{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:51:13Z","timestamp":1790794273466,"version":"4.1.0"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,3,19]],"date-time":"2019-03-19T00:00:00Z","timestamp":1552953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,20]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Genetic studies have strongly linked autophagy to Crohn\u2019s disease (CD), and stimulating autophagy in CD patients may be therapeutically beneficial. The aim of this study was to evaluate the effect of current inflammatory bowel disease (IBD) drugs on autophagy and investigate molecular mechanisms of action and functional outcomes in relation to this cellular process.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Autophagy marker LC3 was evaluated by confocal fluorescence microscopy and flow cytometry. Drug mechanism of action was investigated by polymerase chain reaction (PCR) array with changes in signaling pathways examined by immunoblot and quantitative reverse transcription PCR (RT-qPCR). Clearance of adherent-invasive Escherichia coli (AIEC) and levels of pro-inflammatory cytokine tumor necrosis factor alpha (TNF\u03b1) were evaluated by gentamicin protection assays and RT-qPCR, respectively. The marker LC3 was analyzed in peripheral blood mononuclear cells (PBMCs) from pediatric patients by flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Azathioprine induces autophagy via mechanisms involving modulation of mechanistic target of rapamycin (mTORC1) signaling and stimulation of the unfolded protein response (UPR) sensor PERK. Induction of autophagy with azathioprine correlated with the enhanced clearance of AIEC and dampened AIEC-induced increases in TNF\u03b1. Azathioprine induced significant increase in autophagosome bound LC3-II in PBMC populations ex vivo, supporting in vitro findings. In patients, the CD-associated ATG16L1 T300A single-nucleotide polymorphism did not attenuate azathioprine induction of autophagy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Modulation of autophagy via mTORC1 and the UPR may contribute to the therapeutic efficacy of azathioprine in IBD.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ibd\/izz039","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T03:40:28Z","timestamp":1553053228000},"page":"1481-1496","source":"Crossref","is-referenced-by-count":26,"title":["The Inflammatory Bowel Disease Drug Azathioprine Induces Autophagy via mTORC1 and the Unfolded Protein Response Sensor PERK"],"prefix":"10.1093","volume":"25","author":[{"given":"Kirsty M","family":"Hooper","sequence":"first","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Casanova","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadie","family":"Kemp","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A","family":"Staines","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Satsangi","sequence":"additional","affiliation":[{"name":"Centre for Genomic & Experimental Medicine, University of Edinburgh, Western General Hospital Campus, Crewe Road, Edinburgh Scotland"},{"name":"Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, England"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G","family":"Barlow","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Henderson","sequence":"additional","affiliation":[{"name":"Child Life and Health, University of Edinburgh, Edinburgh, Scotland"},{"name":"Department of Pediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Stevens","sequence":"additional","affiliation":[{"name":"School of Applied Sciences, Edinburgh Napier University, Sighthill Campus, Sighthill Court, Edinburgh, Scotland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,3,19]]},"reference":[{"key":"2019082011452468500_CIT0001","article-title":"2013\/14 NHS Standard Contract for Colorectal: Complex Inflammatory Bowel Disease (Adult)","volume-title":"NHS England","author":"NHS CB","year":"2013"},{"key":"2019082011452468500_CIT0002","doi-asserted-by":"crossref","first-page":"44","DOI":"10.12703\/P7-44","article-title":"Pathogenesis of Crohn\u2019s disease","volume":"7","author":"Boyapati","year":"2015","journal-title":"F1000prime Rep."},{"key":"2019082011452468500_CIT0003","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/ibd.21339","article-title":"Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases","volume":"17","author":"Frank","year":"2011","journal-title":"Inflamm Bowel Dis."},{"key":"2019082011452468500_CIT0004","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1053\/j.gastro.2004.04.061","article-title":"High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn\u2019s disease","volume":"127","author":"Darfeuille-Michaud","year":"2004","journal-title":"Gastroenterology."},{"key":"2019082011452468500_CIT0005","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/ng.3760","article-title":"Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease","volume":"49","author":"Lange","year":"2017","journal-title":"Nat. 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