Cited by 386Gut microbiota and healthInflammatory Bowel DiseaseMicroscopic Colitis

Multi-omics analyses of the ulcerative colitis gut microbiome link Bacteroides vulgatus proteases with disease severity

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Mills, Robert H., Dulai, Parambir S., Vázquez-Baeza, Yoshiki, Sauceda, Consuelo, Daniel, Noëmie, Gerner, Romana R., Batachari, Lakshmi E., Malfavon, Mario +15 more·2022·Nature Microbiology

Abstract

Ulcerative colitis (UC) is driven by disruptions in host-microbiota homoeostasis, but current treatments exclusively target host inflammatory pathways. To understand how host-microbiota interactions become disrupted in UC, we collected and analysed six faecal- or serum-based omic datasets (metaproteomic, metabolomic, metagenomic, metapeptidomic and amplicon sequencing profiles of faecal samples and proteomic profiles of serum samples) from 40 UC patients at a single inflammatory bowel disease centre, as well as various clinical, endoscopic and histologic measures of disease activity. A validation cohort of 210 samples (73 UC, 117 Crohn's disease, 20 healthy controls) was collected and analysed separately and independently. Data integration across both cohorts showed that a subset of the clinically active UC patients had an overabundance of proteases that originated from the bacterium Bacteroides vulgatus. To test whether B. vulgatus proteases contribute to UC disease activity, we first profiled B. vulgatus proteases found in patients and bacterial cultures. Use of a broad-spectrum protease inhibitor improved B. vulgatus-induced barrier dysfunction in vitro, and prevented colitis in B. vulgatus monocolonized, IL10-deficient mice. Furthermore, transplantation of faeces from UC patients with a high abundance of B. vulgatus proteases into germfree mice induced colitis dependent on protease activity. These results, stemming from a multi-omics approach, improve understanding of functional microbiota alterations that drive UC and provide a resource for identifying other pathways that could be inhibited as a strategy to treat this disease.

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  • Some proteases correlated with ulcerative colitis include serine and metalloproteases that largely function in the extracellular space and may exacerbate disease activity.

    “Some of the correlated proteases included serine and metalloproteases that largely function in the extracellular space and may exacerbate disease activity.”
  • A subset of clinically active ulcerative colitis patients had an overabundance of proteases derived from Bacteroides vulgatus.

    “A subset of the clinically active UC patients had an overabundance of proteases derived from the bacterium Bacteroides vulgatus.”

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Authors
Mills, R. H., Dulai, P. S., Vázquez-Baeza, Y., Sauceda, C., Daniel, N., Gerner, R. R., Batachari, L. E., Malfavon, M., Zhu, Q., Weldon, K., Humphrey, G., Carrillo-Terrazas, M., Goldasich, L. D., Bryant, M., Raffatellu, M., Quinn, R. A., Gewirtz, A. T., Chassaing, B., Chu, H., Sandborn, W. J., Dorrestein, P. C., Knight, R., & Gonzalez, D. J.
Affiliations
  • University of California San Diego (US)
  • Centre National de la Recherche Scientifique (FR)
  • Michigan State University (US)
  • Georgia State University (US)
Corresponding author
  • Knight, Rob
  • Gonzalez, David J.
Venue
Nature Microbiology
Published
2022-01-27
Volume
7
Issue
2
Pages
262-276
ISSN
2058-5276 (ISSN-L)
OpenAlex
W4213182271
Cited by
385
References
111
Citations by year
2026: 79 · 2025: 100 · 2024: 113 · 2023: 61 · 2022: 32
FWCI
25.05
Type
journal article
Language
en
Open access
Locations
  • Nature Microbiology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK007202, P30 DK120515)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Health Sciences › Medicine › Epidemiology › Microscopic Colitis
Keywords
ulcerative colitis, Bacteroides vulgatus, bacterial proteases, gut microbiota, host-microbiota interactions, disease severity, Crohn's disease, intestinal barrier dysfunction, protease inhibitors, IL-10-deficient mice, germ-free mice, fecal microbiota transplantation, multi-omics integration, metaproteomics, metabolomics, metagenomics, serum proteomics
MeSH terms
Gastrointestinal Microbiome, Adult, Animals, Bacterial Proteins, Bacteroides, Colitis, Ulcerative, Feces, Female, Humans, Longitudinal Studies, Male, Middle Aged, Peptide Hydrolases, Severity of Illness Index, Cohort Studies, Proteomics, Mice, Metagenome, Metagenomics

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