{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T23:51:32Z","timestamp":1793058692793,"version":"4.5.0"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.16901.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000}}],"reference-count":80,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016580","name":"Kennedy Trust for Rheumatology Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016580","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["RCF19\/016"],"award-info":[{"award-number":["RCF19\/016"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["101734"],"award-info":[{"award-number":["101734"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["212240"],"award-info":[{"award-number":["212240"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Patients with primary sclerosing cholangitis (PSC) frequently have co-ocurring ulcerative colitis (UC) and develop colorectal cancer. Colorectal cancer risk in patients with PSC-associated ulcerative colitis (PSC\/UC) is elevated relative to patients with ulcerative colitis (UC) alone, reasons for which remain obscure. Understanding the molecular and microbial basis for differences between these two patient groups and how these vary across intestinal sites is important for the development of therapies to prevent colorectal cancer development in at-risk individuals. \u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    We employed ribonucleic acid sequencing (RNA-seq) analysis of biopsy samples across three intestinal tissue locations (ileum, caecum and rectum) in patients with PSC\/UC (ileum n = 7, caecum n = 7, rectum n = 7), UC (ileum n = 9, caecum n = 10, rectum n = 10) and healthy controls (ileum n = 11, caecum n = 9, rectum n = 12) to determine tissue-dependent transcriptional alterations in PSC\/UC. We also performed 16S ribosomal RNA (rRNA) amplicon sequencing to determine bacterial associations with PSC\/UC.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    Tissue-defining transcriptional signatures revealed that the ileum was enriched for genes involved in lipid and drug metabolism, the caecum for activated immune cells and the rectum for enteric neurogenesis. Transcriptional alterations relative to healthy control samples were largely shared between patients with PSC\/UC or UC although were distinct across tissue locations. Nevertheless, we observed reduced expression of gamma-glutamyl transferase 1 (\n                    <ns4:italic>GGT1<\/ns4:italic>\n                    ) specifically in the ileum and caecum of patients with PSC\/UC.\n                  <\/ns4:p>\n                  <ns4:p>\n                    Analysis of the bacterial component of the microbiome revealed high inter-individual variability of microbiome composition and little evidence for tissue-dependency. We observed a reduction in\n                    <ns4:italic>Parabacteroides<\/ns4:italic>\n                    relative abundance in the rectum of patients with PSC\/UC.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    The role of gamma-glutamyl transferase in maintaining the redox environment through the glutathione salvage pathway makes our observed alterations a potential pathway to PSC-associated colorectal cancer.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.16901.2","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T08:44:03Z","timestamp":1667551443000},"page":"199","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Tissue-dependent transcriptional and bacterial associations in primary sclerosing cholangitis-associated inflammatory bowel 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V.","family":"Arancibia-C\u00e1rcamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Powrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Geremia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"1161-1170","DOI":"10.1056\/NEJMra1506330","article-title":"Primary Sclerosing Cholangitis.","volume":"375","author":"K Lazaridis","year":"2016","journal-title":"N Engl J Med."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"91-96","DOI":"10.1136\/gut.2004.046615","article-title":"PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.","volume":"54","author":"E 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T05:50:14Z","timestamp":1668405014000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":80,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.16901.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.20393.r53187","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.20393.r53187","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,4]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.20393.r53187, Naiara Beraza, Meha Patel, Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, UK, 14 Nov 2022, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2#referee-response-53187","order":0,"name":"referee-response-53187","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.18645.r48286, Gideon Hirschfield, Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada, 21 Feb 2022, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v1#referee-response-48286","order":1,"name":"referee-response-48286","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Nicholas Ilott<\/b>; \n<i>Posted: 12 Sep 2022<\/i>; Reviewer #2: Professor Gideon Hirschfield  Nice study; important to try and extend the observations. The challenge for the field is getting studies that are adequately powered and which capture the clinical diversity of patients with PSC-UC and UC. The diseases are very variable, patients are on different treatments, and liver disease severity\/recent infective complications are all hard to control. I didn't get the full sense of the clinical background for the participants. Furthermore the literature hasn't found a clear single answer to how the microbiome is involved in this disease. This paper is nevertheless well written. It is provocative and the findings need extension and validation but methodologically the data is well presented, and transparent. It sets the scene for larger collaborative efforts.  \n<b>We would like to thank Professor Gideon Hirschfield for taking the time to review our manuscript. There are a number of challenges in the field and we agree with professor Hirschfield that this is a first step towards understanding molecular alterations in PSC-UC. Large, prospective cohorts with well curated metadata are indeed required to be able to disentangle the multiple host and\/or microbial factors that contribute to both the development and the heterogeneity in PSC-UC.<\/b>  \n<b>We have included the reference provided by Professor Hirschfield in the introduction of the manuscript.<\/b>","URL":"https:\/\/wellcomeopenresearch.org\/articles\/6-199\/v2#referee-comment-5114","order":2,"name":"referee-comment-5114","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust (101734, <a href=https:\/\/doi.org\/10.35802\/101734>https:\/\/doi.org\/10.35802\/101734<\/a>, 212240, <a href=https:\/\/doi.org\/10.35802\/212240>https:\/\/doi.org\/10.35802\/212240<\/a>), the National Institute for Health Research (RCF19\/016) and the Kennedy Trust for Rheumatology Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}