{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:27:18Z","timestamp":1762957638523,"version":"3.41.2"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021856","name":"Ministero dell'Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PE_00000019"],"award-info":[{"award-number":["PE_00000019"]}],"id":[{"id":"10.13039\/501100021856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and aim<\/jats:title><jats:p>Patients with ulcerative colitis (UC) undergoing colectomy with ileal-anal pouch anastomosis can develop chronic pouchitis (CP). Since treatment options are very limited for patients with CP, identification of factors\/mechanisms that amplify the CP-associated inflammatory response could help develop novel treatments. We here assessed the expression of Smad7, an inhibitor of TGF-\u03b21 signaling and positive regulator of gut inflammation, in CP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mucosal samples were taken from the inflamed pouch of patients with CP, whose activity was evaluated by the modified Pouchitis Disease Activity Index (mPDAI). Controls included mucosal biopsy samples taken from the uninflamed pouch of patients with a history of CP and ileal samples taken from normal\/inflamed pre-pouch of patients with CP and normal controls. Smad7 expression was assessed by Western blotting and immunofluorescence, and the Smad7-expressing lamina propria mononuclear cells (LPMCs) were evaluated by flow cytometry. Mucosal samples taken from the inflamed pouch of CP patients were cultured with a Smad7 antisense (AS) or sense oligonucleotide and TNF-\u03b1 and interleukin (IL)-8 were evaluated by real-time PCR and ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Enhanced Smad7 expression was seen in the inflamed pouch of patients with CP compared to the normal or inflamed ileum of the same patients and the uninflamed pouch of patients with no pouchitis and normal controls. In the inflamed mucosa of patients with CP, Smad7 was more abundant in LPMCs, mainly in T lymphocytes. Knockdown of Smad7 in <jats:italic>ex vivo<\/jats:italic> mucosal explants taken from CP patients was associated with a reduction in TNF-\u03b1 and IL-8 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>High Smad7 occurs in the inflamed mucosa of patients with CP, further supporting the pathogenic role of Smad7 in the gut.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1549193","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:16:42Z","timestamp":1740979002000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["High Smad7 marks inflammation in patients with chronic pouchitis"],"prefix":"10.3389","volume":"16","author":[{"given":"Claudia","family":"Maresca","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Iannucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Colella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachele","family":"Frascatani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Laudisi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Lolli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Marafini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Zorzi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Salvatori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan","family":"Monteleone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvatore","family":"Bellinvia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmine","family":"Stolfi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Monteleone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-326390","article-title":"Efficacy of biological therapies and small molecules in moderate to severe ulcerative colitis: systematic review and network meta-analysis","volume":"71","author":"Burr","year":"2022","journal-title":"Gut"},{"key":"B2","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.dld.2022.08.039","article-title":"Colectomy rates in ulcerative colitis: A systematic review and meta-analysis","volume":"55","author":"Dai","year":"2023","journal-title":"Digest Liver Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13197","article-title":"Systematic review: the financial burden of surgical complications in patients with ulcerative colitis","volume":"41","author":"Lindsay","year":"2015","journal-title":"Aliment Pharmacol Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1016\/j.cgh.2021.09.037","article-title":"Patients with pouchitis demonstrate a significant cost burden in the first two years after ileal pouch-anal anastomosis","volume":"20","author":"Barnes","year":"2022","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B5","article-title":"Diagnosis and treatment of pouchitis","volume":"4","author":"Shen","year":"2008","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"B6","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1136\/flgastro-2012-100171","article-title":"Pouchitis: a practical guide","volume":"4","author":"Steinhart","year":"2013","journal-title":"Frontline Gastroenterol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/biom14091164","article-title":"Are small molecules effective in treating inflammatory pouch disorders following ileal pouch-anal anastomosis for ulcerative colitis? Here is where we stand","volume":"14","author":"Gravina","year":"2024","journal-title":"Biomolecules"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1097\/DCR.0b013e31823e2d18","article-title":"Genetic risk profiling and gene signature modeling to predict risk of complications after IPAA","volume":"55","author":"Sehgal","year":"2012","journal-title":"Dis Colon Rectum"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v11.i46.7323","article-title":"Combined carriership of TLR9 -1237C and