TY - JOUR

T1 - Acute Experimental Barrier Injury Triggers Ulcerative Colitis–Specific Innate Hyperresponsiveness and Ulcerative Colitis–Type Microbiome Changes in Humans

AU - Seidelin, Jakob Benedict

AU - Bahl, Martin Iain

AU - Licht, Tine Rask

AU - Mead, Benjamin E

AU - Karp, Jeffrey M

AU - Johansen, Jens Vilstrup

AU - Riis, Lene Buhl

AU - Galera, Marina Ramírez

AU - Woetmann, Anders

AU - Bjerrum, Jacob Tveiten

N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2021

Y1 - 2021

N2 - BACKGROUND AND AIMS: The trigger hypothesis opens the possibility of anti-flare-initiation therapies by stating that ulcerative colitis (UC) flares originates 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. Post-injury responses were assessed repeatedly by high resolution imaging and sampling to perform Geboes scoring, RNA sequencing, and injury niche microbiota 16S rRNA gene sequencing.RESULTS: UC patients had more severe endoscopic post-injury inflammation than controls (p<0.01), an elevated modified Geboes score (p<0.05), a rapid induction of innate response gene sets (p<0.05) and anti-microbial peptides (p<0.01), and engagement of neutrophils (p<0.01). Innate lymphoid cells type 3 (ILC3s) markers were increased pre-injury (p<0.01) and ILC3 activating cytokines were highly induced post-injury resulting in an increase in ILC3 type cytokine IL-17A. Across groups, the post-injury mucosal microbiome had higher bacterial load (p<0.0001) and lower α-diversity (p<0.05).CONCLUSIONS: UC patients in remission respond to mucosal breaks by an innate hyper-response engaging resident regulatory ILC3s and a subsequent adaptive activation. The post-injury IBD-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 anti-trigger directed therapies.

AB - BACKGROUND AND AIMS: The trigger hypothesis opens the possibility of anti-flare-initiation therapies by stating that ulcerative colitis (UC) flares originates 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. Post-injury responses were assessed repeatedly by high resolution imaging and sampling to perform Geboes scoring, RNA sequencing, and injury niche microbiota 16S rRNA gene sequencing.RESULTS: UC patients had more severe endoscopic post-injury inflammation than controls (p<0.01), an elevated modified Geboes score (p<0.05), a rapid induction of innate response gene sets (p<0.05) and anti-microbial peptides (p<0.01), and engagement of neutrophils (p<0.01). Innate lymphoid cells type 3 (ILC3s) markers were increased pre-injury (p<0.01) and ILC3 activating cytokines were highly induced post-injury resulting in an increase in ILC3 type cytokine IL-17A. Across groups, the post-injury mucosal microbiome had higher bacterial load (p<0.0001) and lower α-diversity (p<0.05).CONCLUSIONS: UC patients in remission respond to mucosal breaks by an innate hyper-response engaging resident regulatory ILC3s and a subsequent adaptive activation. The post-injury IBD-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 anti-trigger directed therapies.

U2 - 10.1016/j.jcmgh.2021.06.002

DO - 10.1016/j.jcmgh.2021.06.002

M3 - Journal article

C2 - 34118489

VL - 12

SP - 1281

EP - 1296

JO - Cellular and Molecular Gastroenterology and Hepatology

JF - Cellular and Molecular Gastroenterology and Hepatology

SN - 2352-345X

IS - 4

ER -