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PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Fig. 2ECs in CD.a, UMAP plot of small intestinal epithelial EPCAM cells in HCs (n = 3) and in participants with CD (n = 5). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | b, Bubble plot showing the expression of selected genes defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | c, Local neighborhood enrichment of EPCAM cells in ACD versus HCs. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Color indicates enrichment (log fold change (FC)) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates false discovery rate (FDR)-adjusted −log10 values. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, TA cells (left) and early enterocytes (right) in HCs and CD, as a proportion of total EPCAM cells. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | e, Pseudotime trajectory of gene expression of EPCAM ECs, colored by pseudotime axis (left), cluster identity (middle) and lineage (right). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Arrows indicate putative direction of cell differentiation. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | f, Density of cells along pseudotime trajectory axis split by disease state: ACD (red), TCD (blue) and HCs (gray). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | g, Smoothed heat map showing expression of selected genes related to intestinal absorption along pseudotime trajectories relating to secretory (toward left) and absorptive (toward right) lineage. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h, Volcano plot displaying differentially expressed gene transcripts between HCs and ACD in total ECs. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, Unpaired two-tailed t-test. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Data are presented as mean values ± s.e.m. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | a, UMAP plot of small intestinal epithelial EPCAM cells in HCs (n = 3) and in participants with CD (n = 5). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | b, Bubble plot showing the expression of selected genes defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | c, Local neighborhood enrichment of EPCAM cells in ACD versus HCs. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Color indicates enrichment (log fold change (FC)) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates false discovery rate (FDR)-adjusted −log10 values. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, TA cells (left) and early enterocytes (right) in HCs and CD, as a proportion of total EPCAM cells. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | e, Pseudotime trajectory of gene expression of EPCAM ECs, colored by pseudotime axis (left), cluster identity (middle) and lineage (right). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Arrows indicate putative direction of cell differentiation. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | f, Density of cells along pseudotime trajectory axis split by disease state: ACD (red), TCD (blue) and HCs (gray). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | g, Smoothed heat map showing expression of selected genes related to intestinal absorption along pseudotime trajectories relating to secretory (toward left) and absorptive (toward right) lineage. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h, Volcano plot displaying differentially expressed gene transcripts between HCs and ACD in total ECs. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, Unpaired two-tailed t-test. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Data are presented as mean values ± s.e.m. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | A LYZ Paneth cell-like population (MMP7REG1ASOD3PLA2G2A) was also identified (Fig. 2a,b), although defensin gene expression was not detected. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | This population expressed PGC, mucins including MUC5AC, MUC1 and MUC6 and AQP5, suggesting it also contained Brunner’s gland cells or ectopic gastric pyloric gland cells. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | This cell type was enriched in active celiac disease (ACD; Fig. 2c,d), perhaps in response to IFNγ. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Thus, this population could represent inflammation-driven gastric cell metaplasia. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Transit-amplifying (TA) cells were increased in CD, along with enrichment of uniform manifold approximation and projection (UMAP) areas corresponding to EC progenitors (stem cells, TA cells and early enterocytes; Fig. 2c,d). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | This persisted in treated celiac disease (TCD; Extended Data Fig. 1b,c). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | In parallel, more actively cycling ECs were observed in ACD and TCD (Extended Data Fig. 1d,e). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Pseudotime analyses identified epithelial developmental trajectories, from undifferentiated progenitor states toward absorptive and secretory lineages (Fig. 2e). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | In CD, ECs were shifted to earlier pseudotime states, with loss of mature ECs (Fig. 2f). