Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation

Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation Alexandre Denadai-Souza, Elodie Modave, Ceyhun Alar, Yan Wu, Javier Escudero Morlanes, and 36 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7535904/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract The intestinal epithelium integrates host- and environment-derived cues to coordinate barrier defense, nutrient absorption, and fluid homeostasis 1-3. Single-cell atlases have delineated key regional differences between the small and large intestines and revealed extensive epithelial rewiring in inflammatory gastrointestinal diseases. However, whether comparable epithelial alterations occur in the absence of active inflammation remains unknown. In particular, the epithelial landscape in functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), as well as in symptomatic patients with Crohn’s disease (CD) in remission, has not been defined. Here, using integrated single-cell and spatial transcriptomics, we generate a high-resolution map of the human colorectal epithelium across health, IBS, and symptomatic CD remission. In healthy tissue, we identify robust regional partitioning within absorptive lineages, with the rectum exhibiting transcriptional programs biased towards chloride secretion. Strikingly, in IBS and symptomatic CD remission, we observe the emergence of ectopic epithelial programs despite the absence of overt inflammation. These include antigen-sampling microfold cells in the rectum of patients with IBS and two aberrant absorptive subsets in the ascending colon of symptomatic CD patients in remission, both transcriptionally enriched for antigen sampling and chloride secretory pathways. Together, these findings reveal previously unrecognized epithelial rewiring that emerges or persists in patients with debilitating gastrointestinal symptoms despite the absence of overt inflammation. Biological sciences/Cell biology/Mechanisms of disease Health sciences/Diseases/Immunological disorders/Inflammatory diseases single-cell sequencing spatial transcriptomics cell plasticity colorectal epithelial cells transcriptional rewiring Full Text Additional Declarations Yes there is potential Competing Interest. MF received research grants from AbbVie, EG Pharma, Janssen, Pfizer, Takeda and Viatris; consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Merck Sharp and Dohme, MRM Health, Pfizer, Takeda and ThermoFisher; and speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris. BV received research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda, speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris, and has stock options Vagustim and Thethis Pharma. Supplementary Files ExtendedDataFigures.pdf Extended Data Fig. 1. Overview of the human cohort and omics workflow. a, Primary human cohort showing gastrointestinal symptom status and experimental approaches applied to each subject’s samples. b,Extended human cohort used for validation experiments. c, Multi-omics workflow applied in this study. Created in BioRender. (2025) href="https://biorender.com/di5leki">https://BioRender.com/di5leki. Extended Data Fig. 2. Relative expression of heat-stress genes. a, Violin plot comparing mean expression of a 38‑gene heat‑stress panel between our dataset and a previously published study using 3‑ vs. 35‑minute enzymatic digestion at 37 °C, respectively. b, Feature plot showing spatial enrichment of individual heat‑stress genes in the healthy human colorectum. Extended Data Fig. 3. Transcription factors differentially active within the human health colorectum. a, Dot plot showing the proportion of cell types and states enriched for transcription factors in the healthy colorectum. b, Feature plot highlighting enrichment of individual transcription factors from the FOS and HOX gene families in the healthy colorectum. Extended Data Fig. 4. Stemness potential index inferred by CytoTRACE 2. a, Box plot showing hierarchical ordering of stemness potential index across cell types and states, as inferred by CytoTRACE2. b, UMAP representation of phenotype clustering by cell type and state. c, Feature plot indicating potency categories from multipotent to differentiated. d, Feature plot illustrating relative