Identification of a secreted protease from Bacteroides fragilis that induces intestinal pain and inflammation by cleavage of PAR2
Lakemeyer, M.; Latorre, R.; Blazkova, K.; Jensen, D.; Wood, H. M.; Shakil, N.; Thomas, S. C.; Saxena, D.; Malpuri, Y.; Poolman, D.; Duran de Haro, P.; Keller, L. J.; Reed, D. E.; Schmidt, B. L.; Lomax, A. E.; Bunnett, N. W.; Bogyo, M.
Show 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). To identify potential bacterial regulators of PAR2 activity, we developed a functional assay for PAR2 processing and used it to screen conditioned media from a library of diverse gut commensal microbes. We found that multiple bacteria secrete proteases that cleave host PAR2. Using chemoproteomic profiling with a covalent irreversible inhibitor, we identified a previously uncharacterized Bacteroides fragilis serine protease Bfp1, and showed 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 a new axis of host-commensal-interaction in the gut that has the potential to be targeted for therapeutic intervention in IBD or IBS.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1+ macrophages regulates the intestinal cytokine milieu 94%
- A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity 94%
- MrgprA3-expressing pruriceptors drive pruritogen-induced alloknesis through mechanosensitive Piezo2 channel 94%
Similar papers in this journal
- Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling 94%
- Blood-borne immune cells carry low biomass DNA remnants of microbes in patients with colorectal cancer or inflammatory bowel disease 94%
- Human gut commensal Alistipes timonensis modulates the host lipidome and delivers anti-inflammatory outer membrane vesicles to suppress colitis in an Il10-deficient mouse model 93%
Similar papers in this journal
Similar papers in this journal
- Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33. 96%
- Intelectin-2 is a broad-spectrum antimicrobial lectin 95%
- Biosynthetic Enzyme-guided Disease Correlation Connects Gut Microbial Metabolites Sulfonolipids to Inflammatory Bowel Disease Involving TLR4 Signaling 95%