Acute Experimental Barrier Injury Triggers Ulcerative Colitis-Specific Innate Hyperresponsiveness and Ulcerative Colitis-Type Microbiome Changes in Humans

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

doi:10.1016/j.jcmgh.2021.06.002

Acute Experimental Barrier Injury Triggers Ulcerative Colitis-Specific Innate Hyperresponsiveness and Ulcerative Colitis-Type Microbiome Changes in Humans

Cell Mol Gastroenterol Hepatol. 2021;12(4):1281-1296. doi: 10.1016/j.jcmgh.2021.06.002. Epub 2021 Jun 9.

Affiliations

¹ Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: jakob.benedict.seidelin@regionh.dk.
² National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark.
³ 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.
⁴ 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.
⁵ Bioinformatics Core Facility, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark; LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
⁸ Department of Gastroenterology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.

Abstract

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.

Keywords: Acute Mucosal Injury; Flare Initiation; ILC3; Innate Intestinal Response; Innate Lymphoid Cells Type 3; Microbiome; Ulcerative Colitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Biomarkers
Case-Control Studies
Colitis, Ulcerative / diagnostic imaging
Colitis, Ulcerative / etiology*
Colitis, Ulcerative / metabolism
Colitis, Ulcerative / pathology*
Cytokines / metabolism
Disease Progression
Disease Susceptibility
Dysbiosis
Endoscopy
Female
Gastrointestinal Microbiome*
Host Microbial Interactions
Humans
Immunity, Innate*
Immunohistochemistry
Inflammation Mediators / metabolism
Intestinal Mucosa / immunology*
Intestinal Mucosa / metabolism
Intestinal Mucosa / microbiology*
Intestinal Mucosa / pathology
Lymphocyte Subsets / immunology
Lymphocyte Subsets / metabolism
Male
Middle Aged

Substances

Biomarkers
Cytokines
Inflammation Mediators