A leaky human colon model reveals uncoupled apical/basal cytotoxicity in early Clostridioides difficile toxin exposure

( ) toxins A (TcdA) and B (TcdB) cause antibiotic-associated colitis in part by disrupting epithelial barrier function. Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell...

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Veröffentlicht in:American journal of physiology: Gastrointestinal and liver physiology 2023-04, Vol.324 (4), p.G262-G280
Hauptverfasser: Ok, Meryem T, Liu, Jintong, Bliton, R Jarrett, Hinesley, Caroline M, San Pedro, Ekaterina Ellyce T, Breau, Keith A, Gomez-Martinez, Ismael, Burclaff, Joseph, Magness, Scott T
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container_issue 4
container_start_page G262
container_title American journal of physiology: Gastrointestinal and liver physiology
container_volume 324
creator Ok, Meryem T
Liu, Jintong
Bliton, R Jarrett
Hinesley, Caroline M
San Pedro, Ekaterina Ellyce T
Breau, Keith A
Gomez-Martinez, Ismael
Burclaff, Joseph
Magness, Scott T
description ( ) toxins A (TcdA) and B (TcdB) cause antibiotic-associated colitis in part by disrupting epithelial barrier function. Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell lines and organoids inherently limit these efforts. We developed adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigated the impact of toxins on apical/basal aspects of monolayers, and evaluated whether a leaky epithelial barrier enhances toxicity. Single-cell RNA-sequencing (scRNAseq) mapped -relevant genes to human lineages. Transcriptomics compared hCE to Caco-2, informed timing of in vitro stem cell differentiation, and revealed transcriptional responses to TcdA. Transepithelial electrical resistance (TEER) and fluorescent permeability assays measured cytotoxicity. Contribution of TcdB toxicity was evaluated in a diclofenac-induced leaky gut model. scRNAseq demonstrated broad and variable toxin receptor expression. Absorptive colonocytes in vivo displayed increased toxin receptor, Rho GTPase, and cell junction gene expression. Advanced TcdA toxicity generally decreased cytokine/chemokine and increased tight junction and death receptor genes. Differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes in vivo. Basal exposure of TcdA/B caused greater toxicity and apoptosis than apical exposure. Apical exposure to toxins was enhanced by diclofenac. Apical/basal toxicities are uncoupled with more rapid onset and increased magnitude postbasal toxin exposure. Leaky junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive system to evaluate the impact of microbial toxins on gut epithelium. Novel human colonocyte monolayer cultures, benchmarked by transcriptomics for physiological relevance, detect early cytopathic impacts of toxins TcdA and TcdB. A fluorescent ZO-1 reporter in primary human colonocytes is used to track epithelial barrier disruption in response to TcdA. Basal TcdA/B exposure generally caused more rapid onset and cytotoxicity than apical exposure. Transcriptomics demonstrate changes in tight junction, chemokine, and cytokine receptor gene expression post-TcdA exposure. Diclofenac-induced leaky epithelium enhanced apical exposure toxicity.
