{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:00:32Z","timestamp":1781632832469,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pbio.3003766","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:00:00Z","timestamp":1781568000000}}],"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP7746"],"award-info":[{"award-number":["MOP7746"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Research Institute of Northern Alberta","award":["Boytzun Studentship in Colorectal Cancer"],"award-info":[{"award-number":["Boytzun Studentship in Colorectal Cancer"]}]}],"content-domain":{"domain":["www.plosbiology.org"],"crossmark-restriction":false},"short-container-title":["PLoS Biol"],"abstract":"<jats:p>\n                    Mutations in the innate immune receptor NOD2 are the greatest single genetic risk factor for Crohn\u2019s disease, yet the mechanisms by which NOD2 regulates intestinal homeostasis remain unclear. We used a CRISPR-generated zebrafish model to determine the impacts of NOD2 deficiency on intestinal health. In cellular, molecular, and transcriptomic studies, we uncovered substantial effects of NOD2 deficiency on epithelial and immune compartments, including deregulated expression of developmental pathways that establish and maintain the gut epithelium, and an unexpected increase in the expression of multiple estrogen-response genes. In functional assays, we uncovered a mechanistic link between estrogenic signals and NOD2-deficiency phenotypes, whereby exposure to estrogen alone replicated the effects of NOD2-deficiency, and treatment with the estrogen receptor modulator tamoxifen reverted the epithelial defects observed in\n                    <jats:italic>nod2<\/jats:italic>\n                    mutants. Our findings identify a NOD2-estrogen regulatory axis that supports intestinal homeostasis and suggest that hormonal signaling may contribute to sex-specific aspects of Crohn\u2019s disease.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3003766","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T17:38:42Z","timestamp":1781026722000},"page":"e3003766","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen impacts NOD2-dependent regulation of intestinal homeostasis"],"prefix":"10.1371","volume":"24","author":[{"given":"Mckenna","family":"Eklund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edan","family":"Foley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"issue":"6","key":"pbio.3003766.ref001","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/s41575-025-01063-x","article-title":"Shaping the future of inflammatory bowel disease: a global research agenda for better management and public health response","volume":"22","author":"V Solitano","year":"2025","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"6837","key":"pbio.3003766.ref002","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/35079107","article-title":"Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn\u2019s disease","volume":"411","author":"JP Hugot","year":"2001","journal-title":"Nature"},{"issue":"6837","key":"pbio.3003766.ref003","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/35079114","article-title":"A frameshift mutation in NOD2 associated with susceptibility to Crohn\u2019s disease","volume":"411","author":"Y Ogura","year":"2001","journal-title":"Nature"},{"issue":"6568","key":"pbio.3003766.ref004","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1038\/379821a0","article-title":"Mapping of a susceptibility locus for Crohn\u2019s disease on chromosome 16","volume":"379","author":"JP Hugot","year":"1996","journal-title":"Nature"},{"issue":"4","key":"pbio.3003766.ref005","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1086\/339432","article-title":"CARD15\/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease","volume":"70","author":"S Lesage","year":"2002","journal-title":"Am J Hum Genet"},{"issue":"7","key":"pbio.3003766.ref006","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1136\/gut.35.7.950","article-title":"Similarity of colorectal cancer in Crohn\u2019s disease and ulcerative colitis: implications for carcinogenesis and prevention","volume":"35","author":"PM Choi","year":"1994","journal-title":"Gut"},{"issue":"4","key":"pbio.3003766.ref007","doi-asserted-by":"crossref","first-page":"284","DOI":"10.4240\/wjgs.v8.i4.284","article-title":"NOD2 mutations and colorectal cancer \u2013 where do we stand?","volume":"8","author":"D Branquinho","year":"2016","journal-title":"World J Gastrointest Surg"},{"issue":"5710","key":"pbio.3003766.ref008","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1126\/science.1104911","article-title":"Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract","volume":"307","author":"KS Kobayashi","year":"2005","journal-title":"Science"},{"issue":"11","key":"pbio.3003766.ref009","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1136\/gut.2003.032805","article-title":"NOD2 (CARD15) mutations in Crohn\u2019s disease are associated with diminished mucosal \u03b1-defensin expression","volume":"53","author":"J Wehkamp","year":"2004","journal-title":"Gut"},{"issue":"1","key":"pbio.3003766.ref010","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0016-5085(03)00661-9","article-title":"Crohn\u2019s disease and the NOD2 gene: a role for paneth cells","volume":"125","author":"S Lala","year":"2003","journal-title":"Gastroenterology"},{"issue":"50","key":"pbio.3003766.ref011","doi-asserted-by":"crossref","first-page":"18129","DOI":"10.1073\/pnas.0505256102","article-title":"Reduced Paneth cell alpha-defensins in ileal Crohn\u2019s disease","volume":"102","author":"J Wehkamp","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"pbio.3003766.ref012","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1074\/jbc.C200651200","article-title":"Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection","volume":"278","author":"SE Girardin","year":"2003","journal-title":"J Biol Chem"},{"issue":"8","key":"pbio.3003766.ref013","doi-asserted-by":"crossref","first-page":"5509","DOI":"10.1074\/jbc.C200673200","article-title":"Host recognition of bacterial muramyl dipeptide mediated through NOD2. 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