ordering from less differentiated to differentiated cell states. Extended Data Fig. 5. Spot-level deconvolution of epithelial cell populations in the healthy human rectum. a, Stem and transit-amplifying cells. b, AbC types and states. c,Chemosensory cells. d, Goblet cells. Extended Data Fig. 6. Colorectal expression of intestinal barrier and solute carrier genes. a-e, Dot plots showing the global proportion of cells and average expression levels between colon and rectum of genes encoding for a) intestinal barrier elements, b) bile acids transporters and receptors, c) nutrient transporters, d)ion transporters, and e) inorganic and organic solute carriers. Extended Data Fig. 7. Overview of cell-cell interactions in the healthy colorectal epithelium. a,b, Circle plots illustrating the number and strength of interactions between cell types and states in the ascending colon and rectum, respectively. c,d, Chord diagrams showing ligand–receptor pairs between cell states in the ascending colon and rectum, respectively. e,f, Bubble plots indicating communication probabilities of ligand–receptor pairs between cell states in the ascending colon and rectum, respectively. Extended Data Fig. 8. MHC Class II gene enrichment in rectal epithelial cells from IBS-D. a, Dot plot depicting cell types/states enriched for transcription factor activity. b, UMAP highlighting MFCs within the rectal epithelium landscape of HV and IBS. c-e,Feature and violin plots depicting global and group gene expression of c, ETV7 , d, genes encoding for retinoic acid receptor and TNFR2 ( RARG and TNFRSF1B , respectively), e, MHC Class II genes and their master regulator CIITA . Extended Data Fig. 9. Xenium in situ integration of rectal tissue samples. a, Bar plot comparing percentage distribution of rectal epithelial cell types captured by scRNA-seq and Xenium in situ assays across sample groups. b, Bar plot displaying percentage distribution of cell types per tissue section labeled by anonymized patient ID (PIN) and section number (-1 or -2). Extended Data Fig. 10. Expression of barrier and transporter genes in IBS. a–f, Dot plots showing the proportion of cells and average expression levels of genes associated with infectious or congenital diarrhea (a), ion transporters (b), intestinal barrier function (c), inorganic and organic solute carriers (d), nutrient transporters (e), and bile acid receptors and transporters (f) in HV and IBS patients. Extended Data Fig. 11. Frequency and signature of aberrant cell types in CD. a, Violin plot showing combined frequency of SymAC-1 and -2 populations expressed as a percentage of total cells per subject. The dashed line indicates the 75th percentile threshold. b,Heatmap displaying per-subject combined frequencies of SymAC-1 and -2 in HV and CD groups. c, Dot plot depicting cell types/states enriched for transcription factor activity. d, UMAP highlighting SymAC-1 and -2 within the integrated colonic epithelium landscape of HV and CD. e-j,Feature plots depicting colonic expression of e, HOXB13 , f,pyloric INFLARE marker genes, g, surface foveolar-like cell marker genes, h, canonical Paneth cell marker genes. h,j, Feature and violin plots depicting global and group gene expression of MHC Class II genes, their master regulator CIITA and the co-stimulatory molecule CD40. Extended Data Fig. 12. Xenium in situ integration of colonic tissue samples. a, Bar plot comparing the percentage distribution of colonic epithelial cell types captured by scRNA-seq and Xenium in situ. b, Bar plot showing the percentage distribution of cell types per tissue section labeled by anonymized patient ID (PIN) and section number (-1 or -2). Extended Data Fig. 13. Expression of genes associated with diarrhea in CD. a, Dot plot showing the proportion of cells and average expression of genes associated with infectious or congenital diarrhea. b,Dot plot highlighting the proportion of cell types and states expressing SLC9A3 negatively associated with diarrhea. c, Dot plot showing SLC9A3 expression by cell types and states in HV and CD patients with or without IBS-like symptoms. Extended Data Fig. 14. Expression of barrier and transporter genes in CD. a–e, Dot plots showing the proportion of cells and average expression levels of genes encoding a) ion