University of Louisville researchers have discovered how naturally occurring microbial compounds may help protect the gut and support future treatment strategies for inflammatory bowel disease (IBD).
IBD, which includes diseases such as Crohn’s disease and ulcerative colitis, affects millions of people worldwide. This disease is characterized by chronic inflammation and damage to the intestinal lining. A healthy intestinal barrier prevents harmful bacteria from escaping the intestines while allowing nutrients to enter the body. In people with IBD, that barrier is weakened, leading to inflammation, pain, and long-term complications.
A research team led by Venkatakrishna Rao Jala, associate professor in the Department of Microbiology and Immunology and the University Brown Cancer Center, has discovered how a natural microbial metabolite called urolithin A (UroA), produced by gut bacteria after the digestion of foods such as pomegranates, walnuts, and berries, activates protective pathways in the gut and may help maintain gut health.
Research published in journals nature communications, We focus on aryl hydrocarbon receptors (AHRs), proteins that act as sensors for environmental, dietary, and microbial signals. Researchers have long known that AHR can cause harmful effects when activated by certain environmental toxins, but previous research also suggests that activation by beneficial dietary compounds may support gut health. Scientists so far do not fully understand why this is the case.
These new findings suggest that outcomes depend on where and how strongly AHR is activated.
UofL researchers discovered that UroA selectively activates AHR in intestinal epithelial cells, specialized cells that line and protect the intestines. Targeted activation of AHR in intestinal epithelial cells triggers a cellular defense system known as the NLRP6 inflammasome. Although inflammasomes are commonly associated with harmful inflammatory responses, this study found that they may also play a protective role.
When activated by UroA in intestinal epithelial cells, the NLRP6 inflammasome triggered the release of appropriate amounts of molecules that are associated with maintaining normal intestinal function and help repair the intestinal lining, strengthen the intestinal barrier, increase production of protective mucus, and strengthen antimicrobial defenses rather than promoting inflammation.
This study shows for the first time how natural microbial products work together with the body’s responses to control complex molecular and cellular processes during intestinal injury, helping to maintain intestinal health and reduce tissue damage.
“The results of this study show that not all inflammatory pathways are harmful,” said Sweta Ghosh, previously a postdoctoral fellow in Jala’s lab and principal investigator on the study. “Under the right conditions and the right cells, these pathways can play an important role in maintaining gut health and supporting tissue repair.”
The researchers confirmed the mechanism using multiple experimental systems, including cell and organoid studies, as well as intestinal tissue samples from IBD patients, and demonstrated that UroA activates the same protective pathways in human tissues. Their findings indicate that it may be possible to develop new treatments for IBD and other gastrointestinal diseases that target specific protective pathways in specific cell types, rather than broadly suppressing the immune system.
This research will help us better understand how natural compounds produced through interactions between diet, gut bacteria, and the body influence disease processes. Identification of this specific defense pathway may allow the development of more targeted therapeutic approaches that restore intestinal balance rather than broadly suppressing the immune response. ”
Venkatakrishna Rao Jala, Associate Professor, Department of Microbiology and Immunology and University Brown Cancer Center
Jala previously led a study that discovered the beneficial effects of UroA in the intestine. This study furthers that work by revealing how UroA interacts with the immune system to improve gut health.
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Reference magazines:
Ghosh, S. Others. (2026). Urolithin A activates the aryl hydrocarbon receptor NLRP6-mediated pathway in intestinal epithelial cells, modulating mucosal immunity and strengthening intestinal barrier integrity. Nature Communications. DOI: 10.1038/s41467-026-73760-3. https://www.nature.com/articles/s41467-026-73760-3
