{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T15:14:16Z","timestamp":1783091656334,"version":"3.54.6"},"reference-count":10,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01-AI167285"],"award-info":[{"award-number":["R01-AI167285"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011684","name":"Crohn's and Colitis Foundation","doi-asserted-by":"publisher","award":["#648423"],"award-info":[{"award-number":["#648423"]}],"id":[{"id":"10.13039\/100011684","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007930","name":"Institute of Clinical and Translational Sciences","doi-asserted-by":"publisher","award":["#UL1TR002345"],"award-info":[{"award-number":["#UL1TR002345"]}],"id":[{"id":"10.13039\/100007930","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Inflamm. Res."],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The inflammatory bowel diseases (IBD) Crohn\u2019s disease (CD) and ulcerative colitis (UC) are disorders that cause chronic inflammation of the gastrointestinal tract. Both genetic and environmental factors contribute to the pathogenesis of IBD. There are currently &gt;200 known genetic susceptibility loci for the development of IBD. The physiological impact of the majority of these loci remain a gap in our knowledge. One such locus is the single nucleotide polymorphism rs1077773, located ~56 kbp downstream from the aryl hydrocarbon receptor (\n                      <jats:italic>AHR<\/jats:italic>\n                      ) gene. AHR is a ligand-activated transcription factor that is crucial to maintaining intestinal homeostasis. We hypothesized that rs1077773 enhances AHR activity to regulate mucosal immune response and maintain intestinal homeostasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>All study procedures and reagents were approved by the Washington University Institutional Review Board (#202011003). Patient biopsies were collected at Barnes Jewish Hospital and genotyped using the IBD Genetics Consortium custom GSA SNP chip (Broad Institute) followed by imputation using TopMed Imputation Server at University of Michigan. Patient derived organoids (PDOs; N=3 G\/G, N=4 G\/A, N=5 A\/A) were derived and maintained in 3D culture and supplemented with 50% L-WRN conditioned medium with passage every 3\u20134 days as previously described. PDOs were treated with AHR agonist 6-Formylindolo[3,2-b]carbazole (FICZ) or vehicle for 48 h. Expression of AHR and its transcriptional targets Cytochrome P450 1A1 (CYP1A1) and CYP1B1 was assessed by RT-qPCR. Blood was collected from pediatric patients undergoing intestinal resection at St. Louis Children\u2019s Hospital and was genotyped with custom TaqMan SNP assay (N=3 G\/G, N=5 G\/A). Peripheral blood monocyte-derived macrophages (MDM\u03a6s) were treated with lipopolysaccharide in the presence or absence of AHR ligands FICZ or indole-3-carboxaldehyde for 24 h. Cytokine levels in culture supernatant were measured via using the ProcartaPlex human cytokine, chemokine, and growth factor 45-plex (ThermoFisher) on a Luminex FLEXMAP3D instrument.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>AHR<\/jats:italic>\n                      expression was similar across genotypes and treatments. PDOs homozygous for rs1077773 demonstrate enhanced\n                      <jats:italic>CYP1A1<\/jats:italic>\n                      expression in response to AHR activation. In MDM\u03a6s, cytokine secretion was stimulated by LPS treatment and was abrogated by FICZ treatment. MDM\u03a6s with rs1077773 alternate allele demonstrated significant reduction in secretion of 12 cytokines and chemokines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This work demonstrates that rs1077773 enhances AHR activity and modulates epithelial and immune cell function in vitro. Further mechanistic understanding of this locus and its correlates could improve our understanding of the molecular mechanisms of IBD susceptibility and may lead to novel personalized therapeutic approaches in IBD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00011-026-02236-3","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:55:22Z","timestamp":1775800522000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["IBD risk locus rs1077773 enhances aryl hydrocarbon receptor activity and modulates immune cell function in vitro"],"prefix":"10.1007","volume":"75","author":[{"given":"Ashley C.","family":"King","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Seiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry","family":"Swanson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Ciorba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Alvarado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"2236_CR1","doi-asserted-by":"publisher","first-page":"511","DOI":"10.14309\/ajg.0000000000002180","volume":"118","author":"Y Sun","year":"2023","unstructured":"Sun Y, Yuan S, Chen X, et al. The contribution of genetic risk and lifestyle factors in the development of adult-onset inflammatory bowel disease: a prospective cohort study. Am J Gastroenterol. 2023;118:511\u201322.","journal-title":"Am J Gastroenterol"},{"key":"2236_CR2","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1038\/s41575-021-00430-8","volume":"18","author":"B Stockinger","year":"2021","unstructured":"Stockinger B, Shah K, Wincent E. AHR in the intestinal microenvironment: safeguarding barrier function. Nat Rev Gastroenterol Hepatol. 2021;18:559\u201370.","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2236_CR3","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/ng.3359","volume":"47","author":"JZ Liu","year":"2015","unstructured":"Liu JZ, van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. 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Epithelial indoleamine 2,3-dioxygenase 1 modulates aryl hydrocarbon receptor and notch signaling to increase differentiation of secretory cells and alter mucus-associated microbiota. Gastroenterology. 2019;157:1093\u2013108. e11.","journal-title":"Gastroenterology"},{"key":"2236_CR9","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1128\/CVI.00349-16","volume":"23","author":"S Bekkering","year":"2016","unstructured":"Bekkering S, Blok BA, Joosten LA, et al. In vitro experimental model of trained innate immunity in human primary monocytes. Clin Vaccine Immunol. 2016;23:926\u201333.","journal-title":"Clin Vaccine Immunol"},{"key":"2236_CR10","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.cgh.2023.05.023","volume":"22","author":"S Ben-Horin","year":"2024","unstructured":"Ben-Horin S, Salomon N, Karampekos G, et al. Curcumin-qingdai combination for patients with active ulcerative colitis: a randomized, double-blinded, placebo-controlled trial. Clin Gastroenterol Hepatol. 2024;22:347\u201356. e6.","journal-title":"Clin Gastroenterol Hepatol"}],"container-title":["Inflammation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00011-026-02236-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00011-026-02236-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00011-026-02236-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:55:23Z","timestamp":1775800523000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00011-026-02236-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,10]]},"references-count":10,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2236"],"URL":"https:\/\/doi.org\/10.1007\/s00011-026-02236-3","relation":{},"ISSN":["1420-908X"],"issn-type":[{"value":"1420-908X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,10]]},"assertion":[{"value":"30 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 April 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}}],"article-number":"88"}}