transporters, b) barrier components, c) inorganic and organic solute carriers, d) nutrient transporters and e) bile acid transporters and receptors in HV and CD groups. SupplementaryTable1Heatstressgenepanel.csv Supplementary Table 1. Panel of 40 heat-stress genes SupplementaryTable2Top20genesHVcolorectum.csv Supplementary Table 2. Cluster_top20genespercluster_logFC_colorectum_HV_cohort SupplementaryTable3GenepanelXeniuminsitu.csv Supplementary Table 3. CellChat defnet data from healthy colonic epithelial cells SupplementaryTable4CellChatdefnetdataHVcolon.zip Supplementary Table 4. CellChat defnet data from healthy rectal epithelial cells SupplementaryTable5CellChatdefnetdataHVrectum.zip Supplementary Table 5. Gene panel for Xenium in situ SupplementaryTable6Top20genesHVIBS.csv Supplementary Table 6. Cluster_top20genespercluster_logFC_rectum_HV_IBS_cohort SupplementaryTable7Top20genesHVCD.zip Supplementary Table 7. Cluster_top20genespercluster_logFC_colon_HV_CD_cohort SupplementaryTable8DifferentialabundanceinCD.zip Supplementary Table 8. Differential abundance analysis (miloR) in CD Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7535904","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":600803156,"identity":"d5a0ef11-dbd1-42e8-8100-38bf641011bd","order_by":0,"name":"Alexandre 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Created in BioRender. (2025) \u003ca href=\"https://biorender.com/di5leki\"\u003ehttps://BioRender.com/di5leki\u003c/a\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 2.\u003c/strong\u003e \u003cstrong\u003eRelative expression of heat-stress genes. a,\u003c/strong\u003e Violin plot comparing mean expression of a 38‑gene heat‑stress panel between our dataset and a previously published study using 3‑ vs. 35‑minute enzymatic digestion at 37 °C, respectively. \u003cstrong\u003eb,\u003c/strong\u003e Feature plot showing spatial enrichment of individual heat‑stress genes in the healthy human colorectum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 3.\u003c/strong\u003e \u003cstrong\u003eTranscription factors differentially active within the human health colorectum. a,\u003c/strong\u003e Dot plot showing the proportion of cell types and states enriched for transcription factors in the healthy colorectum. \u003cstrong\u003eb,\u003c/strong\u003e Feature plot highlighting enrichment of individual transcription factors from the FOS and HOX gene families in the healthy colorectum.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 4.\u003c/strong\u003e \u003cstrong\u003eStemness potential index inferred by CytoTRACE 2. a,\u003c/strong\u003e Box plot showing hierarchical ordering of stemness potential index across cell types and states, as inferred by CytoTRACE2. \u003cstrong\u003eb,\u003c/strong\u003e UMAP representation of phenotype clustering by cell type and state. \u003cstrong\u003ec,\u003c/strong\u003e Feature plot indicating potency categories from multipotent to differentiated. \u003cstrong\u003ed,\u003c/strong\u003e Feature plot illustrating relative ordering from less differentiated to differentiated cell states.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 5. Spot-level deconvolution of epithelial cell populations in the healthy human rectum. a,\u003c/strong\u003e Stem and transit-amplifying cells. \u003cstrong\u003eb,\u003c/strong\u003e AbC types and states. \u003cstrong\u003ec,\u003c/strong\u003eChemosensory cells. \u003cstrong\u003ed,\u003c/strong\u003e Goblet cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 6.\u003c/strong\u003e \u003cstrong\u003eColorectal expression of intestinal barrier and solute carrier genes. a-e,\u003c/strong\u003e Dot plots showing the global proportion of cells and average expression levels between colon and rectum of genes encoding for \u003cstrong\u003ea)\u003c/strong\u003e intestinal barrier elements, \u003cstrong\u003eb) \u003c/strong\u003ebile acids transporters and receptors, \u003cstrong\u003ec)\u003c/strong\u003e nutrient transporters, \u003cstrong\u003ed)\u003c/strong\u003eion transporters, and \u003cstrong\u003ee)\u003c/strong\u003e inorganic and organic solute carriers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 7.