Natural microbial compound helps protect the gut from chronic inflammation

University of Louisville researchers have discovered how a naturally occurring microbial compound may help protect the gut and support future treatment strategies for inflammatory bowel disease (IBD).

IBD, which includes conditions such as Crohn's disease and ulcerative colitis, affects millions of people worldwide. The disease is characterized by chronic inflammation and damage to the intestinal lining. A healthy gut barrier helps keep harmful bacteria from leaking out of the intestines, while allowing nutrients to enter the body. In people with IBD, that barrier becomes 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 UofL's Brown Cancer Center, discovered how a naturally occurring microbial metabolite called urolithin A, or UroA, which is generated by gut bacteria after digestion of foods such as pomegranates, walnuts and berries, activates a protective pathway in the intestine that may help preserve gut health.

The study, published in the journal Nature Communications, focuses on the aryl hydrocarbon receptor, or AHR, a protein that acts as a sensor for environmental, dietary and microbial signals. Researchers have long known that AHR can contribute to harmful effects when activated by certain environmental toxins, but previous studies also suggested that activation by beneficial dietary compounds may support gut health. Scientists have not fully understood why this is the case until now.

These new findings suggest that the outcome depends on where and how strongly AHR is activated.

Researchers at UofL found that UroA selectively activates AHR in intestinal epithelial cells, the specialized cells that line and protect the gut. That 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 they can also serve as a protective role.

When activated by UroA in intestinal epithelial cells, the NLRP6 inflammasome led to the release of the right amount of molecules that are associated with maintaining normal intestinal function and that help repair the gut lining, strengthen the intestinal barrier, increase protective mucus production and enhance antimicrobial defenses, rather than promoting inflammation.

This study shows, for the first time, how a natural microbial product works together with the body's response to control complex molecular and cellular processes during intestinal injury, helping preserve gut health and reduce 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."

The team confirmed the mechanism using multiple experimental systems, including cell and organoid studies, as well as intestinal tissue samples from patients with IBD, demonstrating that UroA activated the same protective pathway in human tissue. Their findings indicate that rather than broadly suppressing the immune system, it may be possible to develop new therapies for IBD and other gastrointestinal diseases that target specific protective pathways in certain cell types.

This study helps us better understand how natural compounds produced through interactions between diet, gut microbes and the body can influence disease processes. 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."

Venkatakrishna Rao Jala, Associate Professor, Department of Microbiology and Immunology and UofL's Brown Cancer Center

Jala previously led research that discovered the beneficial effects of UroA in the gut. This study furthers that work by revealing how UroA interacts with the immune system to improve intestinal health.