et al.  The prenylflavonoid isoxanthohumol from hops (Humulus lupulus L.) is activated into the potent phytoestrogen 8-prenylnaringenin in vitro and in the human intestine. , 2006, The Journal of nutrition.

[5]  D. Dupont,et al.  Validation of a new in vitro dynamic system to simulate infant digestion. , 2014, Food chemistry.

[6]  W. Verstraete,et al.  Different human gut models reveal the distinct fermentation patterns of Arabinoxylan versus inulin. , 2013, Journal of agricultural and food chemistry.

[7]  R. Singh,et al.  Gastric emptying rate and chyme characteristics for cooked brown and white rice meals in vivo. , 2013, Journal of the science of food and agriculture.

[8]  M. Wickham,et al.  The Design, Operation, and Application of a Dynamic Gastric Model , 2012 .

[9]  S Blanquet-Diot,et al.  Digestion of cooked meat proteins is slightly affected by age as assessed using the dynamic gastrointestinal TIM model and mass spectrometry. , 2016, Food & function.

[10]  W. D. de Vos,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. , 2009, Environmental microbiology.

[11]  J. Elashoff,et al.  Analysis of gastric emptying data. , 1982, Gastroenterology.

[12]  R. Singh,et al.  Gastric pH Distribution and Mixing of Soft and Rigid Food Particles in the Stomach using a Dual-Marker Technique , 2014, Food Biophysics.

[13]  R. Havenaar,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. , 2016, International journal of pharmaceutics.

[14]  J. Cardot,et al.  Use of Artificial Digestive Systems to Investigate the Biopharmaceutical Factors Influencing the Survival of Probiotic Yeast During Gastrointestinal Transit in Humans , 2011, Pharmaceutical Research.

[15]  S. Marze,et al.  A microfluidic device to study the digestion of trapped lipid droplets. , 2014, Food & function.

[16]  L. Marciani,et al.  Antral motility measurements by magnetic resonance imaging , 2001, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[17]  R. Havenaar,et al.  Estimation of the bioavailability of iron and phosphorus in cereals using a dynamic in vitro gastrointestinal model. , 1997 .

[18]  A. Gáspár,et al.  Preparation and characterization of a packed bead immobilized trypsin reactor integrated into a PDMS microfluidic chip for rapid protein digestion. , 2017, Talanta.

[19]  P. Åman,et al.  Digestion of barley malt porridges in a gastrointestinal model: Iron dialysability, iron uptake by Caco-2 cells and degradation of β-glucan , 2005 .

[20]  A. Bast,et al.  Effect of bioprocessing of wheat bran in wholemeal wheat breads on the colonic SCFA production in vitro and postprandial plasma concentrations in men. , 2011, Food chemistry.

[21]  L. Marciani,et al.  Effect of meal viscosity and nutrients on satiety, intragastric dilution, and emptying assessed by MRI. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[22]  D. Bergel Geigy Scientific Tables , 1991 .

[23]  Andreas Stallmach,et al.  Every slow-wave impulse is associated with motor activity of the human stomach. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[24]  A. Esteban-Fernández,et al.  Application of a new dynamic gastrointestinal simulator (SIMGI) to study the impact of red wine in colonic metabolism , 2015 .

[25]  W. D. de Vos,et al.  Evaluating the microbial diversity of an in vitro model of the human large intestine by phylogenetic microarray analysis. , 2010, Microbiology.

[26]  David Martin Phinney,et al.  Design, Construction, and Evaluation of a Reactor Designed to Mimic Human Gastric Digestion , 2013 .

[27]  R. Singh,et al.  Disintegration of solid foods in human stomach. , 2008, Journal of food science.

[28]  W. Verstraete,et al.  Validation of the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) Reactor Using Microorganism-associated Activities , 1994 .

[29]  D. Dupont,et al.  Impact of pasteurization of human milk on preterm newborn in vitro digestion: Gastrointestinal disintegration, lipolysis and proteolysis. , 2016, Food chemistry.