doi_str_mv 10.1152/ajpgi.00251.2022
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Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell lines and organoids inherently limit these efforts. We developed adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigated the impact of toxins on apical/basal aspects of monolayers, and evaluated whether a leaky epithelial barrier enhances toxicity. Single-cell RNA-sequencing (scRNAseq) mapped -relevant genes to human lineages. Transcriptomics compared hCE to Caco-2, informed timing of in vitro stem cell differentiation, and revealed transcriptional responses to TcdA. Transepithelial electrical resistance (TEER) and fluorescent permeability assays measured cytotoxicity. Contribution of TcdB toxicity was evaluated in a diclofenac-induced leaky gut model. scRNAseq demonstrated broad and variable toxin receptor expression. Absorptive colonocytes in vivo displayed increased toxin receptor, Rho GTPase, and cell junction gene expression. Advanced TcdA toxicity generally decreased cytokine/chemokine and increased tight junction and death receptor genes. Differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes in vivo. Basal exposure of TcdA/B caused greater toxicity and apoptosis than apical exposure. Apical exposure to toxins was enhanced by diclofenac. Apical/basal toxicities are uncoupled with more rapid onset and increased magnitude postbasal toxin exposure. Leaky junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive system to evaluate the impact of microbial toxins on gut epithelium. Novel human colonocyte monolayer cultures, benchmarked by transcriptomics for physiological relevance, detect early cytopathic impacts of toxins TcdA and TcdB. A fluorescent ZO-1 reporter in primary human colonocytes is used to track epithelial barrier disruption in response to TcdA. Basal TcdA/B exposure generally caused more rapid onset and cytotoxicity than apical exposure. Transcriptomics demonstrate changes in tight junction, chemokine, and cytokine receptor gene expression post-TcdA exposure. 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Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell lines and organoids inherently limit these efforts. We developed adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigated the impact of toxins on apical/basal aspects of monolayers, and evaluated whether a leaky epithelial barrier enhances toxicity. Single-cell RNA-sequencing (scRNAseq) mapped -relevant genes to human lineages. Transcriptomics compared hCE to Caco-2, informed timing of in vitro stem cell differentiation, and revealed transcriptional responses to TcdA. Transepithelial electrical resistance (TEER) and fluorescent permeability assays measured cytotoxicity. Contribution of TcdB toxicity was evaluated in a diclofenac-induced leaky gut model. scRNAseq demonstrated broad and variable toxin receptor expression. Absorptive colonocytes in vivo displayed increased toxin receptor, Rho GTPase, and cell junction gene expression. Advanced TcdA toxicity generally decreased cytokine/chemokine and increased tight junction and death receptor genes. Differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes in vivo. Basal exposure of TcdA/B caused greater toxicity and apoptosis than apical exposure. Apical exposure to toxins was enhanced by diclofenac. Apical/basal toxicities are uncoupled with more rapid onset and increased magnitude postbasal toxin exposure. Leaky junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive system to evaluate the impact of microbial toxins on gut epithelium. Novel human colonocyte monolayer cultures, benchmarked by transcriptomics for physiological relevance, detect early cytopathic impacts of toxins TcdA and TcdB. A fluorescent ZO-1 reporter in primary human colonocytes is used to track epithelial barrier disruption in response to TcdA. Basal TcdA/B exposure generally caused more rapid onset and cytotoxicity than apical exposure. Transcriptomics demonstrate changes in tight junction, chemokine, and cytokine receptor gene expression post-TcdA exposure. Diclofenac-induced leaky epithelium enhanced apical exposure toxicity.