{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:48:50Z","timestamp":1790804930533,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T00:00:00Z","timestamp":1702080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Crohns and Colitis UK","award":["M2018-4"],"award-info":[{"award-number":["M2018-4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>No effective therapeutic intervention exists for intestinal fibrosis in Crohn\u2019s disease [CD]. We characterized fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We undertook immunohistochemistry, metabolic, signalling pathway and epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD\/NSCD fibroblasts were cultured with TGF\u03b2 and valproic acid [VPA].<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Stricturing CD was characterized by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGF\u03b2 stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appeared \u2018metabolically primed\u2019 and responded more strongly to both TGF\u03b2 and VPA. Treatment with VPA revealed TGF\u03b2-dependent and TGF\u03b2-independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype and metabolic priming characterize SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGF\u03b2-mediated CD fibrosis. HDAC inhibitor therapy may \u2018reset\u2019 the epigenetic changes associated with fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ecco-jcc\/jjad209","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T18:45:24Z","timestamp":1701801924000},"page":"895-907","source":"Crossref","is-referenced-by-count":24,"title":["Epigenetic and Metabolic Reprogramming of Fibroblasts in Crohn\u2019s Disease Strictures Reveals Histone Deacetylases as Therapeutic Targets"],"prefix":"10.1093","volume":"18","author":[{"given":"Amy","family":"Lewis","sequence":"first","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T","family":"Humphreys","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute , Sydney, NSW 2010 , Australia"},{"name":"St Vincent\u2019s Clinical School, University of New South Wales , Sydney, NSW 2052 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belen","family":"Pan-Castillo","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Berti","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Felice","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"},{"name":"Department of Internal Medicine University of Padua, Internal Medicine 1 Unit, Ca\u2019 Foncello Hospital , Treviso , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Gordon","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radha","family":"Gadhok","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Nijhuis","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine & Dentistry , London E1 2AT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shameer","family":"Mehta S","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Child 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