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

Robert H. Mills, Parambir S. Dulai, Yoshiki Vázquez-Baeza, Consuelo Sauceda, Noëmie Daniel, Romana R. Gerner, Lakshmi E. Batachari, Mario Malfavon, Qiyun Zhu, Kelly Weldon, Greg Humphrey, Marvic Carrillo-Terrazas, Lindsay De Right Goldasich, MacKenzie K. Bryant, Manuela Raffatellu, Robert A. Quinn, Andrew T. Gewirtz, Benoit Chassaing, Hiutung Chu, William J. SandbornPieter C. Dorrestein, Rob Knight, David J. Gonzalez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)262-276
Number of pages15
JournalNature Microbiology
Volume7
Issue number2
DOIs
StatePublished - Feb 2022
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

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