腸内痛に対するナノ粒子治療と新酵素の発見(Microbiome and Nanoparticle Discoveries Hold Promise for Treating Gut Pain)

2025-10-07 ニューヨーク大学(NYU)

Fluorescent nanoparticles (purple) carrying a drug to treat pain accumulate in the cells of a mouse colon. Credit: Bunnett Lab

<関連情報>

• https://www.nyu.edu/about/news-publications/news/2025/october/gut-pain-microbiome-nanoparticles.html
• https://www.pnas.org/doi/10.1073/pnas.2412687122
• https://www.cell.com/cell-host-microbe/abstract/S1931-3128(25)00376-2

エンドソーム内のプロテアーゼ活性化受容体2を標的としたナノ医薬品は持続的な鎮痛効果をもたらす Nanomedicines targeting protease-activated receptor 2 in endosomes provide sustained analgesia

Shavonne L. Teng, Rocco Latorre, Divya Bhansali, +16 , and Nigel W. Bunnett
Proceedings of the National Academy of Sciences  Published:October 7, 2025
DOI:https://doi.org/10.1073/pnas.2412687122

Significance

There is a pressing need to develop nonopioid treatments for pain. In the diseased colon, proteases that activate PAR₂ on nociceptors and colonocytes evoke pain. Since PAR₂ endosomal signaling underlies pain, PAR₂ in endosomes is a relevant therapeutic target. We leveraged the predisposition of NPs to accumulate in endosomes to deliver the PAR₂ antagonist, AZ3451, to intracellular sites of pain signaling. NPs that delivered AZ3451 to endosomes effectively reversed PAR₂ endosomal signals, whereas unencapsulated AZ3451 was minimally effective. When administered into the colonic lumen of mice, NP-encapsulated AZ3451, but not unencapsulated AZ3451, reversed pain and normalized aberrant behavior in preclinical models of inflammatory bowel disease. Nanomedicines that block intracellular signaling of PAR₂, and possibly other GPCRs, effectively relieve visceral pain.

バクテロイデス・フラギリスのプロテアーゼは宿主のPAR2を活性化し、腸の痛みと炎症を引き起こす A Bacteroides fragilis protease activates host PAR2 to induce intestinal pain and inflammation

Markus Lakemeyer ∙ Rocco Latorre ∙ Kristyna Blazkova ∙ … ∙ Alan E. Lomax ∙ Nigel W. Bunnett ∙ Matthew Bogyo
Cell Host & Microbe  Published:September 26, 2025
DOI:https://doi.org/10.1016/j.chom.2025.09.010

Highlights

• Intestinal bacteria secrete proteases that affect host PAR₂ signaling
• Chemoproteomics identifies Bfp1, a serine protease released by Bacteroides fragilis
• Bfp1 activates PAR₂ to disrupt epithelial integrity, induce nociception, and inflammation
• The Bfp1-PAR₂ axis links the microbiota to pain and inflammation in the gut

Summary

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.