\u003c/strong\u003e \u003cstrong\u003eOverview of cell-cell interactions in the healthy colorectal epithelium. a,b,\u003c/strong\u003e Circle plots illustrating the number and strength of interactions between cell types and states in the ascending colon and rectum, respectively. \u003cstrong\u003ec,d,\u003c/strong\u003e Chord diagrams showing ligand–receptor pairs between cell states in the ascending colon and rectum, respectively. \u003cstrong\u003ee,f,\u003c/strong\u003e Bubble plots indicating communication probabilities of ligand–receptor pairs between cell states in the ascending colon and rectum, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 8. MHC Class II gene enrichment in rectal epithelial cells from IBS-D. a,\u003c/strong\u003e Dot plot depicting cell types/states enriched for transcription factor activity. \u003cstrong\u003eb,\u003c/strong\u003e UMAP highlighting MFCs within the rectal epithelium landscape of HV and IBS. \u003cstrong\u003ec-e,\u003c/strong\u003eFeature and violin plots depicting global and group gene expression of \u003cstrong\u003ec,\u003c/strong\u003e \u003cem\u003eETV7\u003c/em\u003e, \u003cstrong\u003ed,\u003c/strong\u003e genes encoding for retinoic acid receptor and TNFR2 (\u003cem\u003eRARG\u003c/em\u003eand \u003cem\u003eTNFRSF1B\u003c/em\u003e, respectively), \u003cstrong\u003ee,\u003c/strong\u003e MHC Class II genes and their master regulator \u003cem\u003eCIITA\u003c/em\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 9. Xenium in situ integration of rectal tissue samples. a,\u003c/strong\u003e Bar plot comparing percentage distribution of rectal epithelial cell types captured by scRNA-seq and Xenium in situ assays across sample groups. \u003cstrong\u003eb,\u003c/strong\u003e Bar plot displaying percentage distribution of cell types per tissue section labeled by anonymized patient ID (PIN) and section number (-1 or -2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 10.\u003c/strong\u003e \u003cstrong\u003eExpression of barrier and transporter genes in IBS. a–f,\u003c/strong\u003e Dot plots showing the proportion of cells and average expression levels of genes associated with infectious or congenital diarrhea (a), ion transporters (b), intestinal barrier function (c), inorganic and organic solute carriers (d), nutrient transporters (e), and bile acid receptors and transporters (f) in HV and IBS patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 11.\u003c/strong\u003e \u003cstrong\u003eFrequency and signature of aberrant cell types in CD. a,\u003c/strong\u003e Violin plot showing combined frequency of SymAC-1 and -2 populations expressed as a percentage of total cells per subject. The dashed line indicates the 75th percentile threshold. \u003cstrong\u003eb,\u003c/strong\u003eHeatmap displaying per-subject combined frequencies of SymAC-1 and -2 in HV and CD groups. \u003cstrong\u003ec,\u003c/strong\u003e Dot plot depicting cell types/states enriched for transcription factor activity. \u003cstrong\u003ed,\u003c/strong\u003e UMAP highlighting SymAC-1 and -2 within the integrated colonic epithelium landscape of HV and CD. \u003cstrong\u003ee-j,\u003c/strong\u003eFeature plots depicting colonic expression of \u003cstrong\u003ee,\u003c/strong\u003e \u003cem\u003eHOXB13\u003c/em\u003e, \u003cstrong\u003ef,\u003c/strong\u003epyloric INFLARE marker genes, \u003cstrong\u003eg,\u003c/strong\u003e surface foveolar-like cell marker genes, \u003cstrong\u003eh,\u003c/strong\u003e canonical Paneth cell marker genes. \u003cstrong\u003eh,j,\u003c/strong\u003e Feature and violin plots depicting global and group gene expression of MHC Class II genes, their master regulator \u003cem\u003eCIITA\u003c/em\u003e and the co-stimulatory molecule CD40.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 12. Xenium in situ integration of colonic tissue samples. a,\u003c/strong\u003e Bar plot comparing the percentage distribution of colonic epithelial cell types captured by scRNA-seq and Xenium in situ. \u003cstrong\u003eb,\u003c/strong\u003e Bar plot showing the percentage distribution of cell types per tissue section labeled by anonymized patient ID (PIN) and section number (-1 or -2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 13.