Diets containing berries and pomegranates are believed to have potentially manifold benefits to human health, and scientists in India and the U.S. have now demonstrated in mice how one pomegranate-derived metabolite that is produced by microorganisms residing naturally in the gut can help to protect against and reduce the severity of inflammatory bowel disease (IBD). The studies, by researchers at the Institute of Stem Cell Biology and Regenerative Medicine (inStem) in Bangalore, and the University of Louisville, showed that the pomegranate polyphenol-derived metabolite Urolithin (UroA), and a synthetic UroA analog UAS03, both effectively reduced inflammation and restored gut barrier integrity in the mouse models.
Reporting their findings in Nature Communications, the team suggests that as well as having therapeutic uses in the control of inflammatory bowel diseases, UroA and its stable synthetic analog UAS03 may also have clinical applications in other disorders involving gut barrier dysfunction and inflammation. “Restoring the gut barrier and reducing the inflammation using a small-molecule will provide a better therapeutic output in the treatment of IBDs,” said Praveen Kumar Vemula, PhD, at inStem, who is one of the senior authors on the team’s published paper. “A synthetic analog overcomes the stability limitation that a microbial metabolite poses, thus enhancing the efficacy.” The researchers reported their findings in a paper titled, “Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.”
Crohn’s disease and ulcerative colitis are IBDs that result in intestinal inflammation and changes to gut microbiota. The key role of gut microbiota and their metabolites in biological processes are well recognized, so any alterations to the gut microbiome could be linked with adverse outomes in diseases such as IBD, as well as in cancer, neurological disorders, diabetes, and obesity, the authors wrote.
The gut microbiome is closely associated with the gut epithelium, a single layer of cells lining the gut that acts as a barrier between the gut lumen and the environment outside the gut. Integrity of this gut barrier depends on tight junctions between the epithelial cells, which are maintained by a number of proteins including claudins (Cldn), Zona occlude-1 (ZO1), and occluding (Ocln). “Microbiota in our gut has evolved to generate beneficial microbial metabolites in the proximity of the gut barrier,” notes co-senior author Venkaakrishna Rao Jala, PhD, an assistant professor at the University of Louisville, “However, the exact role of these metabolites have not been identified and the mechanism in which they exert their function is elusive.”
Research has suggested that tight junction proteins are downregulated in IBD, which could impact on barrier integrity. “Previously, it has been reported that levels of tight junction proteins are significantly down-regulated under IBD conditions leading to increased gut permeability to microbial ligands and noxious metabolites resulting in systemic inflammatory responses,” the researchers commented. “Despite the availability of large metagenomics data, the functional dynamics of microbiota and their metabolites in IBDs are unknown.”