{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:33:53Z","timestamp":1790174033873,"version":"4.1.0"},"posted":{"date-parts":[[2024,12,8]]},"group-title":"Gastroenterology","reference-count":67,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T00:00:00Z","timestamp":1733616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma, sex hormones, and peristalsis-associated mechanical deformations play a key role in driving inflammation, fibrosis, and disease progression in male and female IBD patients.<\/jats:p>","DOI":"10.1101\/2024.12.05.24318563","type":"posted-content","created":{"date-parts":[[2024,12,8]],"date-time":"2024-12-08T14:15:56Z","timestamp":1733667356000},"source":"Crossref","is-referenced-by-count":6,"title":["Human Organ Chips Reveal New Inflammatory Bowel Disease Drivers"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3825-5899","authenticated-orcid":false,"given":"Alican","family":"\u00d6zkan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenn E.","family":"Merry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan R.","family":"Posey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Stejskalova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Calderon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8310-5358","authenticated-orcid":false,"given":"Megan","family":"Sperry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Piatok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo E.","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Carlotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2386-4915","authenticated-orcid":false,"given":"Stuart A. C.","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J.","family":"Winton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Riccardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Bordeianou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girija","family":"Goyal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald E.","family":"Ingber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025060402155490000_2024.12.05.24318563v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01520-5"},{"key":"2025060402155490000_2024.12.05.24318563v2.2","first-page":"740","article-title":"Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease","volume":"17","year":"2020","journal-title":"Nature Reviews Gastroenterology & Hepatology 2020 17:12"},{"key":"2025060402155490000_2024.12.05.24318563v2.3","first-page":"4","article-title":"Pregnancy and inflammatory bowel disease","volume":"5","year":"2007","journal-title":"South African Gastroenterology Review"},{"key":"2025060402155490000_2024.12.05.24318563v2.4","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.25617"},{"key":"2025060402155490000_2024.12.05.24318563v2.5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-0436.2002.700908.x"},{"key":"2025060402155490000_2024.12.05.24318563v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.029"},{"key":"2025060402155490000_2024.12.05.24318563v2.7","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2009.31"},{"key":"2025060402155490000_2024.12.05.24318563v2.8","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1007\/s00261-014-0258-y","article-title":"Identifying decreased peristalsis of abnormal small bowel segments in Crohn\u2019s disease using cine MR enterography: the frozen bowel sign","volume":"40","year":"2015","journal-title":"Abdom Imaging"},{"key":"2025060402155490000_2024.12.05.24318563v2.9","doi-asserted-by":"publisher","DOI":"10.1007\/s44164-022-00017-w"},{"key":"2025060402155490000_2024.12.05.24318563v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-00968-3"},{"key":"2025060402155490000_2024.12.05.24318563v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-022-00466-9"},{"key":"2025060402155490000_2024.12.05.24318563v2.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00675-x"},{"key":"2025060402155490000_2024.12.05.24318563v2.13","first-page":"507","article-title":"Human Colon-on-a-Chip Enables Continuous In Vitro Analysis of Colon Mucus Layer Accumulation and Physiology","volume":"9","year":"2020","journal-title":"Cmgh"},{"key":"2025060402155490000_2024.12.05.24318563v2.14","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-019-0702-x"},{"key":"2025060402155490000_2024.12.05.24318563v2.