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | CCL25, encoding the ligand for CCR9 (implicated in CD pathogenesis), was expressed predominantly by progenitor cells (Fig. 2b and Extended Data Fig. 1f). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | We examined putative EC functions through functional gene-set analysis (Extended Data Fig. 1a), identifying functions of secretory Paneth-like/Brunner’s gland cells (secreted protein and vesicle pathways), BEST4 enterocytes (chloride/anion channel activity), tuft cells (taste perception) and enteroendocrine cells (EECs... |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Mature enterocytes expressed key metabolic and macronutrient catabolic pathways, and active transport and absorption mechanisms. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Early ECs and TA cells did not express these pathways. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Absorptive function genes were limited to cell states at the end of absorptive epithelium pseudotime trajectories, consistent with EC development along the crypt–villus axis (Fig. 2g). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Notably, gene sets related to lipid, carbohydrate, cholesterol, vitamin and iron processing and absorption were all downregulated in mature enterocytes in ACD (Extended Data Fig. 1g–i). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | These transcriptional changes normalized in TCD, although some pathways, including fructose metabolism and lipid catabolism, remained reduced (Extended Data Fig. 1h). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Overall, absorptive capacity is reduced in ACD not simply by reduction in villus surface area, but through a relative increase of EC progenitors lacking absorptive machinery, and pathway downregulation in mature enterocytes. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | ECs in ACD upregulated multiple antigen-presentation molecules, including classical HLA class I and class II genes (except HLA-DQ) and nonclassical genes including HLA-E and HLA-F (Fig. 2h). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Interferon-stimulated genes (types I and II) dominated the epithelial response, including STAT1 (Fig. 2h and Supplementary Table 5). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | The major disease-associated responses were observed in all EC lineages (Extended Data Fig. 1j–l), including antigen-presentation pathways, type I/II interferon responses, lymphocyte-mediated immunity and cytotoxicity and cell adhesion regulation (Extended Data Fig. 1m,n). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Some transcriptional changes were cell-type specific. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | IL32 was highly expressed in ACD by mature enterocytes (Extended Data Fig. 1k), perhaps regulated by interferons. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | The reduction of fatty acid catabolism/transport (APOA1, FABP2), metal ion transport (iron: FTH1, FTL; zinc: SLC39A4) and carbohydrate metabolism (ALDOB, PCK1) was restricted to absorptive lineages, mainly mature enterocytes (Extended Data Fig. 1k,n). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Progenitor cells upregulated genes associated with cell division and differentiation, and downregulated those associated with tissue repair and homeostasis (Extended Data Fig. 1m,n). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Secretory lineages showed increased expression of gut hormone genes, LYZ, and chemokines (CXCL17, CXCL2; Extended Data Fig. 1l). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | The duodenum, where CD inflammation predominates, has sensory and neurohormonal functions. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | We extended EEC clustering, revealing multiple transcriptional states, including NEUROG3 progenitors and EEC subtypes, which showed similar CD-related transcriptional changes to other ECs (Extended Data Fig. 2). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | EEC proportions altered in CD, with increases in NEUROG3 progenitor cells and somatostatin-producing D cells (Extended Data Fig. 2i–k). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | In adults (dataset 1), CD4 T cells formed subsets dominated by TH1-polarized and IL-17-producing helper T (TH17)-polarized effectors, as well as small naive and FOXP3 regulatory populations (Fig. 3a–c and Supplementary Table 6). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | There was a cluster of TFH-like CD4 T cells expressing PDCD1, BTLA, CD28, ICOS and intermediate CXCR5. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Dataset 2 (pediatric) contained analogous subsets (Extended Data Fig. 3a), including CD31CR2 recent thymic emigrants, a CCR7 TFH-like subset and the TFH-like subset expressing PD1, ICOS, CTLA4, BTLA and CD161 at the protein level (Fig. 3d,e).Fig. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | 3CD4 T cells in CD.a–c, Intestinal CD4 T cells in health and CD in dataset 1 (adult—10x Genomics). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | a, UMAP plot of intestinal CD4 T cells in health and CD (n = 8). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | b, Bubble plot showing the expression of selected genes defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | c, CD4 T cell UMAP plots overlaid with expression of TNFSF8, PDCD1, TOX2, CXCR3, CXCL13, CD200, CXCR5 and TRBV7-2. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Intestinal CD4 T cells in health and CD in dataset 2 (pediatric—BD Rhapsody; d–f). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, UMAP plot of intestinal CD4 T cells in health and CD (n = 15). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | e, Bubble plot showing the expression of selected genes and proteins defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene/protein expression indicated by color; proportion of cells expressing the gene/protein indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | f, Local neighborhood enrichment of CD4 cells in ACD versus HCs (dataset 1). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Color indicates enrichment (log fold change) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates −log10FDR. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | g, Scatterplot of mean proportion (± s.e.) |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | of CD4 T cell clusters in HCs (n = 3) versus ACD (n = 5) in dataset 1. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Clusters above the line of unity are enriched in ACD. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h,i, Treg (h) and TFH (i) CD4 T cell populations in HCs and CD, as a proportion of total CD4 T cells in dataset 1 (HCs n = 3, ACD n = 5) and dataset 2 (HCs n = 5, ACD n = 10). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | j, UMAP plot of CD4 T cells in dataset 2, overlaid with IL21 and IFNG expression. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | k, UMAP plot of CD4 T cells in dataset 1, overlaid with CXCL13, IL21, IFNG and TNFSF8 expression. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h,i, Two-sided Mann–Whitney test. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Data are presented as mean values ± s.e.m. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Ab, antibody; Tc17, IL17CD8 T cells; DP, CD4CD8 double positive cells. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | a–c, Intestinal CD4 T cells in health and CD in dataset 1 (adult—10x Genomics). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | a, UMAP plot of intestinal CD4 T cells in health and CD (n = 8). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | b, Bubble plot showing the expression of selected genes defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene expression indicated by color; proportion of cells expressing the gene indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | c, CD4 T cell UMAP plots overlaid with expression of TNFSF8, PDCD1, TOX2, CXCR3, CXCL13, CD200, CXCR5 and TRBV7-2. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Intestinal CD4 T cells in health and CD in dataset 2 (pediatric—BD Rhapsody; d–f). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | d, UMAP plot of intestinal CD4 T cells in health and CD (n = 15). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | e, Bubble plot showing the expression of selected genes and proteins defining specific cluster identities. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Scaled gene/protein expression indicated by color; proportion of cells expressing the gene/protein indicated by bubble size. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | f, Local neighborhood enrichment of CD4 cells in ACD versus HCs (dataset 1). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Color indicates enrichment (log fold change) of cells in ACD versus HCs in that UMAP neighborhood; size of dot indicates −log10FDR. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | g, Scatterplot of mean proportion (± s.e.) |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | of CD4 T cell clusters in HCs (n = 3) versus ACD (n = 5) in dataset 1. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Clusters above the line of unity are enriched in ACD. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h,i, Treg (h) and TFH (i) CD4 T cell populations in HCs and CD, as a proportion of total CD4 T cells in dataset 1 (HCs n = 3, ACD n = 5) and dataset 2 (HCs n = 5, ACD n = 10). |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | j, UMAP plot of CD4 T cells in dataset 2, overlaid with IL21 and IFNG expression. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | k, UMAP plot of CD4 T cells in dataset 1, overlaid with CXCL13, IL21, IFNG and TNFSF8 expression. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | h,i, Two-sided Mann–Whitney test. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Data are presented as mean values ± s.e.m. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Ab, antibody; Tc17, IL17CD8 T cells; DP, CD4CD8 double positive cells. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | This TFH-like population in adults and children showed similar phenotypic profiles to those of gut-resident gluten-specific CD4 T cells in CD (Extended Data Fig. 3b), and expressed TOX2, CD200, IL21 and CXCL13. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | The cluster showed enrichment of TRBV7-2, a V-gene enriched in gluten-specific CD4 T cell HLA-DQ2.5 TCR repertoires. |
PMC12133578 | Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease. | Treg and TFH-like CD4 T cells were increased in ACD in adults and children (Fig. 3f–i). |
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