[30]  W. Verstraete,et al.  Microbial and dietary factors associated with the 8-prenylnaringenin producer phenotype: a dietary intervention trial with fifty healthy post-menopausal Caucasian women , 2007, British Journal of Nutrition.

[31]  W. Verstraete,et al.  Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem , 1993, Applied Microbiology and Biotechnology.

[32]  K. Venema,et al.  The Effect of Lactulose on the Composition of the Intestinal Microbiota and Short-chain Fatty Acid Production in Human Volunteers and a Computer-controlled Model of the Proximal Large Intestine , 2003 .

[33]  Philippe Marteau,et al.  A Multicompartmental Dynamic Computer-controlled Model Simulating the Stomach and Small Intestine , 1995 .

[34]  E. Zoetendal,et al.  Arabinoxylans and inulin differentially modulate the mucosal and luminal gut microbiota and mucin-degradation in humanized rats. , 2011, Environmental microbiology.

[35]  Susan A. Barker,et al.  Achieving Antral Grinding Forces in Biorelevant In Vitro Models: Comparing the USP Dissolution Apparatus II and the Dynamic Gastric Model with Human In Vivo Data , 2011, AAPS PharmSciTech.

[36]  Monique Alric,et al.  Increased EHEC survival and virulence gene expression indicate an enhanced pathogenicity upon simulated pediatric gastrointestinal conditions , 2016, Pediatric Research.

[37]  W. Verstraete,et al.  Cholesterol lowering in pigs through enhanced bacterial bile salt hydrolase activity , 1998, British Journal of Nutrition.

[38]  L. Etienne-Mesmin,et al.  Dynamic In Vitro Models of the Human Gastrointestinal Tract as Relevant Tools to Assess the Survival of Probiotic Strains and Their Interactions with Gut Microbiota , 2015, Microorganisms.

[39]  A. Bast,et al.  Bioprocessing of wheat bran in whole wheat bread increases the bioavailability of phenolic acids in men and exerts antiinflammatory effects ex vivo. , 2011, The Journal of nutrition.

[40]  W. Verstraete,et al.  Prebiotic effects of chicory inulin in the simulator of the human intestinal microbial ecosystem. , 2004, FEMS microbiology ecology.

[41]  Elaine C P De Martinis,et al.  Effect of galactooligosaccharides and Bifidobacterium animalis Bb-12 on growth of Lactobacillus amylovorus DSM 16698, microbial community structure, and metabolite production in an in vitro colonic model set up with human or pig microbiota. , 2013, FEMS microbiology ecology.

[42]  R. Havenaar,et al.  Use of a gastro-intestinal model and gastroplus[tm] for the prediction of in vivo performance , 2006 .

[43]  Monique Alric,et al.  Investigation of the Biopharmaceutical Behavior of Theophylline Hydrophilic Matrix Tablets Using USP Methods and an Artificial Digestive System , 2007, Drug development and industrial pharmacy.

[44]  W. Verstraete,et al.  Eubacterium limosum activates isoxanthohumol from hops (Humulus lupulus L.) into the potent phytoestrogen 8-prenylnaringenin in vitro and in rat intestine. , 2008, The Journal of nutrition.

[45]  D. Laukens,et al.  Decreased colonization of fecal Clostridium coccoides/Eubacterium rectale species from ulcerative colitis patients in an in vitro dynamic gut model with mucin environment. , 2012, FEMS microbiology ecology.

[46]  L. Etienne-Mesmin,et al.  Relevance and challenges in modeling human gastric and small intestinal digestion. , 2012, Trends in biotechnology.

[47]  Monique Alric,et al.  Combining the dynamic TNO-gastrointestinal tract system with a Caco-2 cell culture model: application to the assessment of lycopene and alpha-tocopherol bioavailability from a whole food. , 2009, Journal of agricultural and food chemistry.

[48]  J. V. van Bilsen,et al.  Digestibility of transglutaminase cross-linked caseinate versus native caseinate in an in vitro multicompartmental model simulating young child and adult gastrointestinal conditions. , 2013, Journal of agricultural and food chemistry.

[49]  K. Venema,et al.  D-Tagatose increases butyrate production by the colonic microbiota in healthy men and women , 2005 .