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812904106"},{"key":"2025060402155490000_2024.12.05.24318563v2.16","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4307"},{"key":"2025060402155490000_2024.12.05.24318563v2.17","doi-asserted-by":"crossref","first-page":"115648","DOI":"10.1016\/j.biopha.2023.115648","article-title":"Therapeutic targeting of vimentin by ALD-R491 impacts multiple pathogenic processes to attenuate acute and chronic colitis in mice","volume":"168","year":"2023","journal-title":"Biomedicine & Pharmacotherapy"},{"key":"2025060402155490000_2024.12.05.24318563v2.18","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.03.007"},{"key":"2025060402155490000_2024.12.05.24318563v2.19","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2003.026278"},{"key":"2025060402155490000_2024.12.05.24318563v2.20","doi-asserted-by":"publisher","DOI":"10.1038\/S41588-023-01384-0"},{"key":"2025060402155490000_2024.12.05.24318563v2.21","doi-asserted-by":"crossref","first-page":"4535194","DOI":"10.1155\/2017\/4535194","article-title":"Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies","volume":"2017","year":"2017","journal-title":"Oxid Med Cell Longev"},{"key":"2025060402155490000_2024.12.05.24318563v2.22","doi-asserted-by":"publisher","DOI":"10.1136\/gut.45.3.395"},{"key":"2025060402155490000_2024.12.05.24318563v2.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.crohns.2009.04.003"},{"key":"2025060402155490000_2024.12.05.24318563v2.24","unstructured":"WO2019018571A1 - Methods and uses of inflammatory bowel disease biomarkers - Google Patents. https:\/\/patents.google.com\/patent\/WO2019018571A1\/en."},{"key":"2025060402155490000_2024.12.05.24318563v2.25","doi-asserted-by":"publisher","DOI":"10.1097\/00005176-200111000-00007"},{"key":"2025060402155490000_2024.12.05.24318563v2.26","first-page":"278","article-title":"Identification of differentially expressed genes, associated functional terms pathways, and candidate diagnostic biomarkers in inflammatory bowel diseases by bioinformatics analysis","volume":"18","year":"2019","journal-title":"Exp Ther Med"},{"key":"2025060402155490000_2024.12.05.24318563v2.27","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.1021\/acs.molpharmaceut.9b00459","article-title":"Crohn\u2019s Disease Is Associated with Decreased CYP3A4 and P-Glycoprotein Protein Expression","volume":"16","year":"2019","journal-title":"Mol Pharm"},{"key":"2025060402155490000_2024.12.05.24318563v2.28","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.3748\/wjg.v25.i23.2846","article-title":"Role of cytochrome P450 polymorphisms and functions in development of ulcerative colitis","volume":"25","year":"2019","journal-title":"World J Gastroenterol"},{"key":"2025060402155490000_2024.12.05.24318563v2.29","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2006.093484"},{"key":"2025060402155490000_2024.12.05.24318563v2.30","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1093\/ibd\/izab318","article-title":"Deleterious Genetic Variation Across the NOD Signaling Pathway Is Associated With Reduced NFKB Signaling Transcription and Upregulation of Alternative Inflammatory Transcripts in Pediatric Inflammatory Bowel Disease","volume":"28","year":"2022","journal-title":"Inflamm Bowel Dis"},{"key":"2025060402155490000_2024.12.05.24318563v2.31","doi-asserted-by":"publisher","DOI":"10.5009\/gnl.2013.7.1.51"},{"key":"2025060402155490000_2024.12.05.24318563v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/82763"},{"key":"2025060402155490000_2024.12.05.24318563v2.33","first-page":"25","article-title":"Changing epidemiology of colorectal cancer \u2014 birth cohort effects and emerging risk factors","volume":"21","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2025060402155490000_2024.12.05.24318563v2.34","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/s41577-021-00534-x","article-title":"The inflammatory pathogenesis of colorectal cancer","volume":"21","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"2025060402155490000_2024.12.05.24318563v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210029"},{"key":"2025060402155490000_2024.12.05.24318563v2.36","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1430"},{"key":"2025060402155490000_2024.12.05.24318563v2.37","doi-asserted-by":"crossref","first-page":"e2319055121","DOI":"10.1073\/pnas.2319055121","article-title":"Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance","volume":"121","year":"2024","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025060402155490000_2024.12.05.24318563v2.38","first-page":"740","article-title":"Sex matters: impact on pathogenesis, presentation and treatment of inflammatory bowel disease","volume":"17","year":"2020","journal-title":"Nature Reviews Gastroenterology & Hepatology 2020 17:12"},{"key":"2025060402155490000_2024.12.05.24318563v2.39","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/s41575-021-00543-0","article-title":"Revisiting fibrosis in inflammatory bowel disease: the gut thickens","volume":"19","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2025060402155490000_2024.12.05.24318563v2.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13889-6"},{"key":"2025060402155490000_2024.12.05.24318563v2.41","first-page":"1","article-title":"Gastrointestinal functioning and menstrual cycle phase in emerging young adult women: a cross-sectional study","volume":"23","year":"2023","journal-title":"BMC Gastroenterol"},{"key":"2025060402155490000_2024.12.05.24318563v2.42","doi-asserted-by":"crossref","unstructured":"Bellofiore, N. , Ellery, S. , Mamrot, J. , \u2026 D. W.