{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:24:41Z","timestamp":1784204681878,"version":"3.55.0"},"reference-count":42,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,26]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Chronic granulomatous disease (CGD) is an inborn error of immunity that is caused by defects in any 1 of the 5 subunits (gp91phox, p47phox, p22phox, p67phox, p40phox) that form the NAD phosphate oxidase complex 2 (NOX2) or in the chaperone protein essential for reactive oxygen species (ROS) that supports its assembly. These defects lead to severely reduced phagocyte-derived ROS production. Almost 50% of patients with CGD have inflammatory bowel disease (IBD) associated with dysbiosis, and the age of IBD onset may vary according to the CGD genotype. Although we previously demonstrated that the intestinal microbiota determines colitis susceptibility in CGD mice, the underlying mechanisms remain unknown. We hypothesized that NOX2 defects are associated with distinct intestinal microbiome signatures and immune responses, which impact colitis severity. Chemical colitis susceptibility was evaluated in 2 strains of CGD mice (gp91phox\u2013\/\u2013 and p47phox\u2013\/\u2013) with distinct microbiotas from 2 different animal facilities, while also evaluating the impact of microbiota standardization and colitogenic microbiota transfer on mucosal immune responses at the intestinal barrier. Although p47phox\u2013\/\u2013 and gp91phox\u2013\/\u2013 mice that harbored a colitogenic microbiota had increased colitis severity, the intestinal epithelial cells from p47phox\u2013\/\u2013 mice produced more ROS, which was associated with increased NOX isoform gene expression. In contrast, gp91phox\u2013\/\u2013 mice had decreased mucin production and a mucosal immune response profile suggestive of increased inflammasome activation at the intestinal barrier when compared with control and p47phox\u2013\/\u2013 mice. Our findings suggest that the microbiota impacts colitis susceptibility in a CGD genotype\u2013specific manner, thereby potentially explaining differences in the timing of IBD onset in patients with different CGD genotypes and identifying potential novel and personalized therapeutic targets.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024026332","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T19:59:03Z","timestamp":1744833543000},"page":"3153-3165","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":6,"title":["Genotype-specific immune responses at the intestinal barrier predispose to colitis in mouse models of chronic granulomatous disease"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7511-4429","authenticated-orcid":false,"given":"Emma","family":"Darbinian","sequence":"first","affiliation":[{"name":"1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada"},{"name":"2Molecular Biology Programs, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3162-0371","authenticated-orcid":false,"given":"Kodjovi D.","family":"Mlaga","sequence":"additional","affiliation":[{"name":"1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1343-7255","authenticated-orcid":false,"given":"Prabha","family":"Chandrasekaran","sequence":"additional","affiliation":[{"name":"3eHealth and Informatics, LLC, Gaithersburg, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Han","sequence":"additional","affiliation":[{"name":"4Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"Donk\u00f3","sequence":"additional","affiliation":[{"name":"5Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al\u00e9handra","family":"Desjardins","sequence":"additional","affiliation":[{"name":"1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5463-1583","authenticated-orcid":false,"given":"Thomas L.","family":"Leto","sequence":"additional","affiliation":[{"name":"5Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-5464","authenticated-orcid":false,"given":"Steven M.","family":"Holland","sequence":"additional","affiliation":[{"name":"5Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Poudrier","sequence":"additional","affiliation":[{"name":"1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada"},{"name":"6Department of Microbiology, Infectious Diseases and Immunology, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5486-1549","authenticated-orcid":false,"given":"Emilia Liana","family":"Falcone","sequence":"additional","affiliation":[{"name":"1Center for Immunity, Inflammation and Infectious Diseases, Montreal Clinical Research Institute, Montreal, QC, Canada"},{"name":"6Department of Microbiology, Infectious Diseases and Immunology, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"},{"name":"7Department of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"},{"name":"8Division of Microbiology and Infectious Diseases, Department of Medicine, Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al, Montreal, QC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"3","key":"2025062611222124400_bib1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/00005792-200005000-00004","article-title":"Genetic, biochemical, and clinical features of chronic granulomatous disease","volume":"79","author":"Segal","year":"2000","journal-title":"Medicine"},{"issue":"2","key":"2025062611222124400_bib2","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.jaci.2018.09.019","article-title":"EROS\/CYBC1 mutations: decreased NADPH oxidase function and chronic granulomatous disease","volume":"143","author":"Thomas","year":"2019","journal-title":"J Allergy Clin Immunol"},{"issue":"13","key":"2025062611222124400_bib3","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1182\/blood-2009-05-221606","article-title":"Restoration of NET formation by gene therapy in CGD controls aspergillosis","volume":"114","author":"Bianchi","year":"2009","journal-title":"Blood"},{"key":"2025062611222124400_bib4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.freeradbiomed.2018.06.011","article-title":"How the phagocyte NADPH oxidase regulates innate