Sylvain Denis

Relevance and challenges in modeling human gastric and small intestinal digestion

Gastric and small intestinal (GSI) models are increasingly used as an alternative to in vivo assays to answer many questions raised by industry and researchers. A broad range of in vitro systems is available, from static monocompartmental to dynamic multicompartmental models. However, these models require a compromise between technological complexity and biological significance. Further efforts and technological innovations are still needed to improve in vitro models and meet growing demands in the areas of nutrition and health. This review describes the models available to date for the human stomach and small intestine and highlights their relevance in nutritional, toxicological, pharmaceutical, and microbiological studies. Limitations and challenges facing artificial digestion technology are also discussed.

Western diet induces a shift in microbiota composition enhancing susceptibility to Adherent-Invasive E. coli infection and intestinal inflammation.

Recent advances have shown that the abnormal inflammatory response observed in CD involves an interplay among intestinal microbiota, host genetics and environmental factors. The escalating consumption of fat and sugar in Western countries parallels an increased incidence of CD during the latter 20th century. The impact of a HF/HS diet in mice was evaluated for the gut micro-inflammation, intestinal microbiota composition, function and selection of an E. coli population. The HF/HS diet created a specific inflammatory environment in the gut, correlated with intestinal mucosa dysbiosis characterized by an overgrowth of pro-inflammatory Proteobacteria such as E. coli, a decrease in protective bacteria, and a significantly decreased of SCFA concentrations. The expression of GPR43, a SCFA receptor was reduced in mice treated with a HF/HS diet and reduced in CD patients compared with controls. Interestingly, mice treated with an agonist of GPR43 were protected against DSS-induced colitis. Finally, the transplantation of feces from HF/HS treated mice to GF mice increased susceptibility to AIEC infection. Together, our results demonstrate that a Western diet could aggravate the inflammatory process and that the activation of the GPR43 receptor pathway could be used as a new strategy to treat CD patients.

Combining the dynamic TNO-gastrointestinal tract system with a caco-2 cell culture model: application to the assessment of lycopene and α-tocopherol bioavailability from a whole food.

To exert their health effect, phytochemicals such as carotenoids and vitamin E have to be bioavailable. We investigated the digestive stability and intestinal absorption of lycopene and alpha-tocopherol from a whole food containing red tomatoes and sunflower oil using, for the first time, the dynamic gastrointestinal system TNO gastrointestinal tract model (TIM) coupled with Caco-2 cells. Digestive samples were added to Caco-2 cells after appropriate ultracentrifugation, filtration, and dilution. alpha-Tocopherol was stable during digestion in the TIM, whereas a 25% loss was observed for lycopene. The absorption of both compounds was curvilinear, bidirectional, and concentration-dependent. The percentages of alpha-tocopherol absorbed, but not that of lycopene, were lower with digestas compared to those with pure compounds, suggesting competition for absorption with other components of the test meal. According to in vivo data, a lower bioavailability was found for lycopene compared to that for alpha-tocopherol. These results support the usefulness of this in vitro approach for estimating the bioavailability of active compounds from food.

Effect of a New Probiotic Saccharomyces cerevisiae Strain on Survival of Escherichia coli O157:H7 in a Dynamic Gastrointestinal Model

ABSTRACT Survival of Escherichia coli O157:H7 was investigated using a dynamic gastrointestinal model. A high bacterial mortality was observed in the stomach and duodenum. In contrast, bacteria grew in the distal parts of the small intestine. The coadministration of Saccharomyces cerevisiae CNCM I-3856 led to a significant reduction of bacterial resumption, maybe through ethanol production.

Investigation of the Biopharmaceutical Behavior of Theophylline Hydrophilic Matrix Tablets Using USP Methods and an Artificial Digestive System

This work aimed to investigate the biopharmaceutical behavior of hydrophilic matrix tablets of theophylline using different in vitro methods: USP II, USP IV, and a novel in vitro system simulating the gastrointestinal tract in man called the artificial digestive system (ADS). The potentiality of each method was evaluated by establishing in vitro/in vivo correlation. Using USP methods, the drug release was pH-independent and dependent on agitation intensity. Level A IVIVCs could be established using the different in vitro methods but one to one correlation was established only when the ADS method was used. For the prediction of in vivo drug dosage form behavior based on in vitro methods, the ADS showed a high predictability when compared to USP in vitro methods.

