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dc.contributor.authorSkovdahl, Helene Kolstad
dc.contributor.authorGopalakrishnan, Shreya
dc.contributor.authorSvendsen, Tarjei Dahl
dc.contributor.authorGranlund, Atle van Beelen
dc.contributor.authorBakke, Ingunn
dc.contributor.authorGinbot, Zekarias
dc.contributor.authorThorsvik, Silje
dc.contributor.authorFlatberg, Arnar
dc.contributor.authorSporsheim, Bjørnar
dc.contributor.authorOstrop, Jenny
dc.contributor.authorMollnes, Tom Eirik
dc.contributor.authorSandvik, Arne Kristian
dc.contributor.authorBruland, Torunn
dc.date.accessioned2021-10-26T08:12:34Z
dc.date.available2021-10-26T08:12:34Z
dc.date.created2021-06-03T13:04:39Z
dc.date.issued2021
dc.identifier.citationFrontiers in Pharmacology. 2021, 12:679741 1-15.en_US
dc.identifier.issn1663-9812
dc.identifier.urihttps://hdl.handle.net/11250/2825556
dc.description.abstractTreatment of inflammatory bowel disease (IBD) is challenging, with a series of available drugs each helping only a fraction of patients. Patients may face time-consuming drug trials while the disease is active, thus there is an unmet need for biomarkers and assays to predict drug effect. It is well known that the intestinal epithelium is an important factor in disease pathogenesis, exhibiting physical, biochemical and immunologic driven barrier dysfunctions. One promising test system to study effects of existing or emerging IBD treatments targeting intestinal epithelial cells (IECs) is intestinal organoids (“mini-guts”). However, the fact that healthy intestinal epithelium is in a physiologically hypoxic state has largely been neglected, and studies with intestinal organoids are mainly performed at oxygen concentration of 20%. We hypothesized that lowering the incubator oxygen level from 20% to 2% would recapitulate better the in vivo physiological environment of colonic epithelial cells and enhance the translational value of intestinal organoids as a drug testing platform. In the present study we examine the effects of the key IBD cytokines and drug targets TNF/IL17 on human colonic organoids (colonoids) under atmospheric (20%) or reduced (2%) O2. We show that colonoids derived from both healthy controls and IBD-patients are viable and responsive to IBD-relevant cytokines at 2% oxygen. Because chemokine release is one of the important immunoregulatory traits of the epithelium that may be fine-tuned by IBD-drugs, we also examined chemokine expression and release at different oxygen concentrations. We show that chemokine responses to TNF/IL17 in organoids display similarities to inflamed epithelium in IBD-patients. However, inflammation-associated genes induced by TNF/IL17 were attenuated at low oxygen concentration. We detected substantial oxygen-dependent differences in gene expression in untreated as well as TNF/IL17 treated colonoids in all donors. Further, for some of the IBD-relevant cytokines differences between colonoids from healthy controls and IBD patients were more pronounced in 2% O2 than 20% O2. Our results strongly indicate that an oxygen concentration similar to the in vivo epithelial cell environment is of essence in experimental pharmacology.en_US
dc.language.isoengen_US
dc.publisherFrontiersen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titlePatient derived colonoids as drug testing platforms-Critical importance of oxygen concentrationen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.pagenumber1-15en_US
dc.source.volume12:679741en_US
dc.source.journalFrontiers in Pharmacologyen_US
dc.identifier.doi10.3389/fphar.2021.679741
dc.identifier.cristin1913559
dc.relation.projectSamarbeidsorganet mellom Helse Midt-Norge og NTNU: 90285400en_US
dc.relation.projectSamarbeidsorganet mellom Helse Midt-Norge og NTNU: 90284800en_US
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal