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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月18日

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  • Feng Xian,
  • Malena Brenek,
  • Christoph Krisp,
  • Elisabeth Urbauer,
  • Ranjith Kumar Ravi Kumar,
  • Doriane Aguanno,
  • Tharan Srikumar,
  • Qixin Liu,
  • Allison M. Barry,
  • Bin Ma,
  • Jonathan Krieger,
  • Dirk Haller,
  • Manuela Schmidt,
  • David Gómez-Varela

摘要

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.