{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:01:04Z","timestamp":1785416464680,"version":"3.56.0"},"posted":{"date-parts":[[2025,11,9]]},"group-title":"Molecular Biology","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T00:00:00Z","timestamp":1762646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35NS116842"],"award-info":[{"award-number":["R35NS116842"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA160356"],"award-info":[{"award-number":["R01CA160356"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01DK042191"],"award-info":[{"award-number":["R01DK042191"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P30DK097948"],"award-info":[{"award-number":["P30DK097948"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32DK083251"],"award-info":[{"award-number":["T32DK083251"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32GM152319"],"award-info":[{"award-number":["T32GM152319"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Hanna H. Gray Fellowship"],"award-info":[{"award-number":["Hanna H. Gray Fellowship"]}],"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Aims<\/jats:title>\n                  <jats:p>\n                    Inflammatory bowel disease is characterized by progressive epithelial, immune, and stromal dysfunction. Human datasets yield important insights yet are inherently descriptive, requiring animal models for\n                    <jats:italic>in vivo<\/jats:italic>\n                    mechanistic interrogation. The SAMP1\/YitFc (SAMP) mouse model develops spontaneous Crohn\u2019s disease (CD)-like ileitis while allowing controlled manipulation of pathophysiologic pathways. To understand cell-specific disease-associated transcriptional changes, we defined the single-nucleus transcriptomes of inflamed SAMP ilea using single-nucleus RNA-sequencing (snRNA-seq).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We performed whole-ileum snRNA-seq on SAMP (\n                    <jats:italic>n<\/jats:italic>\n                    =4) and control AKR\/J (\n                    <jats:italic>n<\/jats:italic>\n                    =3) mice using the gut-optimized CitraPrep protocol, generating 58,349 high-quality nuclei across epithelial, immune, and stromal lineages. We corroborated SAMP-associated changes with immunofluorescent staining, Western blotting, spatial transcriptomic, and human single-cell RNA-sequencing data.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We observed a primary type 2 immune phenotype in SAMP compared to AKR mice, but most transcriptional changes occurred in stromal and epithelial, not immune, cells. Stromal remodeling included increased fibroblast-derived\n                    <jats:italic>Igf1<\/jats:italic>\n                    . In SAMP epithelium, expansion of tuft cells and emergence of SAMP-specific\n                    <jats:italic>Pcsk6+<\/jats:italic>\n                    crypt enterocytes were observed and confirmed in human CD patients. Finally, we identified cross-compartmental changes in cell-cell signaling, including enterocyte-to-type 3 innate lymphoid cell (ILC3) communication and enhanced global\n                    <jats:italic>Igf1<\/jats:italic>\n                    signaling. These features recapitulate known, as well as novel, characteristics of CD and extend our understanding of disease-associated multicellular networks.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This atlas of ileitis-prone SAMP mice provides a high-resolution resource for dissecting conserved and novel mechanisms of inflammation and tissue remodeling. Herein, we uncover disease-associated transcriptional changes conserved in human CD, presenting a translational platform for future mechanistic and therapeutic studies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.08.684908","type":"posted-content","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T04:40:17Z","timestamp":1762749617000},"source":"Crossref","is-referenced-by-count":0,"title":["Epithelial and stromal remodeling in murine Crohn\u2019s disease-like ileitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5516-3910","authenticated-orcid":false,"given":"Katherine C","family":"Letai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2124-1028","authenticated-orcid":false,"given":"Bianca N","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8779-088X","authenticated-orcid":false,"given":"Paola","family":"Menghini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-1915","authenticated-orcid":false,"given":"Carlo","family":"De Salvo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9244-5070","authenticated-orcid":false,"given":"Neha S","family":"Khandekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5276-493X","authenticated-orcid":false,"given":"Bruce 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