[50]  Robert Havenaar,et al.  In vitro gastrointestinal model (TIM) with predictive power, even for infants and children? , 2013, International journal of pharmaceutics.

[51]  S. Blanquet-Diot,et al.  Enterohemorrhagic Escherichia coli infection has donor-dependent effect on human gut microbiota and may be antagonized by probiotic yeast during interaction with Peyer’s patches , 2015, Applied Microbiology and Biotechnology.

[52]  C. Cueva,et al.  Development of human colonic microbiota in the computer-controlled dynamic SIMulator of the GastroIntestinal tract SIMGI , 2015 .

[53]  R. Havenaar,et al.  Survival of lactic acid bacteria in a dynamic model of the stomach and small intestine: validation and the effects of bile. , 1997, Journal of dairy science.

[54]  M. Ferrua,et al.  Modeling the Fluid Dynamics in a Human Stomach to Gain Insight of Food Digestion , 2010, Journal of food science.

[55]  L. Marciani,et al.  Assessment of antral grinding of a model solid meal with echo-planar imaging. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[56]  W. Verstraete,et al.  Incorporating a mucosal environment in a dynamic gut model results in a more representative colonization by lactobacilli , 2011, Microbial biotechnology.

[57]  H. Flint,et al.  High-protein, reduced-carbohydrate weight-loss diets promote metabolite profiles likely to be detrimental to colonic health. , 2011, The American journal of clinical nutrition.

[58]  D. Dupont,et al.  Holder pasteurization impacts the proteolysis, lipolysis and disintegration of human milk under in vitro dynamic term newborn digestion , 2016 .

[59]  S. Blanquet-Diot,et al.  Development and validation of a new dynamic computer‐controlled model of the human stomach and small intestine , 2016, Biotechnology and bioengineering.

[60]  J. Jardin,et al.  Tracking the in vivo release of bioactive peptides in the gut during digestion: Mass spectrometry peptidomic characterization of effluents collected in the gut of dairy matrix fed mini-pigs , 2014 .

[61]  C. Lentner Units of measurement, body fluids, composition of the body, nutrition , 1981 .

[62]  O. Orwar,et al.  Microfluidic flow cell for sequential digestion of immobilized proteoliposomes. , 2012, Analytical chemistry.

[63]  G. Schaafsma The Protein Digestibility-Corrected Amino Acid Score (PDCAAS)--a concept for describing protein quality in foods and food ingredients: a critical review. , 2005, Journal of AOAC International.

[64]  W. Verstraete,et al.  PCR-DGGE-based quantification of stability of the microbial community in a simulator of the human intestinal microbial ecosystem. , 2004, FEMS microbiology ecology.

[65]  I. Raskin,et al.  Effects of a high fat meal matrix and protein complexation on the bioaccessibility of blueberry anthocyanins using the TNO gastrointestinal model (TIM-1). , 2014, Food chemistry.

[66]  K. Venema,et al.  To pool or not to pool? Impact of the use of individual and pooled fecal samples for in vitro fermentation studies. , 2014, Journal of microbiological methods.

[67]  Survival of cheese-ripening microorganisms in a dynamic simulator of the gastrointestinal tract. , 2016, Food microbiology.

[68]  L. Etienne-Mesmin,et al.  Enterohemorrhagic Escherichia coli O157:H7 Survival in an In Vitro Model of the Human Large Intestine and Interactions with Probiotic Yeasts and Resident Microbiota , 2012, Applied and Environmental Microbiology.

[69]  M. Verstegen,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 , 1999, Alternatives to laboratory animals : ATLA.

[70]  W. Verstraete,et al.  Comparison of five in vitro digestion models to in vivo experimental results: Lead bioaccessibility in the human gastrointestinal tract , 2007, Journal of environmental science and health. Part A, Toxic/hazardous substances & environmental engineering.

[71]  Willy Verstraete,et al.  The HMI™ module: a new tool to study the Host-Microbiota Interaction in the human gastrointestinal tract in vitro , 2014, BMC Microbiology.

