2. Academic Validation
  3. A Bacteroides fragilis protease activates host PAR2 to induce intestinal pain and inflammation

A Bacteroides fragilis protease activates host PAR2 to induce intestinal pain and inflammation

  • Cell Host Microbe. 2025 Oct 8;33(10):1686-1702.e11. doi: 10.1016/j.chom.2025.09.010.
Markus Lakemeyer 1,  Rocco Latorre 2,  Kristyna Blazkova 3,  Hannah M Wood 4,  Dane D Jensen 5,  Nayab Shakil 6,  Scott C Thomas 7,  Deepak Saxena 7,  Yatendra Mulpuri 7,  David Poolman 2,  Paz Duran 5,  Laura J Keller 3,  David E Reed 4,  Brian L Schmidt 5,  Néstor N Jiménez-Vargas 4,  Fangxi Xu 7,  Alan E Lomax 4,  Nigel W Bunnett 8,  Matthew Bogyo 9
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, 07743 Jena, Germany; Cluster of Excellence Balance of the Microverse, Friedrich Schiller University Jena, 07743 Jena, Germany; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
  • 2 Department of Molecular Pathobiology, NYU Dentistry, New York, NY 10010, USA; Pain Research Center, NYU Dentistry, New York, NY 10010, USA.
  • 3 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 4 Gastrointestinal Diseases Research Unit, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 5 Department of Molecular Pathobiology, NYU Dentistry, New York, NY 10010, USA; Pain Research Center, NYU Dentistry, New York, NY 10010, USA; Translational Research Center, NYU Dentistry, New York, NY 10010, USA; Department of Oral and Maxillofacial Surgery, NYU Dentistry, Bluestone Center for Clinical Research, New York, NY 10010, USA.
  • 6 Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, 07743 Jena, Germany.
  • 7 Department of Molecular Pathobiology, NYU Dentistry, New York, NY 10010, USA.
  • 8 Department of Molecular Pathobiology, NYU Dentistry, New York, NY 10010, USA; Pain Research Center, NYU Dentistry, New York, NY 10010, USA. Electronic address: [email protected].
  • 9 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 41015045 DOI: 10.1016/j.chom.2025.09.010
Abstract

Protease-activated Receptor 2 (PAR2) is a central regulator of intestinal barrier function, inflammation, and pain. Upregulated intestinal proteolysis and PAR2 signaling are implicated in inflammatory bowel diseases (IBDs) and irritable bowel syndrome (IBS), conditions often associated with gut microbiome alterations. To identify potential Bacterial regulators of PAR2 activity, we developed a functional assay for PAR2 processing to screen a library of diverse gut microbes. We identify multiple bacteria that secrete proteases capable of cleaving host PAR2. Using chemoproteomic profiling with a covalent irreversible inhibitor, we uncovered a previously uncharacterized Bacteroides fragilis serine protease 1 (Bfp1) and show that it cleaves and activates PAR2 in multicellular and murine models. PAR2 cleavage by Bfp1 disrupts the intestinal barrier, sensitizes nociceptors, and triggers colonic inflammation and abdominal pain. Collectively, our findings uncover Bfp1-mediated PAR2 processing as an axis of host-commensal interaction in the gut that has the potential to be targeted for therapeutic intervention in IBD or IBS.

Keywords

activity-based probe; gut microbiota; inflammation; inflammatory bowel disease; intestinal organoids; irritable bowel syndrome; pain signaling; protease; protease-activated receptors.

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