Comparison of a static and a dynamic in vitro model to estimate the bioaccessibility of As, Cd, Pb and Hg from food reference materials Fucus sp. (IAEA-140/TM) and Lobster hepatopancreas (TORT-2)

Bioaccessibility, the fraction of an element solubilized during gastrointestinal digestion and available for absorption, is a factor that should be considered when evaluating the health risk of contaminants from food. Static and dynamic models that mimic human physiological conditions have been used to evaluate bioaccessibility. This preliminary study compares the bioaccessibility of arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) in two food certified reference materials (CRMs) (seaweed: Fucus sp., IAEA-140/TM; Lobster hepatopancreas: TORT-2), using two in vitro gastrointestinal digestion methods: a static method (SM) and a dynamic multicompartment method (TIM-1). There are significant differences (p<0.05) between the bioaccessible values of As, Cd, Pb and Hg obtained by SM and TIM-1 in the two CRMs. The specific form in which the elements studied are present in the CRM may help to explain the bioaccessibility values obtained.

In Vitro Study of the Release Properties of Soy−Zein Protein Microspheres with a Dynamic Artificial Digestive System

The purpose of this work was to study the performance of microspheres of soy protein isolate (SPI), zein, or SPI-zein complex as vehicles of nutraceutical delivery under fasting and prandial conditions in an artificial digestive system (TIM-1). Riboflavin availability for absorption from the small intestine compartments reached 90% of the total load within 4 h, most of it (65-80%) turning up in the jejunum dialysis fluid, suggesting that this segment is the main site of absorption, regardless of the nature of the microspheres. However, the riboflavin concentrations and the availability for absorption profiles depended on microsphere formulation. Release from pure SPI and zein microspheres in the stomach compartment occurred within 15 min. The availability for absorption from both the jejunum and ileum compartment followed first-order kinetics, indicating that the limiting step in nutrient uptake with these two formulations is absorption by passive diffusion. SPI-zein complex microspheres provided sustained release of riboflavin over 4 h and a near-zero-order nutrient availability for absorption profile in both fasting and prandial states. Suspending SPI-zein complex microspheres in yogurt significantly delayed nutrient release, which would increase the likelihood of gastric-sensitive nutrients passing intact into the intestine for absorption. SPI-zein complex microspheres thus show potential for use as nutraceutical delivery vehicles in the creation of novel functional foods.

Use of Artificial Digestive Systems to Investigate the Biopharmaceutical Factors Influencing the Survival of Probiotic Yeast During Gastrointestinal Transit in Humans

PurposeTo evaluate the influence of the main biopharmaceutical factors on the viability of a new probiotic yeast strain, using dynamic in vitro systems simulating human gastric/small intestinal (TIM) and large intestinal (ARCOL) environments.MethodsThe viability of Saccharomyces cerevisiae CNCM I-3856 throughout the artificial digestive tract was determined by microbial counting. We investigated the effects of galenic formulation, food intake, dose, mode and frequency of administration on yeast survival rate.ResultsIn both fasted and fed states, yeast viability in the upper digestive tract was significantly higher when the probiotic was administered in hydroxypropylmethylcellulose (HPMC) capsules compared to tablets. Food intake led to a delay in yeast release and a two-fold increase in strain survival. Whatever the dose, yeasts were particularly sensitive to the large intestinal environment. High concentrations of probiotic could only be maintained in the colon when it was inoculated twice a day over a 5-h-period.ConclusionsTIM and ARCOL are complementary in vitro tools relevant for screening purposes, supplying valuable information on the effects of galenic form, food intake and dose regimen on the viability of probiotics throughout the human digestive tract.

Enterohemorrhagic Escherichia coli O157:H7 Survival in an In Vitro Model of the Human Large Intestine and Interactions with Probiotic Yeasts and Resident Microbiota

ABSTRACT This is the first report on the fate of enterohemorrhagic Escherichia coli O157:H7 in simulated human colonic conditions. The pathogen was progressively eliminated from the bioreactor and did not modify the major populations of resident microbiota. The coadministration of the Saccharomyces cerevisiae CNCM I-3856 probiotic strain led to a significant increase in acetate production but did not reduce pathogen viability.

MICROBIAL ENZYME PRODUCTION IN A MEMBRANE BIOREACTOR

SummaryErwinia chrysanthemi cells were used to study the possibility of producing bacterial enzymes in a bioreactor coupled with a membrane filtration unit. Continuous fermentations with total cell recycle failed to give good production of pectate lyase (PL). Enzymatic, mechanical and physico-chemical damages were involved in this phenomenon. With a sequential recycle mode, we obtained productivity of 1.5 units·h−1·1−1 with a high PL concentration. Protease accumulation occurred when the bioreactor was coupled to a filtration unit. Moreover we have observed no loss of activity due to high shear stress caused by pumping.