New Avenues in Gut Pain Management
Abdominal pain is a defining symptom of many digestive disorders, from inflammatory bowel disease (IBD) to irritable bowel syndrome (IBS). A pair of pioneering studies is pushing the boundaries of how researchers might treat gut pain by focusing on PAR2, a receptor that drives pain signaling in the gut. The work, published in Cell Host & Microbe and the Proceedings of the National Academy of Sciences (PNAS), highlights a bacterial enzyme that activates PAR2 and a novel drug-delivery approach using nanoparticles to reach the receptor inside cells.
The Bacterial Link: An Enzyme That Ignites Pain
Researchers have long suspected that the microbiome communicates with the host to influence inflammation and pain. In a comprehensive screen of human gut bacteria, scientists found that more than 50 bacterial strains secrete enzymes capable of cleaving and activating PAR2. The standout discovery centered on a previously unknown protease produced by the rod-shaped bacterium Bacteroides fragilis (B. fragilis), a common inhabitant of the human colon.
In collaboration with Nigel Bunnett and colleagues, the team showed that the B. fragilis protease cleaves PAR2, triggering pain signals and disrupting the intestinal barrier. When the enzyme was removed in a modified bacterial strain, pain signaling and inflammation diminished in cell culture and in mouse models of gut disease. The results establish a direct axis of communication between a gut microbe and host pain pathways, offering a potential target for therapies aimed at alleviating gut pain in disorders such as IBD and IBS.
“B. fragilis can act as a sleeping pathogen,” notes study lead Matthew Bogyo, emphasizing how microbial enzymes might modulate symptoms under specific conditions. The work suggests that proteases from gut bacteria can influence how the body perceives pain and mounts inflammatory responses, opening doors to microbiome-targeted strategies for symptom relief.
Blocking PAR2: Nanoparticles as Precision Delivery Vehicles
Separately, researchers explored how to blunt PAR2 signaling more effectively by taking advantage of a cellular behavior: when PAR2 is activated, it moves from the gut lining into endosomes inside cells where it can continue to drive pain and inflammation. This intracellular signaling window requires a drug delivery system capable of reaching the receptor within cellular compartments.
Enter nanoparticles — tiny carriers engineered to ferry drugs to specific cell types and even specific cellular compartments. The team encapsulated an experimental PAR2 blocker, AZ3451, in two nanoparticle formulations designed to reach the epithelial cells lining the intestine and the nerve cells that sense pain. The nanoparticles are designed to release the drug gradually over several days, a feature particularly suited to chronic gut disorders.
In cellular models and in mice with inflammatory bowel disease, nanoparticle-delivered AZ3451 outperformed the drug alone by more effectively inhibiting PAR2 signaling and reducing pain-like behaviors. The findings demonstrate a precision-targeted approach: drugs can be directed not just to particular cells but to the right compartment within those cells, potentially minimizing systemic exposure and side effects.
<h2Implications for Future Therapies
Taken together, the studies illuminate two complementary strategies for tackling gut pain. First, inhibiting the specific bacterial protease that activates PAR2 could disrupt a microbial trigger for pain and inflammation. Second, deploying nanoparticles to deliver PAR2 blockers directly to the receptor’s intracellular signaling sites could provide durable, targeted relief from pain and barrier dysfunction seen in IBD and IBS.
While these findings are early, they hold promise for developing targeted, disease-modifying therapies that address the root causes and signaling pathways of gut pain rather than simply masking symptoms with conventional analgesics. Ongoing research will determine how best to translate these approaches into safe, effective treatments for people living with chronic digestive disorders.
About the Research Teams
The Cell Host & Microbe study was led by Bogyo and Bunnett, with collaborators across NYU College of Dentistry, Stanford, Queen’s University, and other institutions. The PNAS study involved similar teams and additional partners, spanning Columbia University, Wake Forest, and more, with support from the NIH and Takeda Pharmaceuticals.
