Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis.
Adolescent
Adult
Animals
Bacteria
/ drug effects
Bacterial Proteins
/ genetics
Biomarkers
/ metabolism
Case-Control Studies
Child
Colitis, Ulcerative
/ diagnosis
Disease Models, Animal
Fecal Microbiota Transplantation
Feces
/ microbiology
Female
Gastrointestinal Microbiome
/ drug effects
Germ-Free Life
Humans
Male
Metagenome
Metagenomics
Mice, Inbred C57BL
Peptide Hydrolases
/ genetics
Predictive Value of Tests
Prospective Studies
Protease Inhibitors
/ therapeutic use
Proteolysis
Reproducibility of Results
Ribotyping
Young Adult
Microbiome
Proteolytic Activity
Ulcerative Colitis
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
10
04
2020
revised:
02
12
2020
accepted:
02
12
2020
pubmed:
15
12
2020
medline:
8
9
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown. We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs). Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice. We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
Sections du résumé
BACKGROUND & AIMS
Altered gut microbiota composition and function have been associated with inflammatory bowel diseases, including ulcerative colitis (UC), but the causality and mechanisms remain unknown.
METHODS
We applied 16S ribosomal RNA gene sequencing, shotgun metagenomic sequencing, in vitro functional assays, and gnotobiotic colonizations to define the microbial composition and function in fecal samples obtained from a cohort of healthy individuals at risk for inflammatory bowel diseases (pre-UC) who later developed UC (post-UC) and matched healthy control individuals (HCs).
RESULTS
Microbiota composition of post-UC samples was different from HC and pre-UC samples; however, functional analysis showed increased fecal proteolytic and elastase activity before UC onset. Metagenomics identified more than 22,000 gene families that were significantly different between HC, pre-UC, and post-UC samples. Of these, 237 related to proteases and peptidases, suggesting a bacterial component to the pre-UC proteolytic signature. Elastase activity inversely correlated with the relative abundance of Adlercreutzia and other potentially beneficial taxa and directly correlated with known proteolytic taxa, such as Bacteroides vulgatus. High elastase activity was confirmed in Bacteroides isolates from fecal samples. The bacterial contribution and functional significance of the proteolytic signature were investigated in germ-free adult mice and in dams colonized with HC, pre-UC, or post-UC microbiota. Mice colonized with or born from pre-UC-colonized dams developed higher fecal proteolytic activity and an inflammatory immune tone compared with HC-colonized mice.
CONCLUSIONS
We have identified increased fecal proteolytic activity that precedes the clinical diagnosis of UC and associates with gut microbiota changes. This proteolytic signature may constitute a noninvasive biomarker of inflammation to monitor at-risk populations that can be targeted therapeutically with antiproteases.
Identifiants
pubmed: 33310084
pii: S0016-5085(20)35533-5
doi: 10.1053/j.gastro.2020.12.004
pii:
doi:
Substances chimiques
Bacterial Proteins
0
Biomarkers
0
Protease Inhibitors
0
Peptide Hydrolases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Validation Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
1532-1545Subventions
Organisme : CIHR
ID : 143253
Pays : Canada
Organisme : CIHR
ID : 1715-000-001
Pays : Canada
Investigateurs
Paul Beck
(P)
Charles Bernstein
(C)
Kenneth Croitoru
(K)
Leo Dieleman
(L)
Brian Feagan
(B)
Anne Griffiths
(A)
David Guttman
(D)
Kevan Jacobson
(K)
Gilaad Kaplan
(G)
Denis O Krause
(DO)
Karen Madsen
(K)
John Marshall
(J)
Paul Moayyedi
(P)
Mark Ropeleski
(M)
Ernest Seidman
(E)
Mark Silverberg
(M)
Scott Snapper
(S)
Andy Stadnyk
(A)
Hillary Steinhart
(H)
Michael Surette
(M)
Dan Turner
(D)
Thomas Walters
(T)
Bruce Vallance
(B)
Guy Aumais
(G)
Alain Bitton
(A)
Maria Cino
(M)
Jeff Critch
(J)
Lee Denson
(L)
Colette Deslandres
(C)
Wael El-Matary
(W)
Hans Herfarth
(H)
Peter Higgins
(P)
Hien Huynh
(H)
Jeff Hyams
(J)
David Mack
(D)
Jerry McGrath
(J)
Anthony Otley
(A)
Remo Panancionne
(R)
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.