immunity","volume":"125","author":"Thomas","year":"2018","journal-title":"Free Radic Biol Med"},{"issue":"8","key":"2025062611222124400_bib5","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1093\/cid\/ciu1154","article-title":"Common severe infections in chronic granulomatous disease","volume":"60","author":"Marciano","year":"2015","journal-title":"Clin Infect Dis"},{"issue":"3","key":"2025062611222124400_bib6","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.jaci.2014.04.014","article-title":"Inflammatory manifestations in a single-center cohort of patients with chronic granulomatous disease","volume":"134","author":"Magnani","year":"2014","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"2025062611222124400_bib7","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1542\/peds.114.2.462","article-title":"Gastrointestinal involvement in chronic granulomatous disease","volume":"114","author":"Marciano","year":"2004","journal-title":"Pediatrics"},{"key":"2025062611222124400_bib8","first-page":"573","volume-title":"Oxidases. Vol 1982","author":"Falcone","year":"2019","edition":"1st ed."},{"issue":"7758","key":"2025062611222124400_bib9","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/s41586-019-1237-9","article-title":"Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases","volume":"569","author":"Lloyd-Price","year":"2019","journal-title":"Nature"},{"issue":"1","key":"2025062611222124400_bib10","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40168-016-0159-0","article-title":"Colitis susceptibility in p47(phox\u2212\/\u2212) mice is mediated by the microbiome","volume":"4","author":"Falcone","year":"2016","journal-title":"Microbiome"},{"issue":"5","key":"2025062611222124400_bib11","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.chom.2016.04.007","article-title":"Defensive mutualism rescues NADPH oxidase inactivation in gut infection","volume":"19","author":"Pircalabioru","year":"2016","journal-title":"Cell Host Microbe"},{"issue":"7","key":"2025062611222124400_bib12","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.4049\/jimmunol.1103746","article-title":"p40phox expression regulates neutrophil recruitment and function during the resolution phase of intestinal inflammation","volume":"189","author":"Conway","year":"2012","journal-title":"J Immunol"},{"issue":"9","key":"2025062611222124400_bib13","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1084\/jem.194.9.1207","article-title":"Regulation of murine intestinal inflammation by reactive metabolites of oxygen and nitrogen","volume":"194","author":"Krieglstein","year":"2001","journal-title":"J Exp Med"},{"issue":"5","key":"2025062611222124400_bib14","doi-asserted-by":"crossref","first-page":"e97532","DOI":"10.1371\/journal.pone.0097532","article-title":"Deficient production of reactive oxygen species leads to severe chronic DSS-induced colitis in Ncf1\/p47phox-mutant mice","volume":"9","author":"Rodrigues-Sousa","year":"2014","journal-title":"PLoS One"},{"issue":"1","key":"2025062611222124400_bib15","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.immuni.2013.11.020","article-title":"Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation","volume":"40","author":"Campbell","year":"2014","journal-title":"Immunity"},{"issue":"8","key":"2025062611222124400_bib16","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/icb.2011.4","article-title":"Gp91phox contributes to the development of experimental inflammatory bowel disease","volume":"89","author":"Bao","year":"2011","journal-title":"Immunol Cell Biol"},{"issue":"6","key":"2025062611222124400_bib17","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1016\/j.jaci.2023.07.022","article-title":"Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease","volume":"152","author":"Chandrasekaran","year":"2023","journal-title":"J Allergy Clin Immunol"},{"issue":"12","key":"2025062611222124400_bib18","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1086\/657308","article-title":"Complications of tumor necrosis factor\u2013\u03b1 blockade in chronic granulomatous disease\u2013related colitis","volume":"51","author":"Uzel","year":"2010","journal-title":"Clin Infect Dis"},{"issue":"3","key":"2025062611222124400_bib19","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1038\/emm.2014.16","article-title":"Mucosal dendritic cells shape mucosal immunity","volume":"46","author":"Chang","year":"2014","journal-title":"Exp Mol Med"},{"issue":"1","key":"2025062611222124400_bib20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1172\/JCI65831","article-title":"Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair","volume":"123","author":"Leoni","year":"2013","journal-title":"J Clin Invest"},{"issue":"21","key":"2025062611222124400_bib21","doi-asserted-by":"crossref","first-page":"8803","DOI":"10.1073\/pnas.1010042108","article-title":"Enteric commensal bacteria potentiate epithelial restitution via reactive oxygen species-mediated inactivation of focal adhesion kinase phosphatases","volume":"108","author":"Swanson","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025062611222124400_bib22","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1159\/000136357","article-title":"Oxidative innate immune defenses by Nox\/Duox family NADPH oxidases","volume":"15","author":"Rada","year":"2008","journal-title":"Contrib Microbiol"},{"issue":"2","key":"2025062611222124400_bib23","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/mi.2014.74","article-title":"The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium","volume":"8","author":"Sommer","year":"2015","journal-title":"Mucosal Immunol"},{"issue":"7","key":"2025062611222124400_bib24","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1053\/j.gastro.2015.07.062","article-title":"Increased expression of DUOX2 is an epithelial response to mucosal dysbiosis required for immune homeostasis in mouse intestine [published correction appears in Gastroenterology. 