Ultra-sensitive metaproteomics redefines the dark metaproteome, uncovering host-microbiome interactions and drug targets in intestinal diseases

peer-reviewed · Nature Communications · 2025

peer-reviewed · Nature Communications · 2025. Feng Xian et al. The functional characterization of host-gut microbiome interactions remains limited by the sensitivity of…
Date 2025-07-18
Type peer-reviewed
Venue Nature Communications
Publisher Springer Science and Business Media LLC
Contribution downstream-application
DOI 10.1038/s41467-025-61977-7
Citations (OpenAlex) 31
Venue 2-year citedness 17.60

Preprint version: Ultra-sensitivity metaproteomics redefines the gut “dark metaproteome”, uncovering host-microbiome interactions and drug targets in intestinal inflammatory diseases (2024-04-22, bioRxiv)

Abstract

The functional characterization of host-gut microbiome interactions remains limited by the sensitivity of current metaproteomic approaches. Here, we present uMetaP, an ultra-sensitive workflow combining advanced LC-MS technologies with an FDR-validated de novo sequencing strategy, novoMP. uMetaP markedly expands functional coverage and improves the taxonomic detection limit of the gut dark metaproteome by 5000-fold, enabling precise detection and quantification of low-abundance microbial and host proteins. Applied to a mouse model of intestinal injury, uMetaP revealed host-microbiome functional networks underlying tissue damage, beyond genomic findings. Orthogonal validation using transcriptomic data from Crohn’s disease patients confirmed key host protein alterations. Furthermore, we introduce the concept of a druggable metaproteome, mapping functional targets within the host and microbiota. By redefining the sensitivity limits of metaproteomics, uMetaP provides a highly valuable framework for advancing microbiome research and developing therapeutic strategies for microbiome-related diseases.

Authors

  1. Feng Xian · University of Vienna
  2. Malena Brenek · University of Vienna
  3. Christoph Krisp
  4. Elisabeth Urbauer · Technical University of Munich, University of Vienna
  5. Ranjith Kumar Ravi Kumar · University of Vienna
  6. Doriane Aguanno · Technical University of Munich, University of Vienna
  7. Tharan Srikumar · Bruker Ltd., University of Vienna
  8. Qixin Liu · Rapid Novor Inc.
  9. Allison M. Barry · University of Vienna
  10. Bin Ma · Rapid Novor Inc., University of Waterloo, University of Western Ontario, Western University
  11. Jonathan R. Krieger · Bruker Ltd.
  12. Dirk Haller · Technical University of Munich
  13. Manuela Schmidt · University of Vienna
  14. David Gómez-Varela · University of Vienna

Methods and tools

  • uMetaP / novoMP: Ultra-sensitive gut metaproteomics workflow with an FDR-validated de novo strategy (novoMP) that expands the dark metaproteome and maps host-microbiome interactions in intestinal injury.

Data used

  • MaxQuant software for ion mobility enhanced shotgun proteomics (as deposited) · PXD014777

Cites (2)

Cited by (5)

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