[72]  D. Dalgleish,et al.  Effect of gel structure on the gastric digestion of whey protein emulsion gels. , 2014, Soft matter.

[73]  T. R. Licht,et al.  Microbiotas from UC patients display altered metabolism and reduced ability of LAB to colonize mucus , 2013, Scientific Reports.

[74]  S. Rutherfurd,et al.  Rheological Properties and Textural Attributes of Cooked Brown and White Rice During Gastric Digestion in Vivo , 2013, Food Biophysics.

[75]  Cyrille A M Krul,et al.  A new approach to predict human intestinal absorption using porcine intestinal tissue and biorelevant matrices. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[76]  R. Havenaar,et al.  Development of an advanced in vitro model of the stomach and its evaluation versus human gastric physiology , 2016 .

[77]  K. Venema,et al.  Metabolite production during in vitro colonic fermentation of dietary fiber: analysis and comparison of two European diets. , 2011, Journal of agricultural and food chemistry.

[78]  Eric Beyssac,et al.  A level A in vitro/in vivo correlation in fasted and fed states using different methods: applied to solid immediate release oral dosage form. , 2006, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[79]  A. Keshavarzian,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. , 2010, The British journal of nutrition.

[80]  E. Zoetendal,et al.  Microbial Community Development in a Dynamic Gut Model Is Reproducible, Colon Region Specific, and Selective for Bacteroidetes and Clostridium Cluster IX , 2010, Applied and Environmental Microbiology.

[81]  J. Jardin,et al.  Impact of human milk pasteurization on the kinetics of peptide release during in vitro dynamic term newborn digestion , 2016, Electrophoresis.

[82]  D. Jonkers,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 , 2014, PloS one.

[83]  R. Havenaar,et al.  Herring roe protein has a high digestible indispensable amino acid score (DIAAS) using a dynamic in vitro gastrointestinal model. , 2016, Nutrition research.

[84]  J. Groten,et al.  Predicted serum folate concentrations based on in vitro studies and kinetic modeling are consistent with measured folate concentrations in humans. , 2006, The Journal of nutrition.

[85]  B. Krevsky,et al.  Biphasic nature of gastric emptying. , 1988, Gut.

[86]  T. Wiele,et al.  Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model , 2012, The ISME Journal.

[87]  Antioxidant and anti-inflammatory capacity of bioaccessible compounds from wheat fractions after gastrointestinal digestion. , 2010 .

[88]  R. Havenaar,et al.  Assessment of the multi-mycotoxin-binding efficacy of a carbon/aluminosilicate-based product in an in vitro gastrointestinal model. , 2007, Journal of agricultural and food chemistry.

[89]  A. Brodkorb,et al.  Gastric digestion of α-lactalbumin in adult human subjects using capsule endoscopy and nasogastric tube sampling , 2014, British Journal of Nutrition.

[90]  N. Seeram,et al.  Of the major phenolic acids formed during human microbial fermentation of tea, citrus, and soy flavonoid supplements, only 3,4-dihydroxyphenylacetic acid has antiproliferative activity. , 2006, The Journal of nutrition.

[91]  P. Savelkoul,et al.  Evaluation of an optimal preparation of human standardized fecal inocula for in vitro fermentation studies. , 2015, Journal of microbiological methods.

[92]  D. Dupont,et al.  Peptide mapping during dynamic gastric digestion of heated and unheated skimmed milk powder , 2015 .

[93]  R. Singh,et al.  A human gastric simulator (HGS) to study food digestion in human stomach. , 2010, Journal of food science.

[94]  J. Cardot,et al.  Development and Validation of a Continuous In Vitro System Reproducing Some Biotic and Abiotic Factors of the Veal Calf Intestine , 2010, Applied and Environmental Microbiology.

[95]  C. Cueva,et al.  Dynamic gastric digestion of a commercial whey protein concentrate†. , 2018, Journal of the science of food and agriculture.

[96]  B. Bartolomé,et al.  Profiling of microbial-derived phenolic metabolites in human feces after moderate red wine intake. , 2013, Journal of agricultural and food chemistry.