Abdominal pain is one of the most common and frustrating symptoms of digestive disorders like inflammatory bowel disease and irritable bowel syndrome. Now, researchers say they’ve discovered how gut bacteria may help cause that pain and a new way to stop it.
In two companion studies from New York University and Stanford University, scientists found that a common gut bacterium produces an enzyme that activates a pain-signaling receptor in the intestines. They also tested tiny drug-delivery particles, called nanoparticles, that could block the same receptor and ease pain in lab animals.
“In focusing on this receptor, we’ve mapped out a pathway between a bacterial enzyme and pain and determined how to block PAR2 using nanoparticles — both of which may help us to treat pain related to digestive disorders in the future,” said Nigel Bunnett, professor and chair of molecular pathobiology at NYU College of Dentistry and a faculty member in the NYU Pain Research Center.
The receptor, called PAR2, helps regulate pain and inflammation in the gut. When activated by certain enzymes, it sends pain signals through nerves in the intestinal lining.
In one study published in Cell Host & Microbe, researchers identified a new enzyme made by a bacterium called Bacteroides fragilis, which is normally harmless but can cause problems when its balance is disrupted.
“B. fragilis [is] a sleeping pathogen of sorts. It’s an organism that can hang out in the gut without doing any damage, but under certain conditions, it can cause problems. One of the ways it may be doing that is through regulating signals that it sends to the host,” said Matthew Bogyo, professor of pathology, microbiology and immunology at Stanford University School of Medicine.
When the researchers removed the enzyme, pain signaling stopped.
“The results were black and white: if the protease was present, there was pain signaling, and if the protease was not present, there was no pain signaling,” Bogyo said. “Our study identifies a new axis of communication between gut bacteria and the host that has implications for how symptoms may be triggered in inflammatory bowel disease.”
A second study, published in Proceedings of the National Academy of Sciences (PNAS), focused on how to block that pain pathway. Researchers encapsulated a pain-blocking drug inside nanoparticles designed to deliver it directly to the cells that drive gut pain.
“That sustained release is exactly what you want for a chronic disease,” Bunnett said.
In mice, this approach reduced pain-related behaviors far more effectively than the drug on its own.
“Using nanoparticles for drug delivery demonstrates a precision-targeted approach,” Bunnett said. “These nanoparticles are precisely directed not only to a particular cell, but a particular compartment within the cell and a particular receptor within the compartment.”
The findings could help scientists develop safer, more targeted treatments for digestive pain that avoid the side effects of opioids, NSAIDs and steroids.
The studies were supported by the National Institutes of Health, the U.S. Department of Defense, Takeda Pharmaceuticals, the Deutsche Forschungsgemeinschaft and partner institutions including Stanford University, Columbia University, Queen’s University and Wake Forest University.