Researchers at the University of Louisville have identified a way that a naturally produced compound from gut microbes may help protect the intestine and potentially guide new treatment approaches for inflammatory bowel disease (IBD).
IBD includes Crohn's disease and ulcerative colitis and affects millions of people around the world. These conditions involve persistent inflammation and damage to the intestinal lining. Normally, the gut barrier allows nutrients to pass into the body while helping prevent harmful bacteria from escaping the intestines. In people with IBD, this protective barrier can break down, contributing to inflammation, pain, and long-term complications.
A Gut Compound Linked to Intestinal Protection
The research was led by Venkatakrishna Rao Jala, associate professor in the Department of Microbiology and Immunology and UofL's Brown Cancer Center. His team investigated urolithin A, or UroA, a naturally occurring microbial metabolite produced by gut bacteria after the digestion of foods including pomegranates, walnuts and berries.
The researchers found that UroA activates a protective pathway in the intestine that may help maintain gut health.
Their study, published in the journal Nature Communications, centers on the aryl hydrocarbon receptor, or AHR. This protein acts as a sensor that responds to signals from the environment, diet, and gut microbes.
Scientists have known for years that AHR can contribute to harmful effects when it is activated by certain environmental toxins. At the same time, earlier research suggested that beneficial dietary compounds can activate the same receptor in ways that support intestinal health. Until now, researchers had not fully understood why the outcomes could be so different.
The new findings suggest that the effect depends on both the location and the strength of AHR activation.
Turning an Inflammatory System Into a Protective One
The University of Louisville team found that UroA selectively activates AHR in intestinal epithelial cells, which are the specialized cells that form and protect the gut lining.
When AHR is activated in these cells, it triggers a cellular defense system called the NLRP6 inflammasome. Inflammasomes are often associated with damaging inflammatory responses, but the researchers found that this system can also play a protective role under the right conditions.
When UroA activated the NLRP6 inflammasome in intestinal epithelial cells, it prompted the release of appropriate levels of molecules involved in normal intestinal function. Those molecules helped repair the gut lining, reinforce the intestinal barrier, increase the production of protective mucus and strengthen antimicrobial defenses instead of driving additional inflammation.
The researchers say this is the first study to show how a natural product made by microbes can work with the body's own response systems to regulate complex molecular and cellular processes during intestinal injury. That interaction may help preserve gut health and limit tissue damage.
"The findings show that not all inflammatory pathways are harmful," said Sweta Ghosh, previously a postdoctoral researcher in Jala's laboratory and lead investigator on the study. "Under the right conditions and in the right cells, these pathways can play an essential role in maintaining gut health and supporting tissue repair."
A More Targeted Approach to IBD Treatment
The team tested the mechanism using several experimental approaches, including cell studies, organoid models, and intestinal tissue samples from patients with IBD. In the human tissue samples, UroA activated the same protective pathway observed in the other experiments.
The findings raise the possibility that future treatments for IBD and other gastrointestinal diseases could target specific protective pathways in selected cell types rather than suppressing the immune system broadly.
"This study helps us better understand how natural compounds produced through interactions between diet, gut microbes and the body can influence disease processes," Jala said. "By identifying this specific protective pathway, we may be able to develop more targeted therapeutic approaches that restore intestinal balance instead of broadly suppressing immune responses."
Jala previously led research that identified the beneficial effects of UroA in the gut . The new work builds on those findings by explaining more precisely how UroA interacts with the immune system to support intestinal health.
