Ultra-sensitive metaproteomics redefines the dark metaproteome, uncovering host-microbiome interactions and drug targets in intestinal diseases
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. u...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61977-7 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |