{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T18:05:54Z","timestamp":1784225154974,"version":"3.55.0"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K11813"],"award-info":[{"award-number":["24K11813"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"a Research Grant from the Kobayashi Foundation"},{"DOI":"10.13039\/100012045","name":"Kawano Masanori Memorial Public Interest Incorporated Foundation","doi-asserted-by":"publisher","award":["33-waka21"],"award-info":[{"award-number":["33-waka21"]}],"id":[{"id":"10.13039\/100012045","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Hirschsprung-associated enterocolitis remains a major postoperative complication of Hirschsprung\u2019s disease (HD), and impaired epithelial barrier integrity has been proposed as a contributing factor. In this study, we investigated whether 12-hydroxyheptadecatrienoic acid (12-HHT), an endogenous leukotriene B4 receptor 2 (BLT2) agonist, is associated with epithelial barrier enhancement and reduced inflammatory responses in patient-derived colonic organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Normoganglionic specimens from rectal\/rectosigmoid HD at pull-through (HD-N; n\u2009=\u20098) and transverse colon specimens from anorectal malformation (ARM) at colostomy closure (n\u2009=\u200910) were used to generate colonic organoids. Epithelia were isolated using ethylenediaminetetraacetic acid and subsequently embedded in Matrigel. Baseline expression of\n                      <jats:italic>TJP1<\/jats:italic>\n                      ,\n                      <jats:italic>TJP2<\/jats:italic>\n                      ,\n                      <jats:italic>F11R<\/jats:italic>\n                      (encoding junctional adhesion molecule-A),\n                      <jats:italic>JAM2<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN1<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN3<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN4<\/jats:italic>\n                      ) and\n                      <jats:italic>LTB4R2<\/jats:italic>\n                      (encoding BLT2) was assessed by qPCR and immunoblotting. Organoids were then treated with 12-HHT (0.4, 2, or 10 \u03bcM) for 7 days, followed by qPCR. Additional experiments assessed cytokine expression (\n                      <jats:italic>IL1B<\/jats:italic>\n                      ,\n                      <jats:italic>IL6<\/jats:italic>\n                      ) and TJPs after 24 h with tumor necrosis factor-\u03b1 (TNF-\u03b1, 100 ng\/mL) plus phosphate buffered saline or 12-HHT. Barrier function was evaluated using FITC\u2013dextran influx assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HD-N and ARM organoids exhibited similar growth efficiencies. Baseline expression for\n                      <jats:italic>F11R<\/jats:italic>\n                      ,\n                      <jats:italic>JAM2<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN1<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN3<\/jats:italic>\n                      ,\n                      <jats:italic>CLDN4<\/jats:italic>\n                      , and\n                      <jats:italic>LTB4R2<\/jats:italic>\n                      was significantly lower in HD-N than in ARM. TJPs were upregulated by 12-HHT at 2 and 10 \u03bcM in both groups, with stronger effects in ARM. In HD-N organoids, 10 \u03bcM 12-HHT suppressed TNF-\u03b1-induced\n                      <jats:italic>IL1B<\/jats:italic>\n                      and\n                      <jats:italic>IL6<\/jats:italic>\n                      elevation mitigated tight junction proteins (TJPs) downregulation more effectively than 2 \u03bcM. 12-HHT attenuated TNF-\u03b1\u2013induced FITC\u2013dextran influx in HD-N organoids.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in HD-N organoids.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0344140","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T17:35:01Z","timestamp":1784223301000},"page":"e0344140","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in colon organoids of normoganglionosis in Hirschsprung\u2019s disease"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9136-2039","authenticated-orcid":true,"given":"Kazuto","family":"Suda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumpei","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurina","family":"Nishimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Nagasako","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxuan","family":"Rao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5167-0821","authenticated-orcid":true,"given":"Siyi","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Fujiwara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Yamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiho","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4274-1312","authenticated-orcid":true,"given":"Soichi","family":"Shibuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Miyano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"issue":"12","key":"pone.0344140.ref001","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.1172\/JCI85003","article-title":"Hirschsprung\u2019s disease, down syndrome, and missing heritability: too much collagen slows migration","volume":"125","author":"RO Heuckeroth","year":"2015","journal-title":"J Clin Invest"},{"issue":"11","key":"pone.0344140.ref002","doi-asserted-by":"crossref","first-page":"611","DOI":"10.3390\/medicina56110611","article-title":"Hirschsprung\u2019s disease-recent understanding of embryonic aspects, etiopathogenesis and future treatment avenues","volume":"56","author":"M Klein","year":"2020","journal-title":"Medicina (Kaunas)"},{"issue":"5","key":"pone.0344140.ref003","doi-asserted-by":"crossref","first-page":"386","DOI":"10.5455\/medarh.2025.79.386-389","article-title":"Comparative analysis of surgical outcomes following duhamel, soave, and transanal endorectal pull-through techniques in Hirschsprung\u2019s disease","volume":"79","author":"IPA Nasution","year":"2025","journal-title":"Med Arch"},{"issue":"3","key":"pone.0344140.ref004","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1891\/NN-2024-0067","article-title":"Bridging knowledge and practice: insights into Hirschsprung\u2019s disease and home management","volume":"44","author":"S Culnan","year":"2025","journal-title":"Neonatal Netw"},{"issue":"1","key":"pone.0344140.ref005","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s00383-023-05378-1","article-title":"Transanal endorectal or transabdominal pull-through for Hirschsprung\u2019s disease; which is better? 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