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The effects of diet type, amino acid (AA), and apparent metabolizable energy (AME) levels in male broiler diets from d 8 to 21 on blood, small intestine, bone, and growth performance were investigated. Eight experimental diets with 2 protein sources [high inclusion of distiller's dried grains with solubles diet (hDDGS) or high inclusion of meat and bone meal diet (hMBM)], 2 AA densities (moderate or high), and 2 AME densities (2,998kcal/kg or 3,100kcal/kg), were fed to the broiler chicks from 8 to 21 days of age (d). High AME diets may lower feed cost by lowering feed intake. Intestinal morphology changes responded to dietary treatments, which may facilitate nutrients digestion and absorption in high MBM diets as well as in high DDGS diets. In addition, high AA or AME diets from 8 to 20 d improved feed conversion during experimental phase and influenced meat yields at 55 d.

Two-dimensional cell culture and animal models inadequately represent human pharmacokinetics and diseases like inflammatory bowel disease and colorectal cancer. This means missed diagnostic and therapeutic opportunities, high drug attrition rates, and a portfolio of approved drugs that underdeliver the desired benefits to patient outcomes. This encourages the development of a more physiologically relevant intestine model. The objective of this work was to develop a 384-well plate organ-on-a-chip platform, IFlowPlateTM, that can accommodate up to 128 human intestine models with accessible lumens and perfusable branched vasculature in an ECM environment. Fibrin-Matrigel® was used a structurally supportive and biologically instructive substrate that enabled: (1) prolonged cell culture (at least 15 days) with routine refreshment of aprotinin-supplemented medium, (2) formation of a confluent Caco-2 monolayer with barrier function, and (3) de novo assembly of a vascular network with barrier function. A fluorescent dextran permeability assay was used for in situ real-time measurements of epithelial barrier function in a high-throughput manner. Mixed co-culture of endothelial cells and fibroblasts in fibrin-Matrigel® resulted in the formation of an interconnected network of patent vessels that retained an albumin surrogate tracer within the luminal space indicating endothelial barrier function. To improve the success rate of anastomoses between living vessels and fluidic channels, the modification of inherently hydrophobic PDMS and polystyrene culture surfaces with ECM protein was explored. To address the limitations of a cancer cell line-derived intestine model, the replacement of Caco-2 cells with biopsied-derived colon organoid cells was investigated. Different gel formulations were assessed for their ability to induce colon organoid fragments to form monolayers. Finally, the incorporation of multiscale intestinal topography and luminal flow was considered through a modified approach to plate fabrication, whereby moulded alginate is embedded in ECM and sacrificed to generate a scaffold. Work to make the moulded alginate more robust is presented. / Thesis / Master of Applied Science (MASc) / Two-dimensional cell culture and animal models inadequately represent human drug metabolism and diseases like inflammatory bowel disease and colorectal cancer. The objective of this work is to develop a more physiologically relevant human intestine model. Using fabrication techniques pioneered by the semiconductor industry, a custom organ-on- a-chip platform in the format of a 384-well plate was developed. This platform is compatible with standard laboratory equipment and practices and can accommodate up to 128 human intestine models comprised of the intestinal epithelium and associated network of blood vessels. In this platform, the cells of the intestinal epithelium and vasculature are supported by a network of natural proteins. This allows processes like vessel growth to be modelled in this platform. Vessel growth plays a key role in the progression of inflammatory bowel disease and cancer, and this model could help scientists better understand these diseases.

Background: Capsule endoscopy (CE) is a non-invasive imaging modality designed to evaluate various small bowel pathologies. Failure to reach the cecum within the battery lifespan, termed incomplete examination, may result in inadequate testing and possibly delayed therapy. Several studies have attempted to evaluate the association between CE completion and opioid use. However, their results are conflicting. The aim of this meta-analysis is to evaluate the previously published literature on the association between opioid use and CE completion. Methods: We performed a comprehensive literature search in PubMed, PubMed Central, Embase, and ScienceDirect databases from inception through June 1, 2018, to identify all studies that evaluated the association between CE completion and opioid use. We included studies that presented an odds ratio (OR) with a 95% confidence interval (CI) or presented the data sufficient to calculate the OR with a 95% CI. Statistical analysis was performed using the comprehensive meta-analysis (CMA), version 3 software. Results: Five studies with a total of 1,614 patients undergoing CE in the inpatient (IP) and outpatient (OP) setting were included in this study, 349 of which had an incomplete CE (21.6%). The pooled OR for CE completion is 0.50 (95% CI: 0.38-0.66, I2=36.9%) in opioid users compared to non-users. No publication bias was found using Egger's regression test. Conclusions: Our results indicate that patients on opioids are significantly less likely to have a complete CE examination compared to non-users. To our knowledge, this study represents the first meta-analysis to assess this association.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Bc. Anna Štefanová Supervisor: PharmDr. Ivan Vokřál, Ph.D. Title of diploma thesis: Effect of anthelmintics on the transport of drugs in the intestine Several classes of drugs are currently available for the treatment of helminthiasis in humans and animals, the so-called anthelmintics. Most of these drugs are administered by the oral route, where absorption into the systemic circulation occurs through the intestinal barrier. However, the course and extent of this absorption may be limited by biotransforming enzymes and transport proteins, in particular the family of so-called ATP-binding cassette transporters. These transporters are capable of returning many xenobiotics, including many drugs, back into the lumen of the gut and are the first line of defence against the entry of these substances into the body. An important representative of this group of transporters is P-glycoprotein, which is known for its broad substrate specificity. On this transporter, drugs can act as substrates but also as inhibitors and/or inducers, which may lead to the risk of drug-drug interactions. There is relatively little information about the effect of anthelmintics on P-glycoprotein inhibition. The most studied...

