scholarly journals Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Magdalena Kasendra ◽  
Raymond Luc ◽  
Jianyi Yin ◽  
Dimitris V Manatakis ◽  
Gauri Kulkarni ◽  
...  
Keyword(s):  
Drug Transport ◽  
Intestinal Barrier ◽  
New Drugs ◽  
Intestinal Barrier Function ◽  
Human Pharmacokinetics ◽  
Relevant Model ◽  
Cell Subpopulations ◽  
And Function

Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.

scholarly journals Organoid-derived Duodenum Intestine-Chip for preclinical drug assessment in a human relevant system

2019 ◽  
Author(s):  
Magdalena Kasendra ◽  
Raymond Luc ◽  
Jianyi Yin ◽  
Dimitris V. Manatakis ◽  
Athanasia Apostolou ◽  
...  
Keyword(s):  
Drug Transport ◽  
Intestinal Barrier ◽  
New Drugs ◽  
Intestinal Barrier Function ◽  
Human Pharmacokinetics ◽  
Chip Technology ◽  
Cell Subpopulations ◽  
And Function

AbstractInduction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organ-Chip technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo-relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.

scholarly journals Role for diet in normal gut barrier function: developing guidance within the framework of food-labeling regulations

2019 ◽  
Vol 317 (1) ◽  
pp. G17-G39 ◽  
Author(s):  
Michael Camilleri ◽  
Barbara J. Lyle ◽  
Karen L. Madsen ◽  
Justin Sonnenburg ◽  
Kristin Verbeke ◽  
...  
Keyword(s):  
Barrier Function ◽  
Intestinal Barrier ◽  
Normal Function ◽  
Model Systems ◽  
Intestinal Barrier Function ◽  
Dietary Interventions ◽  
Labeling Regulations ◽  
Gut Barrier Function ◽  
And Function

A reduction in intestinal barrier function is currently believed to play an important role in pathogenesis of many diseases, as it facilitates passage of injurious factors such as lipopolysaccharide, peptidoglycan, whole bacteria, and other toxins to traverse the barrier to damage the intestine or enter the portal circulation. Currently available evidence in animal models and in vitro systems has shown that certain dietary interventions can be used to reinforce the intestinal barrier to prevent the development of disease. The relevance of these studies to human health is unknown. Herein, we define the components of the intestinal barrier, review available modalities to assess its structure and function in humans, and review the available evidence in model systems or perturbations in humans that diet can be used to fortify intestinal barrier function. Acknowledging the technical challenges and the present gaps in knowledge, we provide a conceptual framework by which evidence could be developed to support the notion that diet can reinforce human intestinal barrier function to restore normal function and potentially reduce the risk for disease. Such evidence would provide information on the development of healthier diets and serve to provide a framework by which federal agencies such as the US Food and Drug Administration can evaluate evidence linking diet with normal human structure/function claims focused on reducing risk of disease in the general public.

scholarly journals In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

2019 ◽  
Vol 65 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Marcin Ożarowski ◽  
Radosław Kujawski ◽  
Przemysław Ł. Mikołajczak ◽  
Karolina Wielgus ◽  
Andrzej Klejewski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Chemical Compounds ◽  
New Drugs ◽  
Future Application ◽  
Mediators Of Inflammation ◽  
And Function

Summary Flavonoids and their conjugates are the most important group of natural chemical compounds in drug discovery and development. The search for pharmacological activity and new mechanisms of activity of these chemical compounds, which may inhibit mediators of inflammation and influence the structure and function of endothelial cells, can be an interesting pharmacological strategy for the prevention and adjunctive treatments of hypertension, especially induced by pregnancy. Because cardiovascular diseases have multi-factorial pathogenesis these natural chemical compounds with wide spectrum of biological activities are the most interesting source of new drugs. Extracts from one of the most popular plant used in Traditional Chinese Medicine, Scutellaria baicalensis Georgi could be a very interesting source of flavonoids because of its exact content in quercetin, apigenin, chrysin and scutellarin as well as in baicalin. These flavonoids exert vasoprotective properties and many activities such as: anti-oxidative via several pathways, anti-in-flammatory, anti-ischaemic, cardioprotective and anti-hypertensive. However, there is lack of summaries of results of studies in context of potential and future application of flavonoids with determined composition and activity. Our review aims to provide a literature survey of in vitro, in vivo and ex vivo pharmacological studies of selected flavonoids (apigenin, chrysin and scutellarin, baicalin) in various models of hypertension carried out in 2008–2018.

scholarly journals Aflatoxin B1 and Aflatoxin M1 Induce Compromised Intestinal Integrity through Clathrin-Mediated Endocytosis

