Ultra-sensitive metaproteomics redefines the dark metaproteome, uncovering host-microbiome interactions and drug targets in intestinal diseases
peer-reviewed · Nature Communications · 2025
| 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 |
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.
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.