Researchers on the University of Toronto have found compounds naturally occurring within the gut that may be used to alleviate inflammation and other symptoms of digestive problems. This may be achieved by binding the compounds to a very important but poorly understood nuclear receptor.
The gut microbiome is home to bacteria that produce compounds from our digestive residues as byproducts of food intake. The compounds can bind to nuclear receptors that help transcribe DNA to provide proteins and noncoding RNA segments.
By identifying which microbial byproducts may be used to control receptors, researchers hope to unlock their potential to treat disease.
We performed an unbiased screening of small molecules across your complete human gut microbiome. We found that these molecules act similarly to artificial compounds currently used to control the constitutive androstane receptor, also often known as CAR. This makes them suitable candidates for drug development.”
Jiabao Liu, lead creator of the study and a research associate on the Donnelly Center for Cellular and Biomolecular Research at U of T
The study was recently published within the
CAR plays a critical role in regulating the breakdown, uptake and removal of xenobiotics within the liver, including drugs. It is usually involved in intestinal inflammation.
“Certainly one of the challenges in studying CAR is that there isn’t a useful compound that binds to each the human and mouse versions of the receptor – the latter is vital for research and disease modeling before testing in humans,” said Henry Krause , principal investigator of the study and professor of molecular genetics on the Donnelly Center and the Temerty Faculty of Medicine. “Previous efforts have focused on developing molecules with strong binding and activation capabilities. This has led to synthetic regulators that overactivate the receptor, which may result in unintended results. The natural compounds we discovered don’t cause this problem.”
Two of the compounds present in the metabolite screening were diindolylmethane (DIM) and diindolylethane (DIE). While DIM has previously been identified using human intestinal samples, DIE has not. This study is the primary time that DIE has been detected within the human microbiome.
The 2 compounds regulated CAR in each human and mouse liver. They were also found to match the effectiveness of a synthetic human CAR regulator called CITCO.
A promising finding for future research on CAR regulation was that not one of the compounds caused unwanted side effects reminiscent of liver enlargement in mice. Which means DIM and DIE may be used to check CAR function and regulation in mice, with findings transferrable to humans.
“This receptor plays a job in diabetes, Fatty liver disease and small intestinal ulcerative colitis,” Liu said. “We could potentially treat all of those problems with the 2 natural compounds we found that exist already within the human gut.”
This research was supported by the Agence Nationale de la Recherche, the American Cancer Society, the Canadian Institutes of Health Research, the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and the Latest Frontiers in Research Fund.
Source:
Magazine reference:
Liu, J., (2024). Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands. . doi.org/10.1038/s41467-024-46559-3.