Toxins ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 184
Author(s):  
Yanan Gao ◽  
Xiaoyu Bao ◽  
Lu Meng ◽  
Huimin Liu ◽  
Jiaqi Wang ◽  
...  
Keyword(s):  
Aflatoxin B1 ◽  
Intestinal Barrier ◽  
Fluorescein Isothiocyanate ◽  
Intestinal Barrier Function ◽  
Aflatoxin M1 ◽  
Dependent Manner ◽  
Simultaneous Exposure ◽  
Intestinal Integrity

With the growing diversity and complexity of diet, humans are at risk of simultaneous exposure to aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1), which are well-known contaminants in dairy and other agricultural products worldwide. The intestine represents the first barrier against external contaminants; however, evidence about the combined effect of AFB1 and AFM1 on intestinal integrity is lacking. In vivo, the serum biochemical parameters related to intestinal barrier function, ratio of villus height/crypt depth, and distribution pattern of claudin-1 and zonula occluden-1 were significantly affected in mice exposed to 0.3 mg/kg b.w. AFB1 and 3.0 mg/kg b.w. AFM1. In vitro results on differentiated Caco-2 cells showed that individual and combined AFB1 (0.5 and 4 μg/mL) and AFM1 (0.5 and 4 μg/mL) decreased cell viability and trans-epithelial electrical resistance values as well as increased paracellular permeability of fluorescein isothiocyanate-dextran in a dose-dependent manner. Furthermore, AFM1 aggravated AFB1-induced compromised intestinal barrier, as demonstrated by the down-regulation of tight junction proteins and their redistribution, particularly internalization. Adding the inhibitor chlorpromazine illustrated that clathrin-mediated endocytosis partially contributed to the compromised intestinal integrity. Synergistic and additive effects were the predominant interactions, suggesting that these toxins are likely to have negative effects on human health.

scholarly journals A Novel Role of A2AR in the Maintenance of Intestinal Barrier Function of Eteric Glia from Hypoxia-Induced Injury by Combining with mGluR5

2021 ◽  
Vol 12 ◽  
Author(s):  
Lihua Sun ◽  
Xiang Li ◽  
Haidi Guan ◽  
Shuaishuai Chen ◽  
Xin Fan ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptor ◽  
Ischemia Reperfusion ◽  
Intestinal Barrier ◽  
Intestinal Barrier Function ◽  
Metabotropic Glutamate ◽  
Enteric Glial Cells ◽  
Intestinal Ischemia Reperfusion

During acute intestinal ischemia reperfusion (IR) injury, the intestinal epithelial barrier (IEB) function is often disrupted. Enteric glial cells (EGCs) play an important role in maintaining the integrity of IEB functions. However, how EGCs regulate IEB function under IR stimulation is unknown. The present study reveals that the adenosine A2A receptor (A2AR) is important for mediating the barrier-modulating roles of EGCs. A2AR knockout (KO) experiments revealed more serious intestinal injury in A2AR KO mice than in WT mice after IR stimulation. Moreover, A2AR expression was significantly increased in WT mice when challenged by IR. To further investigate the role of A2AR in IEB, we established an in vitro EGC-Caco-2 co-culture system. Hypoxia stimulation was used to mimic the process of in vivo IR. Treating EGCs with the CGS21680 A2AR agonist attenuated hypoxia-induced intestinal epithelium damage through up-regulating ZO-1 and occludin expression in cocultured Caco-2 monolayers. Furthermore, we showed that A2AR and metabotropic glutamate receptor 5 (mGluR5) combine to activate the PKCα-dependent pathway in conditions of hypoxia. This study shows, for the first time, that hypoxia induces A2AR-mGluR5 interaction in EGCs to protect IEB function via the PKCα pathway.

Challenges in translational research on probiotic lactobacilli: from in vitro assays to clinical trials

2013 ◽  
Vol 4 (1) ◽  
pp. 83-100 ◽  
Author(s):  
M. Meijerink ◽  
A. Mercenier ◽  
J.M. Wells
Keyword(s):  
Translational Research ◽  
Selection Criteria ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Intestinal Barrier ◽  
Probiotic Strain ◽  
In Vitro Assays ◽  
Intestinal Barrier Function

Beneficial effects of certain probiotic strains have been established in the treatment and prevention of various immune and intestinal disorders in humans, including allergic diseases, chronic inflammatory diseases and diarrhoea. The proposed mechanisms underlying the immunomodulatory effects of probiotics in humans are not understood in precise detail but include enhancement of intestinal barrier function, altered epithelial signalling, competition with pathogens and effects on immune cells and immunity depending on the probiotic strain. The publication of controversial or inconclusive probiotic studies in humans highlights the need for a better understanding of the mechanisms and improved strain selection criteria. This review focuses on the immunomodulatory properties of lactobacilli and bifidobacteria in vitro and in vivo, current knowledge concerning the mechanisms in vivo and challenges in translational research on probiotics. A better understanding of the molecular mechanisms of probiotics, the effect of probiotic mixtures versus single strains, the effect of formulation of probiotics and the fate of ingested probiotics should help to clarify the value of immune assays as selection criteria for probiotics.

