Mucosal Single-Cell Profiling of Crohn’s-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets
The pathophysiology of Crohn’s-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses. Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum)...
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| Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2024-12, Vol.167 (7), p.1399-1414.e2 |
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| creator | Cao, Siyan Nguyen, Khai M. Ma, Kaiming Du, Xiaotang Liu, Xiuli Ulezko Antonova, Alina Rood, Richard P. Gremida, Anas Chen, Chien-Huan Gutierrez, Alexandra Rubin, Deborah C. Gregory, Martin H. Gergely, Mate Escudero, Guadalupe Oliva Huang, Katherine Jaeger, Natalia Cella, Marina Newberry, Rodney D. Davidson, Nicholas O. Ciorba, Matthew A. Deepak, Parakkal Colonna, Marco |
| description | The pathophysiology of Crohn’s-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses.
Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry.
The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells–inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments.
CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
[Display omitted]
The pathophysiology of Crohn’s-like disease of the pouch in patients with a prior history of ulcerative colitis is revealed and new targets to better treat this challenging condition are identified. |
| doi_str_mv | 10.1053/j.gastro.2024.07.025 |
| format | Article |
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Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry.
The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells–inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments.
CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
[Display omitted]
The pathophysiology of Crohn’s-like disease of the pouch in patients with a prior history of ulcerative colitis is revealed and new targets to better treat this challenging condition are identified.</description><identifier>ISSN: 0016-5085</identifier><identifier>ISSN: 1528-0012</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2024.07.025</identifier><identifier>PMID: 39084267</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenomatous Polyposis Coli - genetics ; Adenomatous Polyposis Coli - immunology ; Adenomatous Polyposis Coli - pathology ; Adenomatous Polyposis Coli - surgery ; Adult ; Colitis, Ulcerative - immunology ; Colitis, Ulcerative - pathology ; Colitis, Ulcerative - surgery ; Colonic Pouches - adverse effects ; Crohn Disease - immunology ; Crohn Disease - pathology ; CyTOF ; Female ; Humans ; IBD ; Ileum - immunology ; Ileum - pathology ; Ileum - surgery ; Intestinal Mucosa - immunology ; Intestinal Mucosa - pathology ; IPAA ; Male ; Middle Aged ; Pouch ; Pouchitis - etiology ; Pouchitis - immunology ; Pouchitis - pathology ; Proctocolectomy, Restorative - adverse effects ; RNA-Seq ; scRNA-seq ; Single-Cell Analysis ; Th17 Cells - immunology</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2024-12, Vol.167 (7), p.1399-1414.e2</ispartof><rights>2024 The Author(s)</rights><rights>Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c287t-102c206872966c54da324ce01274a924a8f9d5e12376ebe24611dcd9bf3efa093</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0016508524052843$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39084267$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Siyan</creatorcontrib><creatorcontrib>Nguyen, Khai M.</creatorcontrib><creatorcontrib>Ma, Kaiming</creatorcontrib><creatorcontrib>Du, Xiaotang</creatorcontrib><creatorcontrib>Liu, Xiuli</creatorcontrib><creatorcontrib>Ulezko Antonova, Alina</creatorcontrib><creatorcontrib>Rood, Richard P.</creatorcontrib><creatorcontrib>Gremida, Anas</creatorcontrib><creatorcontrib>Chen, Chien-Huan</creatorcontrib><creatorcontrib>Gutierrez, Alexandra</creatorcontrib><creatorcontrib>Rubin, Deborah C.</creatorcontrib><creatorcontrib>Gregory, Martin H.</creatorcontrib><creatorcontrib>Gergely, Mate</creatorcontrib><creatorcontrib>Escudero, Guadalupe Oliva</creatorcontrib><creatorcontrib>Huang, Katherine</creatorcontrib><creatorcontrib>Jaeger, Natalia</creatorcontrib><creatorcontrib>Cella, Marina</creatorcontrib><creatorcontrib>Newberry, Rodney D.</creatorcontrib><creatorcontrib>Davidson, Nicholas O.</creatorcontrib><creatorcontrib>Ciorba, Matthew A.</creatorcontrib><creatorcontrib>Deepak, Parakkal</creatorcontrib><creatorcontrib>Colonna, Marco</creatorcontrib><title>Mucosal Single-Cell Profiling of Crohn’s-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets</title><title>Gastroenterology (New York, N.Y. 1943)</title><addtitle>Gastroenterology</addtitle><description>The pathophysiology of Crohn’s-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses.
Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry.
The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells–inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments.
CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
[Display omitted]
The pathophysiology of Crohn’s-like disease of the pouch in patients with a prior history of ulcerative colitis is revealed and new targets to better treat this challenging condition are identified.</description><subject>Adenomatous Polyposis Coli - genetics</subject><subject>Adenomatous Polyposis Coli - immunology</subject><subject>Adenomatous Polyposis Coli - pathology</subject><subject>Adenomatous Polyposis Coli - surgery</subject><subject>Adult</subject><subject>Colitis, Ulcerative - immunology</subject><subject>Colitis, Ulcerative - pathology</subject><subject>Colitis, Ulcerative - surgery</subject><subject>Colonic Pouches - adverse effects</subject><subject>Crohn Disease - immunology</subject><subject>Crohn Disease - pathology</subject><subject>CyTOF</subject><subject>Female</subject><subject>Humans</subject><subject>IBD</subject><subject>Ileum - immunology</subject><subject>Ileum - pathology</subject><subject>Ileum - surgery</subject><subject>Intestinal Mucosa - immunology</subject><subject>Intestinal Mucosa - pathology</subject><subject>IPAA</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pouch</subject><subject>Pouchitis - etiology</subject><subject>Pouchitis - immunology</subject><subject>Pouchitis - pathology</subject><subject>Proctocolectomy, Restorative - adverse effects</subject><subject>RNA-Seq</subject><subject>scRNA-seq</subject><subject>Single-Cell Analysis</subject><subject>Th17 Cells - immunology</subject><issn>0016-5085</issn><issn>1528-0012</issn><issn>1528-0012</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM9u1DAQxi0EotvCGyDkI5eEseP8u1RCC7RIi1iV7dnyOpONl2y8eJJK9NTX6K3P0kfhSXC1LceeRpr5vpn5foy9E5AKyLOP23RjaAw-lSBVCmUKMn_BZiKXVQIg5Es2i6VIcqjyI3ZMtAWAOqvEa3aU1VApWZQzdv19sp5Mz3-6YdNjMse-58vgW9fHBvctnwffDX9vbilZuF_IPztCQxgn93djh_d3Sz_Zjl_gFZqe-OXgfk_Il2bs_AYHJEfcDA1fdRjMHqfRWb4yYYMjvWGv2mjBt4_1hF1-_bKanyeLH2ff5p8WiZVVOSYCpJVQVKWsi8LmqjGZVBZjwlKZWipTtXWTo5BZWeAapSqEaGxTr9sMWxMTn7APh7374ONvNOqdIxtzmgH9RDqDqqhzJUuIUnWQ2uCJArZ6H9zOhD9agH6grrf6QF0_UNdQ6kg92t4_XpjWO2z-m54wR8HpQYAx55XDoMk6HCw2LqAddePd8xf-AZfzmIc</recordid><startdate>202412</startdate><enddate>202412</enddate><creator>Cao, Siyan</creator><creator>Nguyen, Khai M.</creator><creator>Ma, Kaiming</creator><creator>Du, Xiaotang</creator><creator>Liu, Xiuli</creator><creator>Ulezko Antonova, Alina</creator><creator>Rood, Richard P.</creator><creator>Gremida, Anas</creator><creator>Chen, Chien-Huan</creator><creator>Gutierrez, Alexandra</creator><creator>Rubin, Deborah C.</creator><creator>Gregory, Martin H.</creator><creator>Gergely, Mate</creator><creator>Escudero, Guadalupe Oliva</creator><creator>Huang, Katherine</creator><creator>Jaeger, Natalia</creator><creator>Cella, Marina</creator><creator>Newberry, Rodney D.</creator><creator>Davidson, Nicholas O.</creator><creator>Ciorba, Matthew A.</creator><creator>Deepak, Parakkal</creator><creator>Colonna, Marco</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202412</creationdate><title>Mucosal Single-Cell Profiling of Crohn’s-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets</title><author>Cao, Siyan ; Nguyen, Khai M. ; Ma, Kaiming ; Du, Xiaotang ; Liu, Xiuli ; Ulezko Antonova, Alina ; Rood, Richard P. ; Gremida, Anas ; Chen, Chien-Huan ; Gutierrez, Alexandra ; Rubin, Deborah C. ; Gregory, Martin H. ; Gergely, Mate ; Escudero, Guadalupe Oliva ; Huang, Katherine ; Jaeger, Natalia ; Cella, Marina ; Newberry, Rodney D. ; Davidson, Nicholas O. ; Ciorba, Matthew A. ; Deepak, Parakkal ; Colonna, Marco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c287t-102c206872966c54da324ce01274a924a8f9d5e12376ebe24611dcd9bf3efa093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenomatous Polyposis Coli - genetics</topic><topic>Adenomatous Polyposis Coli - immunology</topic><topic>Adenomatous Polyposis Coli - pathology</topic><topic>Adenomatous Polyposis Coli - surgery</topic><topic>Adult</topic><topic>Colitis, Ulcerative - immunology</topic><topic>Colitis, Ulcerative - pathology</topic><topic>Colitis, Ulcerative - surgery</topic><topic>Colonic Pouches - adverse effects</topic><topic>Crohn Disease - immunology</topic><topic>Crohn Disease - pathology</topic><topic>CyTOF</topic><topic>Female</topic><topic>Humans</topic><topic>IBD</topic><topic>Ileum - immunology</topic><topic>Ileum - pathology</topic><topic>Ileum - surgery</topic><topic>Intestinal Mucosa - immunology</topic><topic>Intestinal Mucosa - pathology</topic><topic>IPAA</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pouch</topic><topic>Pouchitis - etiology</topic><topic>Pouchitis - immunology</topic><topic>Pouchitis - pathology</topic><topic>Proctocolectomy, Restorative - adverse effects</topic><topic>RNA-Seq</topic><topic>scRNA-seq</topic><topic>Single-Cell Analysis</topic><topic>Th17 Cells - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Siyan</creatorcontrib><creatorcontrib>Nguyen, Khai M.</creatorcontrib><creatorcontrib>Ma, Kaiming</creatorcontrib><creatorcontrib>Du, Xiaotang</creatorcontrib><creatorcontrib>Liu, Xiuli</creatorcontrib><creatorcontrib>Ulezko Antonova, Alina</creatorcontrib><creatorcontrib>Rood, Richard P.</creatorcontrib><creatorcontrib>Gremida, Anas</creatorcontrib><creatorcontrib>Chen, Chien-Huan</creatorcontrib><creatorcontrib>Gutierrez, Alexandra</creatorcontrib><creatorcontrib>Rubin, Deborah C.</creatorcontrib><creatorcontrib>Gregory, Martin H.</creatorcontrib><creatorcontrib>Gergely, Mate</creatorcontrib><creatorcontrib>Escudero, Guadalupe Oliva</creatorcontrib><creatorcontrib>Huang, Katherine</creatorcontrib><creatorcontrib>Jaeger, Natalia</creatorcontrib><creatorcontrib>Cella, Marina</creatorcontrib><creatorcontrib>Newberry, Rodney D.</creatorcontrib><creatorcontrib>Davidson, Nicholas O.</creatorcontrib><creatorcontrib>Ciorba, Matthew A.</creatorcontrib><creatorcontrib>Deepak, Parakkal</creatorcontrib><creatorcontrib>Colonna, Marco</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Siyan</au><au>Nguyen, Khai M.</au><au>Ma, Kaiming</au><au>Du, Xiaotang</au><au>Liu, Xiuli</au><au>Ulezko Antonova, Alina</au><au>Rood, Richard P.</au><au>Gremida, Anas</au><au>Chen, Chien-Huan</au><au>Gutierrez, Alexandra</au><au>Rubin, Deborah C.</au><au>Gregory, Martin H.</au><au>Gergely, Mate</au><au>Escudero, Guadalupe Oliva</au><au>Huang, Katherine</au><au>Jaeger, Natalia</au><au>Cella, Marina</au><au>Newberry, Rodney D.</au><au>Davidson, Nicholas O.</au><au>Ciorba, Matthew A.</au><au>Deepak, Parakkal</au><au>Colonna, Marco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mucosal Single-Cell Profiling of Crohn’s-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2024-12</date><risdate>2024</risdate><volume>167</volume><issue>7</issue><spage>1399</spage><epage>1414.e2</epage><pages>1399-1414.e2</pages><issn>0016-5085</issn><issn>1528-0012</issn><eissn>1528-0012</eissn><abstract>The pathophysiology of Crohn’s-like disease of the pouch (CDP) in patients with a history of ulcerative colitis (UC) is unknown. We examined mucosal cells from patients with and without CDP using single-cell analyses.