\u003c/strong\u003e \u003cstrong\u003eExpression of genes associated with diarrhea in CD. a,\u003c/strong\u003e Dot plot showing the proportion of cells and average expression of genes associated with infectious or congenital diarrhea. \u003cstrong\u003eb,\u003c/strong\u003eDot plot highlighting the proportion of cell types and states expressing \u003cem\u003eSLC9A3\u003c/em\u003enegatively associated with diarrhea. \u003cstrong\u003ec,\u003c/strong\u003e Dot plot showing \u003cem\u003eSLC9A3\u003c/em\u003eexpression by cell types and states in HV and CD patients with or without IBS-like symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExtended Data Fig. 14.\u003c/strong\u003e \u003cstrong\u003eExpression of barrier and transporter genes in CD. a–e,\u003c/strong\u003e Dot plots showing the proportion of cells and average expression levels of genes encoding \u003cstrong\u003ea)\u003c/strong\u003e ion transporters, \u003cstrong\u003eb)\u003c/strong\u003e barrier components, \u003cstrong\u003ec) \u003c/strong\u003einorganic and organic solute carriers,\u003cstrong\u003e d)\u003c/strong\u003e nutrient transporters and \u003cstrong\u003ee) \u003c/strong\u003ebile acid transporters and receptors in HV and CD groups.\u003c/p\u003e","description":"","filename":"ExtendedDataFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/a193cdb63dd8a40e1a8e27b4.pdf"},{"id":103996771,"identity":"14da3d8a-7999-4ee5-9f35-0b9b8b8c627b","added_by":"auto","created_at":"2026-03-05 12:55:34","extension":"csv","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":8568,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 1. Panel of 40 heat-stress genes\u003c/p\u003e","description":"","filename":"SupplementaryTable1Heatstressgenepanel.csv","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/af371e8a7dfce8e355784ee9.csv"},{"id":103996867,"identity":"aba8a520-e030-47c7-b426-0bf16dbc50ef","added_by":"auto","created_at":"2026-03-05 12:55:43","extension":"csv","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19647,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 2. Cluster_top20genespercluster_logFC_colorectum_HV_cohort\u003c/p\u003e","description":"","filename":"SupplementaryTable2Top20genesHVcolorectum.csv","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/66dc48a767ccbcb010c9b05b.csv"},{"id":103996847,"identity":"fe59fdbc-5e7f-4395-b4c4-24fe20bfd823","added_by":"auto","created_at":"2026-03-05 12:55:39","extension":"csv","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":9029,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 3. CellChat defnet data from healthy colonic epithelial cells\u003c/p\u003e","description":"","filename":"SupplementaryTable3GenepanelXeniuminsitu.csv","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/1dcbf9ca867c5fc90c4536d9.csv"},{"id":103996851,"identity":"fe6257cf-1374-46f0-b7b9-f2c7e6c6d12f","added_by":"auto","created_at":"2026-03-05 12:55:40","extension":"zip","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1539693,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 4. CellChat defnet data from healthy rectal epithelial cells\u003c/p\u003e","description":"","filename":"SupplementaryTable4CellChatdefnetdataHVcolon.zip","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/45df4eaeb5942de501bc087a.zip"},{"id":103996962,"identity":"f20f36da-431b-4ba5-b983-5f62267da07b","added_by":"auto","created_at":"2026-03-05 12:56:12","extension":"zip","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":2931358,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 5. Gene panel for Xenium in situ\u003c/p\u003e","description":"","filename":"SupplementaryTable5CellChatdefnetdataHVrectum.zip","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/3af84b4404affc11d8c33873.zip"},{"id":103996926,"identity":"ce4509fe-0cb1-473a-8008-7037e5c5df8d","added_by":"auto","created_at":"2026-03-05 12:55:58","extension":"csv","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":21134,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 6. Cluster_top20genespercluster_logFC_rectum_HV_IBS_cohort\u003c/p\u003e","description":"","filename":"SupplementaryTable6Top20genesHVIBS.csv","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/b2e5c90a5badf245b9957d13.csv"},{"id":103996942,"identity":"d226c20d-d125-45dd-b98b-539b00fefa62","added_by":"auto","created_at":"2026-03-05 12:56:04","extension":"zip","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":282407,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 