-A. journal of & 2017, undefined. First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus). Elsevier.","DOI":"10.1101\/056895"},{"key":"2025060402155490000_2024.12.05.24318563v2.43","doi-asserted-by":"publisher","DOI":"10.1530\/JME-17-0278"},{"key":"2025060402155490000_2024.12.05.24318563v2.44","first-page":"156","article-title":"RANK drives structured intestinal epithelial expansion during pregnancy","volume":"637","year":"2024","journal-title":"Nature 2024 637:8044"},{"key":"2025060402155490000_2024.12.05.24318563v2.45","unstructured":"Ameku, T. et al. Growth of the maternal intestine during reproduction. Cell 0, (2025)."},{"key":"2025060402155490000_2024.12.05.24318563v2.46","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-322260"},{"key":"2025060402155490000_2024.12.05.24318563v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3880253"},{"key":"2025060402155490000_2024.12.05.24318563v2.48","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1990.0059"},{"key":"2025060402155490000_2024.12.05.24318563v2.49","doi-asserted-by":"publisher","DOI":"10.1053\/gast.1997.v112.agast970594"},{"key":"2025060402155490000_2024.12.05.24318563v2.50","doi-asserted-by":"publisher","DOI":"10.1136\/gut.35.11.1590"},{"key":"2025060402155490000_2024.12.05.24318563v2.51","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.04.038"},{"key":"2025060402155490000_2024.12.05.24318563v2.52","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1093\/ibd\/izz075","article-title":"Challenges in IBD Research: Preclinical Human IBD Mechanisms","volume":"25","year":"2019","journal-title":"Inflamm Bowel Dis"},{"key":"2025060402155490000_2024.12.05.24318563v2.53","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izz078"},{"key":"2025060402155490000_2024.12.05.24318563v2.54","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/s41551-019-0397-0","article-title":"A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip","volume":"3","year":"2019","journal-title":"Nat Biomed Eng"},{"key":"2025060402155490000_2024.12.05.24318563v2.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23276-8"},{"key":"2025060402155490000_2024.12.05.24318563v2.56","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/s41551-022-00899-x","article-title":"Nutritional deficiency in an intestine-on-a-chip recapitulates injury hallmarks associated with environmental enteric dysfunction","volume":"6","year":"2022","journal-title":"Nat Biomed Eng"},{"key":"2025060402155490000_2024.12.05.24318563v2.57","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.07.025"},{"key":"2025060402155490000_2024.12.05.24318563v2.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08374-0"},{"key":"2025060402155490000_2024.12.05.24318563v2.59","first-page":"371","article-title":"Understanding the therapeutic toolkit for inflammatory bowel disease","volume":"22","year":"2025","journal-title":"Nature Reviews Gastroenterology & Hepatology 2025 22:6"},{"key":"2025060402155490000_2024.12.05.24318563v2.60","doi-asserted-by":"publisher","DOI":"10.1039\/c2lc40074j"},{"key":"2025060402155490000_2024.12.05.24318563v2.61","doi-asserted-by":"publisher","DOI":"10.1186\/s40168-019-0702-x"},{"key":"2025060402155490000_2024.12.05.24318563v2.62","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3516"},{"key":"2025060402155490000_2024.12.05.24318563v2.63","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.medj.2023.07.004","article-title":"Organoid co-culture model of the human endometrium in a fully synthetic extracellular matrix enables the study of epithelial-stromal crosstalk","volume":"4","year":"2023","journal-title":"Med"},{"key":"2025060402155490000_2024.12.05.24318563v2.64","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"2025060402155490000_2024.12.05.24318563v2.65","unstructured":"Genomics in the Cloud: Using Docker, GATK, and WDL in Terra - Geraldine A. Van der Auwera, Brian D. O\u2019Connor - Google Books. https:\/\/books.google.com\/books?hl=en&lr=&id=vsXaDwAAQBAJ&oi=fnd&pg=PP1&dq=Van+der+Auwera+GA+%26+O%27Connor+BD.+(2020).+Genomics+in+the+Cloud:+Using+Docker,+GATK,+and+WDL+in+Terra+(1st+Edition).+O%27Reilly+Media.&ots=5lcr0E-qna&sig=43MTbQQNO_yexxB7NxDgVt88kOk#v=onepage&q&f=false."},{"key":"2025060402155490000_2024.12.05.24318563v2.66","doi-asserted-by":"publisher","DOI":"10.1093\/BIOINFORMATICS\/BTY1055"},{"key":"2025060402155490000_2024.12.05.24318563v2.67","doi-asserted-by":"publisher","DOI":"10.1101\/gr.175141.114"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.12.05.24318563","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:22:13Z","timestamp":1768508533000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.12.05.24318563"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,8]]},"references-count":67,"URL":"https:\/\/doi.org\/10.1101\/2024.12.05.24318563","relation":{},"subject":[],"published":{"date-parts":[[2024,12,8]]},"subtype":"preprint"}}