期刊
GASTROENTEROLOGY
卷 160, 期 5, 页码 1532-1545出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2020.12.004
关键词
Ulcerative Colitis; Proteolytic Activity; Microbiome
资金
- Crohn's and Colitis Canada
- Canadian Institutes of Health Research (CIHR) [CMF108031]
- Helmsley Charitable Trust
- CIHR Fellowship/CAG/Ferring Pharmaceuticals Inc
- Department of Medicine, Mount Sinai Hospital, Toronto
- McMaster University, Hamilton
- CAG-CIHR-IMAGINE fellowship
- CIHR [1715-000-001]
- CIHR Fellowship/Canadian Association of Gastroenterology (CAG) postdoctoral fellowship award
- CIHR Foundation grant [143253]
- Canada Research Chair in Inflammatory Bowel Diseases
- Canada Foundation for Innovation
- University of Toronto
- Government of Ontario, Ontario Research Fund-Research Excellence
- Farncombe Institute postdoctoral fellowship from McMaster University, Hamilton
Increased fecal proteolytic activity was found before the clinical diagnosis of UC, which may serve as a noninvasive biomarker of inflammation associated with changes in gut microbiota. The study suggests potential therapeutic targets for at-risk populations based on antiprotease treatments.
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.
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