Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary

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

Cellular and Molecular Gastroenterology and Hepatology (Jan 2021)

Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in HumansSummary

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

Affiliations

Jakob Benedict Seidelin: Department 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.
Martin Iain Bahl: National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
Tine Rask Licht: National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
Benjamin E. Mead: Harvard-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, Massachusetts
Jeffrey M. Karp: Harvard-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, Massachusetts
Jens Vilstrup Johansen: Bioinformatics Core Facility, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark
Lene Buhl Riis: Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
Marina Ramírez Galera: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
Anders Woetmann: Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark
Jacob Tveiten Bjerrum: Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark

Journal volume & issue: Vol. 12, no. 4
pp. 1281 – 1296

Abstract

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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.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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