2023;164(6):1033]","volume":"149","author":"Grasberger","year":"2015","journal-title":"Gastroenterology"},{"key":"2025062611222124400_bib25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.redox.2018.02.003","article-title":"Hydrogen peroxide production by lactobacilli promotes epithelial restitution during colitis","volume":"16","author":"Singh","year":"2018","journal-title":"Redox Biol"},{"issue":"9","key":"2025062611222124400_bib26","doi-asserted-by":"crossref","first-page":"e141676","DOI":"10.1172\/JCI141676","article-title":"DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk","volume":"131","author":"Grasberger","year":"2021","journal-title":"J Clin Invest"},{"issue":"7","key":"2025062611222124400_bib27","doi-asserted-by":"crossref","first-page":"3030","DOI":"10.1073\/pnas.0914795107","article-title":"Reactive oxygen species-independent activation of the IL-1 inflammasome in cells from patients with chronic granulomatous disease","volume":"107","author":"Van De Veerdonk","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"2025062611222124400_bib28","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1182\/blood-2010-01-264218","article-title":"Inflammasome activation in NADPH oxidase defective mononuclear phagocytes from patients with chronic granulomatous disease","volume":"116","author":"Meissner","year":"2010","journal-title":"Blood"},{"key":"2025062611222124400_bib29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.09.030","article-title":"NOX2 deficiency enhances priming and activation of the NLRP3 inflammasome","author":"Monjarret","year":"5  2023","journal-title":"J Allergy Clin Immunol"},{"issue":"2","key":"2025062611222124400_bib30","first-page":"238","article-title":"Clinicopathologic study of dextran sulfate sodium experimental murine colitis","volume":"69","author":"Cooper","year":"1993","journal-title":"Lab Invest"},{"key":"2025062611222124400_bib31","first-page":"229","volume-title":"Preservation of mucus in histological sections, immunostaining of mucins in fixed tissue, and localization of bacteria with FISH","author":"Johansson","year":"2012","edition":"1st ed."},{"issue":"1","key":"2025062611222124400_bib32","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00018-017-2693-8","article-title":"Mouse models for human intestinal microbiota research: a critical evaluation","volume":"75","author":"Hugenholtz","year":"2018","journal-title":"Cell Mol Life Sci"},{"issue":"7746","key":"2025062611222124400_bib33","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41586-019-0992-y","article-title":"Colonic epithelial cell diversity in health and inflammatory bowel disease","volume":"567","author":"Parikh","year":"2019","journal-title":"Nature"},{"issue":"12","key":"2025062611222124400_bib34","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1007\/s10620-016-4317-9","article-title":"B cell-activating factor (BAFF)-targeted B cell therapies in inflammatory bowel diseases","volume":"61","author":"Uzzan","year":"2016","journal-title":"Dig Dis Sci"},{"issue":"5","key":"2025062611222124400_bib35","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.jaci.2010.09.026","article-title":"Innate signals in mucosal immunoglobulin class switching","volume":"126","author":"Puga","year":"2010","journal-title":"J Allergy Clin Immunol"},{"issue":"4","key":"2025062611222124400_bib36","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.immuni.2019.02.006","article-title":"Anti-commensal IgG drives intestinal inflammation and type 17 immunity in ulcerative colitis","volume":"50","author":"Castro-Dopico","year":"2019","journal-title":"Immunity"},{"issue":"5","key":"2025062611222124400_bib37","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.cell.2014.08.006","article-title":"Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease","volume":"158","author":"Palm","year":"2014","journal-title":"Cell"},{"issue":"1","key":"2025062611222124400_bib38","doi-asserted-by":"crossref","first-page":"108949","DOI":"10.1016\/j.celrep.2021.108949","article-title":"NOX1-dependent redox signaling potentiates colonic stem cell proliferation to adapt to the intestinal microbiota by linking EGFR and TLR activation","volume":"35","author":"van der Post","year":"2021","journal-title":"Cell Rep"},{"issue":"2","key":"2025062611222124400_bib39","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41590-020-00857-2","article-title":"Naturalizing mouse models for immunology","volume":"22","author":"Graham","year":"2021","journal-title":"Nat Immunol"},{"issue":"7600","key":"2025062611222124400_bib40","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature17655","article-title":"Normalizing the environment recapitulates adult human immune traits in laboratory mice","volume":"532","author":"Beura","year":"2016","journal-title":"Nature"},{"issue":"6452","key":"2025062611222124400_bib41","doi-asserted-by":"crossref","first-page":"eaaw4361","DOI":"10.1126\/science.aaw4361","article-title":"Laboratory mice born to wild mice have natural microbiota and model human immune responses","volume":"365","author":"Rosshart","year":"2019","journal-title":"Science"},{"issue":"3","key":"2025062611222124400_bib42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1046\/j.1365-2249.1998.00728.x","article-title":"Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines","volume":"114","author":"Dieleman","year":"1998","journal-title":"Clin Exp Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/145\/26\/3153\/2382864\/blood_bld-2024-026332-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/145\/26\/3153\/2382864\/blood_bld-2024-026332-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T15:22:36Z","timestamp":1750951356000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/145\/26\/3153\/536755\/Genotype-specific-immune-responses-at-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,26]]},"references-count":42,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2025,6,26]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2024026332","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,6,26]]},"published":{"date-parts":[[2025,6,26]]}}}