CD14 -260T alleles enhances the risk of developing chronic relapsing pouchitis","volume":"11","author":"Lammers","year":"2005","journal-title":"WJG"},{"key":"B10","article-title":"Pouchitis: insight into the pathogenesis and clinical aspects","volume":"14","author":"de Negreiros","year":"2022","journal-title":"Am J Transl Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/39369","article-title":"Identification of Smad7, a TGF\u03b2-inducible antagonist of TGF-\u03b2 signalling","volume":"389","author":"Nakao","year":"1997","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI12821","article-title":"Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease","volume":"108","author":"Monteleone","year":"2001","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.09.016","article-title":"Inhibition of smad7 with a specific antisense oligonucleotide facilitates TGF-\u03b21\u2013mediated suppression of colitis","volume":"131","author":"Boirivant","year":"2006","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izy062","article-title":"Knockdown of smad7 with a specific antisense oligonucleotide attenuates colitis and colitis-driven colonic fibrosis in mice","volume":"24","author":"Izzo","year":"2018","journal-title":"Inflamm Bowel Dis"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2011.290","article-title":"Phase I clinical trial of smad7 knockdown using antisense oligonucleotide in patients with active crohn\u2019s disease","volume":"20","author":"Monteleone","year":"2012","journal-title":"Mol Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407250","article-title":"Mongersen, an oral SMAD7 antisense oligonucleotide, and crohn\u2019s disease","volume":"372","author":"Monteleone","year":"2015","journal-title":"N Engl J Med"},{"key":"B17","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1053\/j.gastro.2017.08.035","article-title":"Effects of mongersen (GED-0301) on endoscopic and clinical outcomes in patients with active crohn\u2019s disease","volume":"154","author":"Feagan","year":"2018","journal-title":"Gastroenterology"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.14309\/ajg.0000000000000493","article-title":"Mongersen (GED-0301) for active crohn\u2019s disease: results of a phase 3 study","volume":"115","author":"Sands","year":"2020","journal-title":"Am J Gastroenterol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2021.0089","article-title":"Inhomogeneous diastereomeric composition of mongersen antisense phosphorothioate oligonucleotide preparations and related pharmacological activity impairment","volume":"32","author":"Arrico","year":"2022","journal-title":"Nucleic Acid Ther"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/s10350-004-6652-8","article-title":"Modified pouchitis disease activity index: A simplified approach to the diagnosis of pouchitis","volume":"46","author":"Shen","year":"2003","journal-title":"Dis Colon Rectum"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.56.5.559","article-title":"Essential involvement of interleukin-8 (IL-8) in acute inflammation","volume":"56","author":"Harada","year":"1994","journal-title":"J Leukoc Biol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1126\/science.1718038","article-title":"Regulation of rransendothelial neutrophil migration by endogenous interleukin-8","volume":"254","author":"Huber","year":"1991","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(21)00101-1","article-title":"Diagnosis and classification of ileal pouch disorders: consensus guidelines from the International Ileal Pouch Consortium","volume":"6","author":"Shen","year":"2021","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.17.9314","article-title":"Vascular MAD s: Two novel MAD -related genes selectively inducible by flow in human vascular endothelium","volume":"94","author":"Topper","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-021-02202-2","article-title":"Silencing Smad7 potentiates BMP2-induced chondrogenic differentiation and inhibits endochondral ossification in human synovial-derived mesenchymal stromal cells","volume":"12","author":"Xiao","year":"2021","journal-title":"Stem Cell Res Ther"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/BF02049839","article-title":"Cytokine production in pouchitis is similar to that in ulcerative colitis","volume":"38","author":"Patel","year":"1995","journal-title":"Dis Colon Rectum"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303654200","article-title":"A failure of transforming growth factor-\u03b21 negative regulation maintains sustained NF-\u03baB activation in gut inflammation","volume":"279","author":"Monteleone","year":"2004","journal-title":"J Biol Chem"},{"key":"B28","doi-asserted-by":"publisher","first-page":"a000141","DOI":"10.1101\/cshperspect.a000141","article-title":"NF- B as a critical link between inflammation and cancer","volume":"1","author":"Karin","year":"2009","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.292961","article-title":"The deubiquitinase CYLD targets smad7 protein to regulate transforming growth factor \u03b2 (TGF-\u03b2) signaling and the development of regulatory T cells","volume":"286","author":"Zhao","year":"2011","journal-title":"J Biol Chem"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1549193\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:16:47Z","timestamp":1740979007000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1549193\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,3]]},"references-count":29,"alternative-id":["10.3389\/fimmu.2025.1549193"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1549193","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,3,3]]},"article-number":"1549193"}}