Researchers at the University of Louisville have identified a way that a compound produced naturally from gut microbes may help protect the gut and potentially guide new treatment approaches for inflammatory bowel disease (IBD).
IBD includes Crohn’s disease and ulcerative colitis and affects millions of people worldwide. These conditions involve persistent inflammation and damage to the intestinal lining. Normally, the intestinal barrier allows nutrients to pass into the body while helping to 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.
An intestinal compound linked to intestinal protection
The research was led by Venkatakrishna Rao Jala, associate professor in the Department of Microbiology and Immunology and the Brown Cancer Center at UofL. His team investigated urolithin A, or UroA, a naturally occurring microbial metabolite produced by gut bacteria after the digestion of foods such as pomegranates, nuts, and berries.
The researchers found that UroA activates a protective pathway in the gut that may help maintain gut health.
His study, published in the journal nature communications, focuses 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 activated by certain environmental toxins. At the same time, previous research suggested that beneficial dietary compounds can activate the same receptor in ways that support gut health. Until now, researchers had not fully understood why the results could be so different.
The new findings suggest that the effect depends on both the location and strength of AHR activation.
Convert an inflammatory system into a protective one
The University of Louisville team discovered that UroA selectively activates AHR in intestinal epithelial cells, which are the specialized cells that form and protect the intestinal lining.
When AHR is activated in these cells, it triggers a cellular defense system called the NLRP6 inflammasome. Inflammasomes are often associated with harmful inflammatory responses, but 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 caused the release of appropriate levels of molecules involved in normal intestinal function. Those molecules helped repair the intestinal lining, strengthen the intestinal barrier, increase the production of protective mucus, and strengthen antimicrobial defenses instead of causing 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 can help preserve intestinal 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 lab and principal investigator of 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 treating IBD
The team tested the mechanism using several experimental approaches, including cellular studies, organoid models, and intestinal tissue samples from IBD patients. In the human tissue samples, UroA activated the same protective pathway seen in the other experiments.
The findings raise the possibility that future treatments for IBD and other gastrointestinal diseases may target specific protective pathways in select cell types rather than suppressing the immune system in general.
“This study helps us better understand how natural compounds produced through interactions between diet, gut microbes and the body can influence pathological processes,” Jala said. “By identifying this specific protective pathway, we will be able to develop more targeted therapeutic approaches that restore intestinal balance rather than broadly suppressing immune responses.”
Jala previously led an investigation that identified the beneficial effects of UroA in the intestine. The new work builds on those findings by more precisely explaining how UroA interacts with the immune system to support gut health.