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

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.