@article{7feb7be46b774455b0d83cd800103621,
title = "Cytokine responsive networks in human colonic epithelial organoids unveil a molecular classification of inflammatory bowel disease",
abstract = "Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we mapped the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines interferon gamma, interleukin-13, -17A, and tumor necrosis factor alpha with next-generation sequencing, we unveil shared and distinct regulation patterns of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from patients with IBD (n = 1,009) reveals a molecular classification of mucosal inflammation defined by gradients of cytokine-responsive transcriptional signatures. Our systems biology approach detected signaling bottlenecks in cytokine-responsive networks and highlighted their translational potential as theragnostic targets in intestinal inflammation.",
keywords = "Colon/pathology, Cytokines, Humans, Inflammation/pathology, Inflammatory Bowel Diseases/pathology, Interferon-gamma/pharmacology, Interleukin-13, Intestinal Mucosa/pathology, Organoids/pathology, Tumor Necrosis Factor-alpha",
author = "Polychronis Pavlidis and Anastasia Tsakmaki and Agatha Treveil and Katherine Li and Domenico Cozzetto and Feifei Yang and Umar Niazi and Hayee, {Bu Hussain} and Mansoor Saqi and Joshua Friedman and Tamas Korcsmaros and Gavin Bewick and Nick Powell",
note = "Funding Information: We would like to thank the NIHR BRC Translational Bioinformatics Team for providing access to the Ingenuity Pathway Analysis platform. This work was funded by the Wellcome Trust (WT101159) (N.P.), Imperial College Biomedical Research Centre (N.P. and T.K.), KHP Challenge Fund (N.P. and P.P.), forCrohn's/GutsUK (N.P. and P.P.), and Crohn's and Colitis UK (N.P.). A.T. was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (grant number BB/M011216/1). The work of T.K. was supported by the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK) and strategically supported by UKRI Biotechnological and Biosciences Research Council (BBSRC) UK grants (BB/CSP17270/1, BB/R012490/1 and its constituent project(s) (BBS/E/F/000PR10353 and BBS/E/F/000PR10355). P.P. conceptualized the study, designed experiments, analyzed data, and wrote the manuscript; A.T. performed experiments and contributed to manuscript preparation; A.T. K.L. D.C. F.Y. U.N. M.S. J.F. T.K. and G.B. performed analysis and contributed to manuscript preparation; organoid analysis was performed in the G.B. lab; systems biology analysis was performed in the T.K. lab; G.B. M.S. K.L. J.F. and T.K. provided scientific and analytical input; N.P. conceptualized the study, designed experiments, supervised the project, analyzed data, and wrote the manuscript. K.L. F.Y. and J.F. are/were employees of Janssen Pharmaceuticals. Funding Information: We would like to thank the NIHR BRC Translational Bioinformatics Team for providing access to the Ingenuity Pathway Analysis platform. This work was funded by the Wellcome Trust ( WT101159 ) (N.P.), Imperial College Biomedical Research Centre (N.P. and T.K.), KHP Challenge Fund (N.P. and P.P.), forCrohn{\textquoteright}s/GutsUK (N.P. and P.P.), and Crohn{\textquoteright}s and Colitis UK (N.P.). A.T. was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (grant number BB/M011216/1 ). The work of T.K. was supported by the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK) and strategically supported by UKRI Biotechnological and Biosciences Research Council (BBSRC) UK grants ( BB/CSP17270/1 , BB/R012490/1 and its constituent project(s) ( BBS/E/F/000PR10353 and BBS/E/F/000PR10355 ). Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = sep,
day = "27",
doi = "10.1016/j.celrep.2022.111439",
language = "English",
volume = "40",
pages = "111439",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier BV",
number = "13",
}