Endoscopic samples were collected from pouch body and prepouch ileum (pouch/ileum) of 50 patients with an ileal pouch-anal anastomosis. Single-cell RNA sequencing was performed on pouch/ileal tissues of patients with normal pouch/ileum and CDP. Mass cytometry was performed on mucosal immune cells from patients with UC with normal pouch/ileum, CDP, pouchitis, and those with familial adenomatous polyposis after pouch formation. Findings were independently validated using immunohistochemistry.
The cell populations/states in the pouch body differed from those in the prepouch ileum, likely secondary to increased microbial burden. Compared with the familial adenomatous polyposis pouch, the UC pouch was enriched in colitogenic immune cells even without inflammation. CDP was characterized by increases in T helper 17 cells, inflammatory fibroblasts, inflammatory monocytes, TREM1+ monocytes, clonal expansion of effector T cells, and overexpression of T helper 17 cells–inducing cytokine genes such as IL23, IL1B, and IL6 by mononuclear phagocytes. Ligand-receptor analysis further revealed a stromal-mononuclear phagocytes-lymphocyte circuit in CDP. Integrated analysis showed that up-regulated immune mediators in CDP were similar to those in CD and pouchitis, but not UC. Additionally, CDP pouch/ileum exhibited heightened endoplasmic reticulum stress across all major cell compartments.
CDP likely represents a distinct entity of inflammatory bowel disease with heightened endoplasmic reticulum stress in both immune and nonimmune cells, which may become a novel diagnostic biomarker and therapeutic target for CDP.
[Display omitted]
The pathophysiology of Crohn’s-like disease of the pouch in patients with a prior history of ulcerative colitis is revealed and new targets to better treat this challenging condition are identified.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39084267</pmid><doi>10.1053/j.gastro.2024.07.025</doi><oa>free_for_read</oa></addata></record> |
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| ispartof | Gastroenterology (New York, N.Y. 1943), 2024-12, Vol.167 (7), p.1399-1414.e2 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adenomatous Polyposis Coli - genetics Adenomatous Polyposis Coli - immunology Adenomatous Polyposis Coli - pathology Adenomatous Polyposis Coli - surgery Adult Colitis, Ulcerative - immunology Colitis, Ulcerative - pathology Colitis, Ulcerative - surgery Colonic Pouches - adverse effects Crohn Disease - immunology Crohn Disease - pathology CyTOF Female Humans IBD Ileum - immunology Ileum - pathology Ileum - surgery Intestinal Mucosa - immunology Intestinal Mucosa - pathology IPAA Male Middle Aged Pouch Pouchitis - etiology Pouchitis - immunology Pouchitis - pathology Proctocolectomy, Restorative - adverse effects RNA-Seq scRNA-seq Single-Cell Analysis Th17 Cells - immunology |
| title | Mucosal Single-Cell Profiling of Crohn’s-Like Disease of the Pouch Reveals Unique Pathogenesis and Therapeutic Targets |
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