Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary
Background and aims: The trigger hypothesis opens the possibility of anti-flare initiation therapies by stating that ulcerative colitis (UC) flares originate from inadequate responses to acute mucosal injuries. However, experimental evidence is restricted by a limited use of suitable human models. W...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X2100117X |
| _version_ | 1819033956162469888 |
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| author | Jakob Benedict Seidelin Martin Iain Bahl Tine Rask Licht Benjamin E. Mead Jeffrey M. Karp Jens Vilstrup Johansen Lene Buhl Riis Marina Ramírez Galera Anders Woetmann Jacob Tveiten Bjerrum |
| author_facet | Jakob Benedict Seidelin Martin Iain Bahl Tine Rask Licht Benjamin E. Mead Jeffrey M. Karp Jens Vilstrup Johansen Lene Buhl Riis Marina Ramírez Galera Anders Woetmann Jacob Tveiten Bjerrum |
| author_sort | Jakob Benedict Seidelin |
| collection | DOAJ |
| description | Background and aims: The trigger hypothesis opens the possibility of anti-flare initiation therapies by stating that ulcerative colitis (UC) flares originate from inadequate responses to acute mucosal injuries. However, experimental evidence is restricted by a limited use of suitable human models. We thus aimed to investigate the acute mucosal barrier injury responses in humans with and without UC using an experimental injury model. Methods: A standardized mucosal break was inflicted in the sigmoid colon of 19 patients with UC in endoscopic and histological remission and 20 control subjects. Postinjury responses were assessed repeatedly by high-resolution imaging and sampling to perform Geboes scoring, RNA sequencing, and injury niche microbiota 16S ribosomal RNA gene sequencing. Results: UC patients had more severe endoscopic postinjury inflammation than did control subjects (P < .01), an elevated modified Geboes score (P < .05), a rapid induction of innate response gene sets (P < .05) and antimicrobial peptides (P < .01), and engagement of neutrophils (P < .01). Innate lymphoid cell type 3 (ILC3) markers were increased preinjury (P < .01), and ILC3 activating cytokines were highly induced postinjury, resulting in an increase in ILC3-type cytokine interleukin-17A. Across groups, the postinjury mucosal microbiome had higher bacterial load (P < .0001) and lower α-diversity (P < .05). Conclusions: UC patients in remission respond to mucosal breaks by an innate hyperresponse engaging resident regulatory ILC3s and a subsequent adaptive activation. The postinjury inflammatory bowel disease–like microbiota diversity decrease is irrespective of diagnosis, suggesting that the dysbiosis is secondary to host injury responses. We provide a model for the study of flare initiation in the search for antitrigger-directed therapies. |
| first_indexed | 2024-12-21T07:26:04Z |
| format | Article |
| id | doaj.art-4c66f520e857498a82ad966486d1bdad |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-21T07:26:04Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-4c66f520e857498a82ad966486d1bdad2022-12-21T19:11:41ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2021-01-0112412811296Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummaryJakob Benedict Seidelin0Martin Iain Bahl1Tine Rask Licht2Benjamin E. Mead3Jeffrey M. Karp4Jens Vilstrup Johansen5Lene Buhl Riis6Marina Ramírez Galera7Anders Woetmann8Jacob Tveiten Bjerrum9Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Correspondence Address correspondence to: Jakob Benedict Seidelin, MD, PhD, DMSc, Department of Gastroenterology D112M, Herlev Hospital, University of Copenhagen, 1 Borgmester Ib Juuls Vej, DK-2730 Herlev, Denmark. fax: 45 44 94 04 56.National Food Institute, Technical University of Denmark, Kongens Lyngby, DenmarkNational Food Institute, Technical University of Denmark, Kongens Lyngby, DenmarkHarvard-MIT Division of Health Sciences and Technology, Institute for Medical and Engineering Science and Harvard Medical School, Cambridge, Massachusetts; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MassachusettsHarvard-MIT Division of Health Sciences and Technology, Institute for Medical and Engineering Science and Harvard Medical School, Cambridge, Massachusetts; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Harvard Medical School, Boston, Massachusetts; Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Cambridge, MassachusettsBioinformatics Core Facility, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, DenmarkDepartment of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, DenmarkDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, DenmarkDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, DenmarkDepartment of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, DenmarkBackground and aims: The trigger hypothesis opens the possibility of anti-flare initiation therapies by stating that ulcerative colitis (UC) flares originate from inadequate responses to acute mucosal injuries. However, experimental evidence is restricted by a limited use of suitable human models. We thus aimed to investigate the acute mucosal barrier injury responses in humans with and without UC using an experimental injury model. Methods: A standardized mucosal break was inflicted in the sigmoid colon of 19 patients with UC in endoscopic and histological remission and 20 control subjects. Postinjury responses were assessed repeatedly by high-resolution imaging and sampling to perform Geboes scoring, RNA sequencing, and injury niche microbiota 16S ribosomal RNA gene sequencing. Results: UC patients had more severe endoscopic postinjury inflammation than did control subjects (P < .01), an elevated modified Geboes score (P < .05), a rapid induction of innate response gene sets (P < .05) and antimicrobial peptides (P < .01), and engagement of neutrophils (P < .01). Innate lymphoid cell type 3 (ILC3) markers were increased preinjury (P < .01), and ILC3 activating cytokines were highly induced postinjury, resulting in an increase in ILC3-type cytokine interleukin-17A. Across groups, the postinjury mucosal microbiome had higher bacterial load (P < .0001) and lower α-diversity (P < .05). Conclusions: UC patients in remission respond to mucosal breaks by an innate hyperresponse engaging resident regulatory ILC3s and a subsequent adaptive activation. The postinjury inflammatory bowel disease–like microbiota diversity decrease is irrespective of diagnosis, suggesting that the dysbiosis is secondary to host injury responses. We provide a model for the study of flare initiation in the search for antitrigger-directed therapies.http://www.sciencedirect.com/science/article/pii/S2352345X2100117XAcute Mucosal InjuryInnate Lymphoid Cells Type 3ILC3Innate Intestinal ResponseFlare InitiationMicrobiome |
| spellingShingle | Jakob Benedict Seidelin Martin Iain Bahl Tine Rask Licht Benjamin E. Mead Jeffrey M. Karp Jens Vilstrup Johansen Lene Buhl Riis Marina Ramírez Galera Anders Woetmann Jacob Tveiten Bjerrum Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary Cellular and Molecular Gastroenterology and Hepatology Acute Mucosal Injury Innate Lymphoid Cells Type 3 ILC3 Innate Intestinal Response Flare Initiation Microbiome |
| title | Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary |
| title_full | Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary |
| title_fullStr | Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary |
| title_full_unstemmed | Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary |
| title_short | Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary |
| title_sort | acute experimental barrier injury triggers ulcerative colitis specific innate hyperresponsiveness and ulcerative colitis type microbiome changes in humanssummary |
| topic | Acute Mucosal Injury Innate Lymphoid Cells Type 3 ILC3 Innate Intestinal Response Flare Initiation Microbiome |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X2100117X |
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