</description><subject>Apoptosis</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacterial Toxins - metabolism</subject><subject>Bacterial Toxins - toxicity</subject><subject>Caco-2 Cells</subject><subject>Cell differentiation</subject><subject>Chemokines</subject><subject>Clostridioides difficile</subject><subject>Clostridioides difficile - metabolism</subject><subject>Colitis</subject><subject>Colon - metabolism</subject><subject>Cytotoxicity</subject><subject>Diclofenac</subject><subject>Electrical resistivity</subject><subject>Enterotoxins - metabolism</subject><subject>Enterotoxins - toxicity</subject><subject>Epithelium</subject><subject>Etiology</subject><subject>Gene expression</subject><subject>Humans</subject><subject>Nonsteroidal anti-inflammatory drugs</subject><subject>Organoids</subject><subject>Permeability</subject><subject>Sensitivity analysis</subject><subject>Stem cells</subject><subject>Toxin A</subject><subject>Toxins</subject><subject>Transcriptomics</subject><subject>Tumor cell lines</subject><issn>0193-1857</issn><issn>1522-1547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1r3DAQQEVpabZp7z0VQS-9eDOSLMs-lbCkHxDoJTmLsSwn2sqWK9lL_O-rTdLQ5CSQ3jw0PEI-MtgyJvkZ7qcbtwXgkm05cP6KbPI1L5gs1WuyAdaIgtVSnZB3Ke0BQHLG3pITUamyaRjbkMM59RZ_r_R2GXCkJvgw0iF01tNoDxZ9ostowjJ521GcnEF_1mJCT806hzncOePmlbqRWox-pTsf0hxd54LrbKKd6_tMeEuPaIbuppCWaN-TN3122w-P5ym5_nZxtftRXP76_nN3flmYksu5qGSrGtMDK4WsBOe1qHvR1YBdXaEp-7ZCZlSPLTRcgcUWoWoAWtagUq2oxSn5-uCdlnawnbHjHNHrKboB46oDOv38ZXS3-iYcNANgWVplw5dHQwx_FptmPbhkrPc42rAkzZUqy0aqkmf08wt0H5Y45v0yVVeNqGohMwUPlIkhpWj7p98w0Meq-r6qvq-qj1XzyKf_t3ga-JdR_AUm_6E-</recordid><startdate>20230401</startdate><enddate>20230401</enddate><creator>Ok, Meryem T</creator><creator>Liu, Jintong</creator><creator>Bliton, R Jarrett</creator><creator>Hinesley, Caroline M</creator><creator>San Pedro, Ekaterina Ellyce T</creator><creator>Breau, Keith A</creator><creator>Gomez-Martinez, Ismael</creator><creator>Burclaff, Joseph</creator><creator>Magness, Scott T</creator><general>American Physiological Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6333-8891</orcidid><orcidid>https://orcid.org/0000-0002-2746-1224</orcidid></search><sort><creationdate>20230401</creationdate><title>A leaky human colon model reveals uncoupled apical/basal cytotoxicity in early Clostridioides difficile toxin exposure</title><author>Ok, Meryem T ; 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Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop preclinical models for new therapies. Properties of cancer cell lines and organoids inherently limit these efforts. We developed adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigated the impact of toxins on apical/basal aspects of monolayers, and evaluated whether a leaky epithelial barrier enhances toxicity. Single-cell RNA-sequencing (scRNAseq) mapped -relevant genes to human lineages. Transcriptomics compared hCE to Caco-2, informed timing of in vitro stem cell differentiation, and revealed transcriptional responses to TcdA. Transepithelial electrical resistance (TEER) and fluorescent permeability assays measured cytotoxicity. Contribution of TcdB toxicity was evaluated in a diclofenac-induced leaky gut model. scRNAseq demonstrated broad and variable toxin receptor expression. Absorptive colonocytes in vivo displayed increased toxin receptor, Rho GTPase, and cell junction gene expression. Advanced TcdA toxicity generally decreased cytokine/chemokine and increased tight junction and death receptor genes. Differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes in vivo. Basal exposure of TcdA/B caused greater toxicity and apoptosis than apical exposure. Apical exposure to toxins was enhanced by diclofenac. Apical/basal toxicities are uncoupled with more rapid onset and increased magnitude postbasal toxin exposure. Leaky junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive system to evaluate the impact of microbial toxins on gut epithelium. Novel human colonocyte monolayer cultures, benchmarked by transcriptomics for physiological relevance, detect early cytopathic impacts of toxins TcdA and TcdB. A fluorescent ZO-1 reporter in primary human colonocytes is used to track epithelial barrier disruption in response to TcdA. Basal TcdA/B exposure generally caused more rapid onset and cytotoxicity than apical exposure. Transcriptomics demonstrate changes in tight junction, chemokine, and cytokine receptor gene expression post-TcdA exposure. Diclofenac-induced leaky epithelium enhanced apical exposure toxicity.</abstract><cop>United States</cop><pub>American Physiological Society</pub><pmid>36749911</pmid><doi>10.1152/ajpgi.00251.2022</doi><orcidid>https://orcid.org/0000-0001-6333-8891</orcidid><orcidid>https://orcid.org/0000-0002-2746-1224</orcidid><oa>free_for_read</oa></addata></record>
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subjects Apoptosis
Bacterial Proteins - metabolism
Bacterial Toxins - metabolism
Bacterial Toxins - toxicity
Caco-2 Cells
Cell differentiation
Chemokines
Clostridioides difficile
Clostridioides difficile - metabolism
Colitis
Colon - metabolism
Cytotoxicity
Diclofenac
Electrical resistivity
Enterotoxins - metabolism
Enterotoxins - toxicity
Epithelium
Etiology
Gene expression
Humans
Nonsteroidal anti-inflammatory drugs
Organoids
Permeability
Sensitivity analysis
Stem cells
Toxin A
Toxins
Transcriptomics
Tumor cell lines
title A leaky human colon model reveals uncoupled apical/basal cytotoxicity in early Clostridioides difficile toxin exposure
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