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There are many gastrointestinal diseases, such as Crohn’s disease, which can be treated effectively with topical, localized medicine delivered to the intestinal wall through the gastrointestinal tract by the use of a targeted drug delivery capsule. The success of such a delivery method is contingent on the properties of the fluid flow near the delivery site; specifically, how well-mixed the medicine will be in the chyme so that it can act on the intestinal wall. Pursuant to understanding the mixed state of the chyme, several fluid simulations were performed with ANSYS Fluent, simulating different types of muscular contractions. Fluid particles – which were originally segregated into three sections of the simulated small intestine – were tracked, and simulation results were compared based on how well-distributed the tracked particles were at the end state, using the second moment of distribution. The results of this comparison have revealed that there is little difference between the mixing produced by segmentation in a 3.0 cm diameter small intestine and that produced in a 2.0 cm diameter small intestine. Results have also shown little difference between mixing produced when the segmentation contractions vary qualitatively in any of several ways. There is, however, some difference between distribution produced by segmentation contractions and peristaltic, or propulsive, contractions. This work could be further pursued with more simulations; of different types of contractions, of contraction patterns with different properties, and with simulations with more comprehensive particle tracking. It would also be straightforward to incorporate analysis of the large intestine into the study. / Mechanical Engineering

The small intestine and the liver regulate several physiological functions together including the absorption and bioavailability of drugs and bile and nitrogen homeostasis. It is important to study these two organs together to gain a holistic understanding of their communication with each other. However, there is a lack of culture models that investigate the use of primary cells/tissues from the liver and the intestine to study their interaction and importance in manifestation of drug toxicity. The studies described in this dissertation were conducted using inverted rat intestinal explants obtained from three regions of the jejunum, named as the proximal, medial and distal jejunum. Markers of enterocyte, goblet cell and Paneth cell function in the jejunum followed in vivo – like spatial trends reported for the entire small intestine. Jejunum explants were integrated with hepatocytes to model the intestine-liver axis. Integration of jejunum explants from the proximal region with hepatocytes had a beneficial effect on both hepatocyte urea secretion and jejunum mucin secretion, hinting at communication between these organs in culture. Integrated cultures of the rat jejunum and hepatocytes were used to investigate ethanol toxicity in vitro. Trends in activities of enzymes involved in ethanol metabolism and mucus secretion in integrated cultures with proximal jejunum explants corroborated with in vivo reports on ethanol toxicity. Various metabolites secreted and metabolized in vitro were also identified using mass spectrometry. Spatial trends in concentrations of several lipids including bile acids, lysophosphatidylcholines and fatty acids corroborated with in vivo reports of lipid metabolism. The integrated intestine-liver cultures can be used as a platform for future investigations of drug toxicity, lipid metabolism and inter-organ communication. / Doctor of Philosophy / The small intestine and the liver perform several functions together. The small intestine is responsible for the digestion of food, absorption of nutrients and metabolism of oral drugs. The liver is involved in the metabolism of glucose, protein, lipids and drugs. It is important to study these two organs together to gain a holistic understanding of their communication with each other. However, there is a lack of culture models that investigate the use of cells/tissues directly obtained from animal liver and intestine to study their interaction and importance in manifestation of drug toxicity. The studies described in this dissertation were conducted using tissues obtained from three regions of the jejunum segment of the rat small intestine. Functional markers of various cell types in the jejunum followed in vivo – like spatial trends reported for the entire small intestine. Jejunum tissues were integrated with liver cells to model the intestine-liver axis. Integration of jejunum tissues from the proximal region with liver cells had a beneficial effect on both liver and intestinal markers, hinting at communication between these organs in culture. Integrated cultures of the rat jejunum and liver cells were used to investigate alcohol toxicity in vitro. Trends in activities of enzymes involved in alcohol metabolism and mucus secretion in integrated cultures with jejunum tissues corroborated with in vivo reports on alcohol toxicity. Various metabolites secreted and metabolized in vitro were also identified using mass spectrometry. Spatial trends in concentrations of lipids including bile acids, lysophosphatidylcholines and fatty acids within the jejunum corroborated with in vivo reports of lipid metabolism. The integrated intestine-liver cultures can be used as a platform for future investigations of drug toxicity, lipid metabolism and inter-organ communication.