Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model.
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.
Pubmed ID: 31933478 RIS Download
Research resources used in this publication
Additional research tools detected in this publication
- ATCC (RRID:SCR_001672)
- DAVID (RRID:SCR_001881)
- Ensembl (RRID:SCR_002344)
- Systems Transcriptional Activity Reconstruction (RRID:SCR_005622)
- Thermo Fisher Scientific (RRID:SCR_008452)
- Santa Cruz Biotechnology (RRID:SCR_008987)
- Subread (RRID:SCR_009803)
- Trimmomatic (RRID:SCR_011848)
- KEGG (RRID:SCR_012773)
- Abcam (RRID:SCR_012931)
- FastQC (RRID:SCR_014583)
- bcl2fastq (RRID:SCR_015058)
- HEK293T (RRID:CVCL_0063)
- Caco-2 (RRID:CVCL_0025)
Antibodies used in this publication
- PEPT1 (E-3) (RRID:AB_10918256)
- Mouse Anti-Bcrp1 (ABCG2) Monoclonal antibody, Unconjugated, Clone 5d3 (RRID:AB_95060)
- Mouse Anti-Human Mucin 2 (Ccp58) Monoclonal, Unconjugated, Clone Ccp58 (RRID:AB_627970)
- E Cadherin antibody [HECD-1] (RRID:AB_300946)
- Rabbit Anti-Human VE Cadherin Polyclonal Antibody, Unconjugated (RRID:AB_870662)
- ZO-1 Monoclonal Antibody (ZO1-1A12) (RRID:AB_2533147)
- Chr-A (C-20) (RRID:AB_2276319)
- Villin antibody [SP145] (RRID:AB_11159755)
- P-Glycoprotein Monoclonal Antibody (F4) (RRID:AB_10979045)
- Polyclonal Rabbit Anti Human Lysozyme EC 3.2.1.17 (RRID:AB_2341230)
Associated grants
- Agency: NIDDK NIH HHS, United States
Id: P30 DK089502 - Agency: NIDDK NIH HHS, United States
Id: R01 DK116352 - Agency: NIDDK NIH HHS, United States
Id: R24 DK099803
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This is a list of tools and resources that we have found mentioned in this publication.
ATCC (tool)
RRID:SCR_001672
Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.
View all literature mentionsDAVID (tool)
RRID:SCR_001881
Bioinformatics resource system including web server and web service for functional annotation and enrichment analyses of gene lists. Consists of comprehensive knowledgebase and set of functional analysis tools. Includes gene centered database integrating heterogeneous gene annotation resources to facilitate high throughput gene functional analysis.
View all literature mentionsEnsembl (tool)
RRID:SCR_002344
Collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. Used to automatically annotate genome, integrate this annotation with other available biological data and make data publicly available via web. Ensembl tools include BLAST, BLAT, BioMart and the Variant Effect Predictor (VEP) for all supported species.
View all literature mentionsSystems Transcriptional Activity Reconstruction (tool)
RRID:SCR_005622
A next-generation web-based application that aims to provide an integrated solution for both visualization and analysis of deep-sequencing data, along with simple access to public datasets.
View all literature mentionsThermo Fisher Scientific (tool)
RRID:SCR_008452
Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsSubread (tool)
RRID:SCR_009803
Software package for high-performance read alignment, quantification and mutation discovery.General purpose read aligner which can be used to map both genomic DNA-seq reads and RNA-seq reads. Subread aligner as fast, accurate and scalable read mapping by seed-and-vote.These programs were also implemented in Bioconductor R package Rsubread.
View all literature mentionsTrimmomatic (tool)
RRID:SCR_011848
Software Java pipeline for trimming tasks for Illumina paired end and single ended data. Flexible Trimmer for Illumina Sequence Data. Pair aware preprocessing tool optimized for Illumina next generation sequencing data. Includes several processing steps for read trimming and filtering. Operating systems Unix/Linux, Mac OS, Windows.
View all literature mentionsKEGG (tool)
RRID:SCR_012773
Integrated database resource consisting of 16 main databases, broadly categorized into systems information, genomic information, and chemical information. In particular, gene catalogs in completely sequenced genomes are linked to higher-level systemic functions of cell, organism, and ecosystem. Analysis tools are also available. KEGG may be used as reference knowledge base for biological interpretation of large-scale datasets generated by sequencing and other high-throughput experimental technologies.
View all literature mentionsAbcam (tool)
RRID:SCR_012931
A commercial antibody supplier which supplies primary and secondary antibodies, biochemicals, proteins, peptides, lysates, immunoassays and other kits.
View all literature mentionsFastQC (tool)
RRID:SCR_014583
Quality control software that perform checks on raw sequence data coming from high throughput sequencing pipelines. This software also provides a modular set of analyses which can give a quick impression of the quality of the data prior to further analysis.
View all literature mentionsbcl2fastq (tool)
RRID:SCR_015058
Conversion software that both demultiplexes data and converts BCL files generated by Illumina sequencing systems to standard FASTQ file formats for downstream analysis.
View all literature mentionsHEK293T (tool)
RRID:CVCL_0063
Cell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCaco-2 (tool)
RRID:CVCL_0025
Cell line Caco-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsPEPT1 (E-3) (antibody)
RRID:AB_10918256
This monoclonal targets PEPT1 (E-3)
View all literature mentionsMouse Anti-Bcrp1 (ABCG2) Monoclonal antibody, Unconjugated, Clone 5d3 (antibody)
RRID:AB_95060
This monoclonal targets Bcrp1 (ABCG2)
View all literature mentionsMouse Anti-Human Mucin 2 (Ccp58) Monoclonal, Unconjugated, Clone Ccp58 (antibody)
RRID:AB_627970
This monoclonal targets Human MUC2
View all literature mentionsE Cadherin antibody [HECD-1] (antibody)
RRID:AB_300946
This monoclonal targets E Cadherin
View all literature mentionsRabbit Anti-Human VE Cadherin Polyclonal Antibody, Unconjugated (antibody)
RRID:AB_870662
This polyclonal targets Human VE Cadherin
View all literature mentionsZO-1 Monoclonal Antibody (ZO1-1A12) (antibody)
RRID:AB_2533147
This monoclonal targets ZO-1
View all literature mentionsVillin antibody [SP145] (antibody)
RRID:AB_11159755
This monoclonal targets Villin antibody [SP145]
View all literature mentionsP-Glycoprotein Monoclonal Antibody (F4) (antibody)
RRID:AB_10979045
This monoclonal targets P-Glycoprotein
View all literature mentionsPolyclonal Rabbit Anti Human Lysozyme EC 3.2.1.17 (antibody)
RRID:AB_2341230
This polyclonal targets Lysozyme
View all literature mentionsFiji (software resource)
RRID:SCR_002285
Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.
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