scholarly journals Probiotic Associated Therapeutic Curli Hybrids (PATCH)

2018 ◽  
Author(s):  
Pichet Praveschotinunt ◽  
Anna M. Duraj-Thatte ◽  
Ilia Gelfat ◽  
Franziska Bahl ◽  
David B. Chou ◽  
...  
Keyword(s):  
Barrier Function ◽  
Unmet Need ◽  
Intestinal Barrier ◽  
Genetically Engineered ◽  
Intestinal Barrier Function ◽  
Beneficial Bacteria ◽  
Fibrous Matrix

AbstractThere is an unmet need for new treatment methods for inflammatory bowel disease (IBD) that can reliably maintain remission without leading to detrimental side effects. Beneficial bacteria have been utilized as an alternative treatment for IBD albeit with low efficacy. We genetically engineered Escherichia coli Nissle 1917 (EcN) to create an anti-inflammatory fibrous matrix in situ. This matrix consists of EcN-produced curli nanofibers displaying trefoil factors (TFFs), known to promote intestinal barrier function and epithelial restitution. We confirmed that engineered EcN was able to secrete the curli-fused TFFs in vitro and in vivo, and was non-pathogenic. We observed an enhanced protective effect of engineered EcN against dextran sodium sulfate induced colitis in mice, associated with barrier function reinforcement and immunomodulation. This work sets the foundation for the development of a novel therapeutic platform in which the in situ production of a therapeutic protein matrix from beneficial bacteria can be exploited.

scholarly journals Modulation of Intestinal Immune and Barrier Functions by Vitamin A: Implications for Current Understanding of Malnutrition and Enteric Infections in Children

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1128 ◽  
Author(s):  
Pedro de Medeiros ◽  
Daniel Pinto ◽  
Juliana de Almeida ◽  
Juliana Rêgo ◽  
Francisco Rodrigues ◽  
...  
Keyword(s):  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Intestinal Barrier ◽  
Barrier Functions ◽  
Vitamin A Status ◽  
Enteric Infections ◽  
Underlying Mechanisms ◽  
And Function

The micronutrient vitamin A refers to a group of compounds with pleiotropic effects on human health. These molecules can modulate biological functions, including development, vision, and regulation of the intestinal barrier. The consequences of vitamin A deficiency and supplementation in children from developing countries have been explored for several years. These children live in an environment that is highly contaminated by enteropathogens, which can, in turn, influence vitamin A status. Vitamin A has been described to modulate gene expression, differentiation and function of diverse immune cells; however, the underlying mechanisms are not fully elucidated. This review aims to summarize the most updated advances on elucidating the vitamin A effects targeting intestinal immune and barrier functions, which may help in further understanding the burdens of malnutrition and enteric infections in children. Specifically, by covering both clinical and in vivo/in vitro data, we describe the effects of vitamin A related to gut immune tolerance/homeostasis, intestinal barrier integrity, and responses to enteropathogens in the context of the environmental enteric dysfunction. Some of the gaps in the literature that require further research are also highlighted.

scholarly journals Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Pichet Praveschotinunt ◽  
Anna M. Duraj-Thatte ◽  
Ilia Gelfat ◽  
Franziska Bahl ◽  
David B. Chou ◽  
...  
Keyword(s):  
Critical Role ◽  
Intestinal Barrier ◽  
Mucosal Healing ◽  
Intestinal Barrier Function ◽  
Protective Effects ◽  
Genetically Engineer ◽  
Protein Matrices

AbstractMucosal healing plays a critical role in combatting the effects of inflammatory bowel disease, fistulae and ulcers. While most treatments for such diseases focus on systemically delivered anti-inflammatory drugs, often leading to detrimental side effects, mucosal healing agents that target the gut epithelium are underexplored. We genetically engineer Escherichia coli Nissle 1917 (EcN) to create fibrous matrices that promote gut epithelial integrity in situ. These matrices consist of curli nanofibers displaying trefoil factors (TFFs), known to promote intestinal barrier function and epithelial restitution. We confirm that engineered EcN can secrete the curli-fused TFFs in vitro and in vivo, and is non-pathogenic. We observe enhanced protective effects of engineered EcN against dextran sodium sulfate-induced colitis in mice, associated with mucosal healing and immunomodulation. This work lays a foundation for the development of a platform in which the in situ production of therapeutic protein matrices from beneficial bacteria can be exploited.

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