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Transcriptome comparison of small and large intestine-derived monolayers and murine intestinal crypts

ABSTRACT: Gastrointestinal toxicity is a major concern in the development of drugs. Here, we establish the ability to use murine small and large intestine-derived monolayers to screen drugs for toxicity. As a proof-of-concept, we applied this system to assess gastrointestinal toxicity of ~50 clinically used oncology drugs, encompassing diverse mechanisms of action. Nearly all tested drugs had a deleterious effect on the gut, with increased sensitivity in the small intestine. The identification of differential toxicity between the small and large intestine enabled us to pinpoint differences in drug uptake (antifolates), drug metabolism (cyclophosphamide) and cell signaling (EGFR inhibitors) across the gut. These results highlight an under-appreciated distinction between small and large intestine toxicity and suggest distinct tissue properties important for modulating drug-induced gastrointestinal toxicity. The ability to accurately predict where and how drugs affect the murine gut will accelerate preclinical drug development.

ORGANISM(S): Mus musculus

PROVIDER: GSE191018 | GEO | 2021/12/18

REPOSITORIES: GEO

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Label-free and targeted mass tandem (TMT-labelled) global proteomic analyses on mucus from the stomach, small and large intestine of pigLabel-free and targeted mass tandem (TMT-labelled) global proteomic analyses on mucus from the stomach, small and large intestine of pig

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2022-03-07 | PXD029371 | Pride

Transcription profiling of mouse small intestine following treatment with dexamethosone and DBZ

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2009-04-10 | E-GEOD-11184 | biostudies-arrayexpress

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2023-05-08 | GSE215285 | GEO

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Gamma-secretase inhibitors reverse glucocorticoid resistance in T-ALL

2008-12-04 | GSE11184 | GEO

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Project description:Background and Aims: Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 humans. Methods: 12,590 single epithelial cells from three independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and capacity for response to extrinsic signals along the gut axis across different humans. Results: Cells were assigned to 25 epithelial lineage clusters. Human intestinal stem cells (ISCs) are not specifically marked by many murine ISC markers. Lysozyme expression is not unique to human Paneth cells (PCs), and PCs lack expression of expected niche-factors. BEST4+ cells express NPY and show maturational differences between SI and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell-junction, and nutrient absorption genes show unappreciated regional expression differences across lineages. Differential expression of receptors and drug targets across lineages reveals biological variation and potential for variegated responses. Conclusions: Our study identifies novel lineage marker genes; covers regional differences; shows important differences between mouse and human gut epithelium; and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomical regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.

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2012-05-31 | E-GEOD-30742 | biostudies-arrayexpress

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2020-07-24 | E-MTAB-9339 | biostudies-arrayexpress

Transcriptome comparison of small and large intestine-derived monolayers and murine intestinal crypts

Project description:Transcriptome comparison of small and large intestine-derived monolayers and murine intestinal crypts

| PRJNA789342 | ENA

RNA-Seq Quantification of Xenobiotic Processing Genes in Various Sections of the Intestine in Comparison to the Liver of Male Mice

Project description:This study aimed to quantify and compare the mRNA abundance of all major XPGs in liver and intestine using RNA-Seq. The mRNA profiles of 304 XPGs, including phase-I, phase-II enzymes, phase-II cosubstrate synthetic enzymes, xenobiotic transporters, as well as xenobiotic-related transcription factors, were systematically examined in liver and various sections of the intestine in adult male C57BL/6J mice. By two-way hierarchical clustering, over 80% of the XPGs had tissue-divergent expression, which partitioned into liver-, small intestine-, and large intestine-predominant patterns. Among the genes, 54% were highest expressed in liver, 21% in duodenum, 4% in jejunum, 6% in ileum, and 15% in large intestine. The highest expressed XPG in liver was Mgst1, in duodenum Cyp3a11, in jejunum and ileum Ces2e, and in large intestine Cyp2c55. Interestingly, XPGs in the same family usually exhibited highly different tissue distribution patterns, and many XPGs were almost exclusively expressed in one tissue and minimally expressed in others. In conclusion, the present study is among the first and the most comprehensive investigation of the real mRNA abundance and tissue-divergent expression of all major XPGs in mouse liver and intestine, which aids in understanding the tissue-specific biotransformation and toxicity of drugs and other xenobiotics.

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