Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis.

Abstract

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.

• Authors: Heather J Galipeau, Alberto Caminero, Williams Turpin, Miriam Bermudez-Brito, Alba Santiago, Josie Libertucci, Marco Constante, Juan Antonio Raygoza Garay, Gaston Rueda, Sarah Armstrong, Alex Clarizio, Michelle I Smith, Michael G Surette, Premysl Bercik, CCC Genetics, Environmental, Microbial Project Research Consortium, Kenneth Croitoru, Elena F Verdu
• Journal: Gastroenterology (Gastroenterology) Vol. 160 Issue 5 Pg. 1532-1545 (04 2021) ISSN: 1528-0012 [Electronic] United States
• PMID: 33310084 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Bacterial Proteins
• Biomarkers
• Protease Inhibitors
• Peptide Hydrolases

Topics

• Adolescent
• Adult
• Animals
• Bacteria (drug effects, enzymology, genetics)
• Bacterial Proteins (genetics, metabolism)
• Biomarkers (metabolism)
• Case-Control Studies
• Child
• Colitis, Ulcerative (diagnosis, drug therapy, microbiology)
• 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, metabolism)
• Predictive Value of Tests
• Prospective Studies
• Protease Inhibitors (therapeutic use)
• Proteolysis
• Reproducibility of Results
• Ribotyping
• Young Adult
• Mice