7. Cluster_top20genespercluster_logFC_colon_HV_CD_cohort\u003c/p\u003e","description":"","filename":"SupplementaryTable7Top20genesHVCD.zip","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/b4c7de726ff6fc68db682c4d.zip"},{"id":103996753,"identity":"99996377-4a50-469c-9fdb-fe92d90a2d8b","added_by":"auto","created_at":"2026-03-05 12:55:33","extension":"zip","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":682019,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Table 8. Differential abundance analysis (miloR) in CD\u003c/p\u003e","description":"","filename":"SupplementaryTable8DifferentialabundanceinCD.zip","url":"https://assets-eu.researchsquare.com/files/rs-7535904/v2/83486478423e3a9e0a7a6351.zip"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nMF received research grants from AbbVie, EG Pharma, Janssen, Pfizer, Takeda and Viatris; consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Merck Sharp and Dohme, MRM Health, Pfizer, Takeda and ThermoFisher; and speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris. BV received research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda, speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris, and has stock options Vagustim and Thethis Pharma.","formattedTitle":"Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"single-cell sequencing, spatial transcriptomics, cell plasticity, colorectal epithelial cells, transcriptional rewiring","lastPublishedDoi":"10.21203/rs.3.rs-7535904/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7535904/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The intestinal epithelium integrates host- and environment-derived cues to coordinate barrier defense, nutrient absorption, and fluid homeostasis 1-3. Single-cell atlases have delineated key regional differences between the small and large intestines and revealed extensive epithelial rewiring in inflammatory gastrointestinal diseases. However, whether comparable epithelial alterations occur in the absence of active inflammation remains unknown. In particular, the epithelial landscape in functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), as well as in symptomatic patients with Crohn’s disease (CD) in remission, has not been defined. Here, using integrated single-cell and spatial transcriptomics, we generate a high-resolution map of the human colorectal epithelium across health, IBS, and symptomatic CD remission. In healthy tissue, we identify robust regional partitioning within absorptive lineages, with the rectum exhibiting transcriptional programs biased towards chloride secretion. Strikingly, in IBS and symptomatic CD remission, we observe the emergence of ectopic epithelial programs despite the absence of overt inflammation. These include antigen-sampling microfold cells in the rectum of patients with IBS and two aberrant absorptive subsets in the ascending colon of symptomatic CD patients in remission, both transcriptionally enriched for antigen sampling and chloride secretory pathways. Together, these findings reveal previously unrecognized epithelial rewiring that emerges or persists in patients with debilitating gastrointestinal symptoms despite the absence of overt inflammation.","manuscriptTitle":"Regional partitioning of colorectal epithelial cells is altered in gastrointestinal disorders without overt inflammation","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-03-05 12:53:19","doi":"10.21203/rs.3.rs-7535904/v2","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-09-11 11:17:39","doi":"10.21203/rs.3.rs-7535904/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f16ce9ca-77fe-4bb6-886c-ba15a5ad624a","owner":[],"postedDate":"March 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":63938142,"name":"Biological sciences/Cell biology/Mechanisms of disease"},{"id":63938143,"name":"Health sciences/Diseases/Immunological disorders/Inflammatory diseases"}],"tags":[],"updatedAt":"2026-04-01T20:40:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-05 12:53:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-7535904","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7535904","identity":"rs-7535904","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}